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Copper(I) complexes with phosphine derived from sparfloxacin. Part II: a first insight into the cytotoxic action mode
Abstract
In this paper we present a first insight into the cytotoxic action mode of copper(i) iodide or copper(i) thiocyanate complexes with a phosphine derivative of sparfloxacin (a 3(rd) generation fluoroquinolone antibiotic agent) and 2,9-dimethyl-1,10-phenanthroline or 2,2'-biquinoline as auxiliary ligands. The in vitro cytotoxic activity of the new complexes was tested against two cancer cell lines (CT26 - mouse colon carcinoma and A549 - human lung adenocarcinoma). An ICP-MS study revealed a marked time-dependent intracellular copper accumulation of the tested compounds. In addition, confocal microscopy imaging showed accumulation of the complexes inside whole cells and their emission of blue light. The complexes generate reactive oxygen species in the cancer cells, which was examined by using two different fluorescent probes. Moreover, (i) DNA intercalation studied by luminescence spectroscopy, circular dichroism and molecular docking, and (ii) plasmid DNA damage also demonstrate their significant cytotoxicity. All these observed biological effects contribute to the induction of apoptosis, observed at a great predominance.
... Several well-known DNA binding dyes with well-established binding modes were used: ethidium bromide (EB; intercalation), 4 ,6-diamidino-2-phenylindole (DAPI; binding to a minor groove), and methyl green (MG; binding to a major groove). The compounds that can bind to DNA more strongly than the above-mentioned binding dyes (EB, DAPI, or MG) reduce the DNA-binding dye emission due to the replacement of dye [40,41]. The emission spectra of the CT DNA-binding dye complex were mea- Figures S1-S4). ...
... The strength of the compounds' interactions with DNA is similar for all complexes discussed ( Figure 2; Supplementary Materials, Figure S1, Table 1). Notably, the trend in its ability to displace intercalator EB from CT DNA was different than in the case previously studied by our group regarding ruthenium(II) and copper(I) complexes based on the same phosphine ligands [11,13,[41][42][43][44]. This trend suggests that the type of metal ions (Cu(I), Ru(II), Ir(III)) have a significant influence on the type and intensity of intercalations with DNA. ...
... Considering the results presented above, we can expect that the resulting complexes will not exhibit high genotoxicity, as opposed to previously reports of similarly mixed copper(I) or ruthenium(II) complexes bearing phosphines derived from fluoroquinolones [11,[41][42][43][44] that exert high systemic toxicity related to strong intercalations with DNA. ...
A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) radicals generation. Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, circular dichroism, and molecular docking studies. DNA binding experiments established that the complexes interact with DNA by moderate intercalation and predominance of minor groove binding without the capability to cause a double-strand cleavage. The molecular docking study confirmed two binding modes: minor groove binding and threading intercalation with the fluoroquinolone part of the molecule involved in pi stacking interactions and the Ir(III)-containing region positioned within the major or minor groove. Fluorescence spectroscopic data (HSA and apo-Tf titration), together with molecular docking, provided evidence that Ir(III) complexes can bind to the proteins in order to be transferred. All the compounds considered herein were found to bind to the tryptophan residues of HSA within site I (subdomain II A). Furthermore, Ir(III) complexes were found to dock within the apo-Tf binding site, including nearby tyrosine residues.
... Komarnicka et al. employed a phosphine ligand decorated with a sparfloxacin moiety (an antibiotic agent) in the synthesis of complexes with the general formula [CuXP (NN)]. Evaluation of the in vitro anticancer activity of these complexes against mouse colon carcinoma (CT26) and human lung adenocarcinoma (A549) revealed that the complexes generate reactive oxygen species in the cancer cells, inducing apoptosis and leading to cell death [17]. Despite the negligible cytotoxic effects of varying the diimine ligand in such complexes, diimines have important roles in the complex-DNA interactions. ...
... Komarnicka et al. employed a phosphine ligand decorated with a sparfloxacin moiety (an antibiotic agent) in the synthesis of complexes with the general formula [CuXP(NN)]. Evaluation of the in vitro anticancer activity of these complexes against mouse colon carcinoma (CT26) and human lung adenocarcinoma (A549) revealed that the complexes generate reactive oxygen species in the cancer cells, inducing apoptosis and leading to cell death [17]. Despite the negligible cytotoxic effects of varying the diimine ligand in such complexes, diimines have important roles in the complex-DNA interactions. ...
... Despite the negligible cytotoxic effects of varying the diimine ligand in such complexes, diimines have important roles in the complex-DNA interactions. For example, biquinoline-containing complexes are proposed to bind via intercalation, while groove-binding was suggested for the complexes with a 2,9-dimethylphenanthroline ligand [17,18]. Complexes [CuBr(1,10-phenanthroline)(PPh3)] and [Cu(1,10-phenanthroline)(P(4-methoxyphenyl)3)2] + have also been tested against several cell lines and exhibited cytotoxic effects comparable to cisplatin against breast and prostate (MFC-7 and P3) cancer cell lines [19]. ...
A set of copper(I) coordination compounds with general formula [CuBr(PPh3)(dppz-R)] (dppz-R = dipyrido[3,2-a:2’,3’-c]phenazine (Cu-1), 11-nitrodipyrido[3,2-a:2’,3’-c]phenazine (Cu-2), 11-cyanodipyrido[3,2-a:2’,3’-c]phenazine (Cu-3), dipyrido[3,2-a:2’,3’-c]phenazine-11-phenone (Cu-4), 11,12-dimethyldipyrido[3,2-a:2’,3’-c]phenazine (Cu-5)) have been prepared and characterized by elemental analysis, ¹H-NMR and ³¹P-NMR spectroscopies as well as mass spectrometry. The structure of Cu-1 was confirmed by X-ray crystallography. The effect of incorporating different functional groups on the dppz ligand on the binding into CT-DNA was evaluated by absorption spectroscopy, fluorescence quenching of EtBr-DNA adducts, and viscosity measurements. The functional groups affected the binding modes and hence the strength of binding affinities, as suggested by the changes in the relative viscosity. The differences in the quenching constants (Ksv) obtained from the fluorescence quenching assay highlight the importance of the functional groups in altering the binding sites on the DNA. The molecular docking data support the DNA-binding studies, with the sites and mode of interactions against B-DNA changing with the different functional groups. Evaluation of the anticancer activities of the five copper compounds against two different cancer cell lines (M-14 and MCF-7) indicated the importance of the functional groups on the dppz ligand on the anticancer activities. Among the five copper complexes, the cyano-containing complex (Cu-3) has the best anticancer activities.
... 18,21 The research on organometallic Ir(III) compounds described herein is a continuation of our project in which phosphines bearing fluoroquinolones: sparfloxacin (PSf ), 24-28 ciprofloxacin (PCp), 27,29,30 lomefloxacin (PLm), 31 and norfloxacin (PNr) 28 were coordinated to various metal centers: Cu(I), Cu(II), Ru(II), Ru(III), Ir(III). In addition to persistent research on anticancer activity of the resulting complexes, [24][25][26][27][28][29][30][31] we have also proved that the introduction of the Ph 2 PCH 2moiety to fluoroquinolones enhances their antibacterial properties. This moiety may generate additional interactions, so it could have an influence on biological activity, bioavailability and toxicity of the original drug. ...
... This moiety may generate additional interactions, so it could have an influence on biological activity, bioavailability and toxicity of the original drug. [24][25][26][27][28][29][30][31] Thus, motivation for the current research was the significant activity of previously studied complexes and the reasonability of possible future structure-activity analysis. Novel synthesized complexes with fluoroquinolone-based phosphines, most of all copper(I) and ruthenium(II) ones, exhibited considerable anti-proliferative activity and were more active than the parent antibiotics, causing apoptotic cancer cell death via the caspase-dependent mitochondrial pathway. ...
... Novel synthesized complexes with fluoroquinolone-based phosphines, most of all copper(I) and ruthenium(II) ones, exhibited considerable anti-proliferative activity and were more active than the parent antibiotics, causing apoptotic cancer cell death via the caspase-dependent mitochondrial pathway. [24][25][26][27] On the other hand, as reported in the recent literature the excellent properties as both phosphorescent probes and anticancer agents make Ir(III) complexes perfect potential candidates for the future development of theranostics. 12,19,[32][33][34] Hence, four half-sandwich complexes (IrPCp, IrPSf, IrPNr, IrPLm) with different phosphino-fluoroquinolone ligands were synthesized and their physicochemical properties were determined using elemental analysis, 1D NMR, UV-Vis spectroscopy and mass spectrometry (ESI-MS). ...
Novel half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroloquinolones (IrPCp, IrPSf, IrPLm, IrPNr) were being studied as possible anticancer chemotherapeutics with potency higher than that of the other well-known metal-based agents i.e., Pt(II) drugs. All compounds were characterized by elemental analysis, selected spectroscopic methods (i.e., absorption and fluorescence spectroscopies, NMR), ESI-MS spectometry, X-ray diffractometry, and electrochemical techniques. Studied complexes exhibited promising cytotoxicity in vitro with IC50 values significantly lower than the reference drug – cisplatin. The insight into the mode of action revealed the uniform distribution of the Ir(III) complexes in both nucleus and cytoplasm (Pearson’s co-localization coefficient of 0.63). Precise cytometric analysis provided clear evidence for predominance of apoptosis in the induced cell death. The activation of caspase-3/7 along with the decrease of mitochondrial membrane potential also confirmed the apoptotic cell death. The investigated Ir(III) complexes may induce the changes in cell cycle leading to G2/M phase arrest. ROS generation as plausible pathway responsible for the cytotoxicity was confirmed by determination of redox potentials enabling the efficient ROS production. Furthermore, Pluronic P-123 micelles loaded with selected Ir(III) complexes were proposed to overcome low solubility and to minimize serious systemic side effects by administareting the complex in a controlled manner. The resulting nanoformulations (IrPCp_M, IrPNr_M) facilitated efficient drug accumulation inside human lung adenocarcinoma and human prostate carcinoma (A549 and DU-145 cell lines), demonstrated by confocal microscopy and ICP-MS analysis. In vitro cytotoxicity assays were also carried out within multicellular tumor spheroids and efficient anticancer action on these 3D assemblies was demonstrated.
... Our team has been working with this class of ligands and their Cu(I), Pt(II) and Ru(II) complexes and, in many cases, the properties of the derivatized molecules and their complexes are more interesting than the parent ones. For example, we worked with trisaminomethylphosphanes derived from morpholine and thiomorpholine (see for example refs 34-37 ) and a variety on N4-substituted piperazines 34,35,[38][39][40][41] , as well as with monoaminomethyldiphenylphosphanes 40-42 , including a derivative of a model dipeptide 43 and the derivatives of selected fluoroquinolones: ciprofloxacin, norfloxacin 44-46 , lomefloxacin 47 and sparfloxacin [48][49][50] . Some of the compounds listed above showed interesting antimicrobial and/ or anti-tumour activity. ...
... These results strongly suggest that the Ke derivatives may present different or additional modes of action underlining their antifungal activity, or override mechanism of drug resistance operative against Ke, since not only they are active against yeast cells that are resistant to azole compounds, and shown to be Ke resistant in this study, but also the behavior in relation both to the parent compound and between the two strains can change. For KeP, the wt cells are less sensitive (MIC 50 9.023 μM) than for Ke, while erg6Δ cells are very sensitive, presenting a MIC 50 value (0.654 μM) which is even smaller than the one found for the parent compound against the wt. KeSeP and KeOP are active against both strains with similar (Table 2). ...
... This result is not unexpected, since it has been previously reported that, when grown in YPD medium, as in this study, BY4741 cells are more sensitive to Hygromycin B than W303, and they also differ in alkali-metal cation tolerance and plasma membrane potential, and in other important physiological parameters, as consequence of their different genome 59,60 . Notwithstanding, it is noteworthy that for both wt strains; the order of MIC 50 values for the different compounds tested is almost the same, the only difference being between KeSeP and KeP, which are the second and third most active against BY4741 and in reverse order for W303 cells. ...
Four new derivatives of ketoconazole (Ke) were synthesized: diphenylphosphane (Kep), and phosphane chalcogenides: oxide (Keop), sulphide (KeSp) and selenide (KeSep). these compounds proved to be promising antifungal compounds towards Saccharomyces cerevisiae and Candida albicans, especially in synergy with fluconazole. Simulations of docking to the cytochrome P450 14α-demethylase (azoles’ primary molecular target) proved that the new Ke derivatives are capable of inhibiting this enzyme by binding to the active site. cytotoxicity towards hAcSs (human adipose-derived stromal cells) of the individual compounds was studied and the ic50 values were higher than the Mic50 for C. albicans and S. cerevisiae. KeP and KeOP increased the level of the p21 gene transcript but did not change the level of p53 gene transcript, a major regulator of apoptosis, and decreased the mitochondrial membrane potential. taken together, the results advocate that the new ketoconazole derivatives have a similar mechanism of action and block the lanosterol 14α-demethylase and thus inhibit the production of ergosterol in C. albicans membranes.
... Also, a different response of normal and tumor cells to copper ions can be a platform for development of copper complexes endowed with antineoplastic characteristic [8][9][10]. Copper(I) complexes constitute a group of compounds that is still not exploited enough, but over the last several years, we can observe a significant interest increase of their anticancer [11][12][13][14][15][16][17], antibacterial [18], antiviral [19,20], antifungal [21], and inflammatory [14] activity. Furthermore, the phosphine ligands forms a strong bond with copper(I) ion which prevents oxidation of the phosphine ligand and copper(I) to copper(II) [12], what was also proven in our previous studies [13][14][15][16][17][22][23][24]. ...
... Copper(I) complexes constitute a group of compounds that is still not exploited enough, but over the last several years, we can observe a significant interest increase of their anticancer [11][12][13][14][15][16][17], antibacterial [18], antiviral [19,20], antifungal [21], and inflammatory [14] activity. Furthermore, the phosphine ligands forms a strong bond with copper(I) ion which prevents oxidation of the phosphine ligand and copper(I) to copper(II) [12], what was also proven in our previous studies [13][14][15][16][17][22][23][24]. Additionally, phosphine ligands can be easily functionalized, which is remarkable. ...
... This article is continuation of our previous projects describing copper(I) complexes bearing phosphine ligands derived from fluoroquinolone antibiotics [14][15][16][17]50,51,58,65]. We demonstrated high cytotoxic activity towards view cancer lines of inorganic derivatives of fluoroquinolones. ...
The main disadvantage of conventional anticancer chemotherapy is the inability to deliver the correct amount of drug directly to cancer. Those molecular delivering systems are very important to destroy cancer cells selectively. Herein we report synthesis of phosphine-peptide conjugate (Ph2PCH2-Sar-Gly-OH, PSG) derived from SarGly (sarcosine-glycine), which can be easily exchanged to other peptide carriers, its oxide (OPh2PCH2-Sar-Gly-OH, OPSG) and the first copper(I) complex ([CuI(dmp)(P(Ph)2CH2-Sar-Gly-OH)], 1-PSG, where dmp stands for 2,9-dimethyl-1,10-phenanthroline). The compounds were characterized by elemental analysis, NMR (1D, 2D), UV-Vis spectroscopy and DFT (Density Functional Theory) methods. PSG and 1-PSG proved to be stable in biological medium in the presence of atmospheric oxygen for several days. The cytotoxicity of the compounds and cisplatin was tested against cancer cell lines: mouse colon carcinoma (CT26; 1-PSGIC50 = 3.12 ± 0.1), human lung adenocarcinoma (A549; 1-PSGIC50 = 2.01 ± 0.2) and human breast adenocarcinoma (MCF7; 1-PSGIC50 = 0.98 ± 0.2) as well as against primary line of human pulmonary fibroblasts (MRC-5; 1-PSGIC50 = 78.56 ± 1.1). Therapeutic index for 1-PSG (MCF7) equals 80. Intracellular accumulation of 1-PSG complex increased with time and was much higher (96%) inside MCF7 cancer cells than in normal MRC5 cells (20%). Attachment of SarGly to cytotoxic copper(I) complex via phosphine motif improved selectivity of copper(I) complex 1-PSG into the cancer cells. Precise mechanistic study revealed that the 1-PSG complex causes apoptotic cells MCF7 death with simultaneous decrease of mitochondrial membrane potential and increase of caspase-9 and -3 activities. Additionally, 1-PSG generated high level of reactive oxygen species that was the reason for oxidative damages to the sugar-phosphate backbone of plasmid DNA.
... Cu(I) complexes have gained great attention in recent decades due to their ability to catalyze the Fenton-like reactions leading to the ROS generation, since the latter allows a cell treating through an oxidation stress or the so-called chemodynamic therapy (CDT) [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. In most cases, the ROS generation via the Fenton-like reactions is triggered by hydrogen peroxide or the gentle temperature increase without light irradiation [1][2][3]. ...
... The IC 50 values calculated from the cell viability data (Fig. S16) are collected in Table 2. The comparative analysis of the IC 50 values ( Table 2) indicates that the cytotoxicity of complexes 1 and 2 is comparable with the literature data on molecular Cu(I) complexes [11][12][13][14]27]. [8, 10, 11, 13-15, 42, 43]. ...
The work presents core–shell nanoparticles (NPs) built from the novel Cu(I) complexes with cyclic P2N2-ligands (1,5-diaza-3,7-diphosphacyclooctanes) that can visualize their entry into cancer and normal cells using a luminescent signal and treat cells by self-enhancing generation of reactive oxygen species (ROS). Variation of P- and N-substituents in the series of P2N2-ligands allows structure optimization of the Cu(I) complexes for the formation of the luminescent NPs with high chemical stability. The non-covalent modification of the NPs with triblock copolymer F-127 provides their high colloidal stability, followed by efficient cell internalization of the NPs visualized by their blue (⁓450 nm) luminescence. The cytotoxic effects of the NPs toward the normal and some of cancer cells are significantly lower than those of the corresponding molecular complexes, which correlates with the chemical stability of the NPs in the solutions. The ability of the NPs to self-enhanced and H2O2-induced ROS generation is demonstrated in solutions and intracellular space by means of the standard electron spin resonance (ESR) and fluorescence techniques correspondingly. The anticancer specificity of the NPs toward HuTu 80 cancer cells and the apoptotic cell death pathway correlate with the intracellular level of ROS, which agrees well with the self-enhancing ROS generation of the NPs. The enhanced level of ROS revealed in HuTu 80 cells incubated with the NPs can be associated with the significant level of their mitochondrial localization.
Supplementary Information
The online version contains supplementary material available at 10.1186/s11671-023-03912-7.
... μM) via reactive oxygen species (ROS) generation, plasmid DNA damage and the induction of cell apoptosis. The order of anticancer activity was found to be-C 67 >C 66 >C 68 >C 69 (Komarnicka et al., 2016b). ...
... Copper(I) complexes of phosphine derivative of sparfloxacin and 2,2'-biquinoline or 2,9-dimethyl-1,10-phenanthroline(Komarnicka et al., 2016b) Fig. 14. Copper(I) complexes of phosphine derivative of lomefloxacin and 2,2'-biquinoline or 2,9-dimethyl-1,10-phenanthroline(Komarnicka et al., 2016a) ...
The copper(I) complexes of N,N-diimine, N,O- and/or N, S-bidentate systems perform significant dose-dependent anticancer activity toward various cell lines viz. MCF-7, LNCap, PSN-1, A431, BxPC3, H157, A2780, HeLa, MDA-MB231, MGC-803 etc. The copper(I) complexes can cross the cellular plasmalemma that results in the accumulation of copper ion in the cancer cells, exhibit significant anticancer effect and overcome the multidrug resistance because these can slightly induce the DNA cleavage as a result of limited generation of reactive oxygen species (ROS). Copper(I) complexes exhibit significantly higher broad-spectrum antiproliferation and cell apoptosis via mitochondrial pathway than that of their corresponding Cu(II), Co(II), Pd(II), and Ni(II) complexes. The copper(I) complexes inhibit the cancer cells not only via ROS generation but also via DNA interactions possibly by attacking the sugar-phosphate backbone of DNA due to their oxidative and partial dissociation behavior. Copper(II/I) complexes are also able to cleave DNA by hydrolytic pathway and induce caspase-dependent-mitochondrial-mediated cell apoptosis by ROS production or blocking the progression of cell cycles. In many cases, the modification in organic moiety and the placement of electronegative substituent near the metallic center of complexes have been found to enhance their anticancer potency in a significant manner. Thus copper(I) complexes may be used as the better anticancer drugs with multiple modes of action compared to the copper(II) complexes due to having oxidative behavior and generation of empty site on copper(I) ion during partial dissociation.
... Such a low activity, however, is not unexpected because 4MP and 4MOP clearly lack a well-defined pharmacophore. Importantly, their low biological activity is typical for the simple aminomethylphosphines [25,26,31,32], especially when compared with the activity of phosphines derived from antifungal ketoconazole [14], or antibacterial fluoroquinolones [17][18][19]21,22,33]. It shows that phosphines, despite their infamy of a very toxic class of ligands, can be safely used as building blocks in the design of biologically active metal complexes. ...
The studies on metal complexes as potential antifungals are of growing interest because they may be the answer to increasingly effective defense mechanisms. Herein we present two new copper(I) iodide or thiocyanide complexes with 2,9-dimethyl-1,10-phenanthroline (dmp) and diphenylphosphine derivative of 1-(4-methoxyphenyl)piperazine (4MP): [CuI(dmp)4MP] (1-4MP) and [CuNCS(dmp)4MP] (2-4MP) - their synthesis, as well as structural and spectroscopic characteristics. Interestingly, while 4MP and its oxide derivative (4MOP) show a very low or no activity against all tested Candida albicans strains (MIC50 ≥ 200 μM against CAF2-1 - laboratory control strain, DSY1050 - mutant without transporters Cdr1, Cdr2, Mdr1; isogenic for CAF2-1, and fluconazole resistant clinical isolates), for 1-4MP and 2-4MP MIC50 values were 0.4 μM, independently on the complex and strain tested. Determination of the viability of NHDF-Ad (Normal Adult Human Dermal Fibroblasts) cell line treated with 1-4MP and 2-4MP showed that for both complexes there was only a 20% reduction in the concentration range ¼ to 2 × MIC50 and the 70% at 4 × MIC50. Subsequently, the MLCT based luminescence of the complexes in aqueous media allowed to record the confocal micrographs of 1-4MP in the cells. The results show that it is situated most likely in the vacuoles (C. albicans) or lysosomes (NHDF-Ad).
... In accordance with that finding, there was a relatively weak apoptotic effect of dinuclear complexes of copper(II) with S-isoalkyl derivatives of thiosalicylic acid on CT26 cells (Figure 9). Good apoptotic activity of various Cu(II) on human colorectal cancer cell lines has been previously described [64][65][66][67]. Similar to the results of this study, Cu(I) thiocyanate complexes with phosphine derivatives of sparfloxacin exert a mild to moderate apoptotic effect on the CT26 cells [68]. ...
The numerous side effects of platinum based chemotherapy has led to the design of new therapeutics with platinum replaced by another transition metal. Here, we investigated the interactions of previously reported copper(II) complexes containing S-isoalkyl derivatives, the salicylic acid with guanosine-5′-monophosphate and calf thymus DNA (CT-DNA) and their antitumor effects, in a colon carcinoma model. All three copper(II) complexes exhibited an affinity for binding to CT-DNA, but there was no indication of intercalation or the displacement of ethidium bromide. Molecular docking studies revealed a significant affinity of the complexes for binding to the minor groove of B-form DNA, which coincided with DNA elongation, and a higher affinity for binding to Z-form DNA, supporting the hypothesis that the complex binding to CT-DNA induces a local transition from B-form to Z-form DNA. These complexes show a moderate, but selective cytotoxic effect toward colon cancer cells in vitro. Binuclear complex of copper(II) with S-isoamyl derivative of thiosalicylic acid showed the highest cytotoxic effect, arrested tumor cells in the G2/M phase of the cell cycle, and significantly reduced the expression of inflammatory molecules pro-IL-1β, TNF-α, ICAM-1, and VCAM-1 in the tissue of primary heterotopic murine colon cancer, which was accompanied by a significantly reduced tumor growth and metastases in the lung and liver.
... µM and 9.80 µM, respectively). Considerable interest in pyrazole-containing copper(I) complexes have been stimulated by promising pharmacological applications, fluorescence sensing, and catalytic properties [105,106]. For instance, the copper(I) complexes 111 with pyrazole-linked triphenylphosphine moieties have been described as photostable and cost-effective fluorescent probes for simultaneously tracking mitochondria and nucleolus via live cell imaging techniques, in a single run and within a timeframe of just 30 min [107]. ...
Pyrazole and its derivatives are considered a privileged N-heterocycle with immense therapeutic potential. Over the last few decades, the pot, atom, and step economy (PASE) synthesis of pyrazole derivatives by multicomponent reactions (MCRs) has gained increasing popularity in pharmaceutical and medicinal chemistry. The present review summarizes the recent developments of multicomponent reactions for the synthesis of biologically active molecules containing the pyrazole moiety. Particularly, it covers the articles published from 2015 to date related to antibacterial, anticancer, antifungal, antioxidant, α-glucosidase and α-amylase inhibitory, anti-inflammatory, antimycobacterial, antimalarial, and miscellaneous activities of pyrazole derivatives obtained exclusively via an MCR. The reported analytical and activity data, plausible synthetic mechanisms, and molecular docking simulations are organized in concise tables, schemes, and figures to facilitate comparison and underscore the key points of this review. We hope that this review will be helpful in the quest for developing more biologically active molecules and marketed drugs containing the pyrazole moiety.
... Modification of quinolones' structure can strengthen their properties (97)(98)(99)(100)(101)(102)(103)(104)(105). However, in such cases introduction of a new drug on the market is difficult due to expensive and longterm procedures including all stages of clinical trial conduction. ...
Quinolones, broad-spectrum antibiotics, are frequently prescribed by urologists for many urological disorders. The mechanism of their bactericidal activity is based on the inhibition of topoisomerase II or IV complex with DNA, which consequently leads to cell death. It has been observed that these antibiotics also act against the analogous enzymes present in eukaryotic cells. Due to their higher accumulation in urine and prostate tissue than in serum, these drugs seem to be ideal candidates for application in genitourinary cancer treatment. In this study, an extensive literature review has been performed to collect information about concentrations achievable in urine and prostate tissue together with information about anticancer properties of 15 quinolones. Special attention was paid to the application of cytotoxic properties of quinolones for bladder and prostate cancer cell lines. Data available in the literature showed promising properties of quinolones, especially in the case of urinary bladder cancer treatment. In the case of prostate cancer, due to low concentrations of quinolones achievable in prostate tissue, combination therapy with other chemotherapeutics or another method of drug administration is necessary.
... Considering that many anticancer drugs exert their antitumor effects by apoptosis activation 53 , the features related to this death pathway were investigated. Apoptosis is a highly privileged cell death mode in discovering novel antitumor agents, mainly because of its self-regulated and well-programmed strategy to maintain homeostasis 36,54,55 . Flow cytometry was applied to quantitatively determine the type of cell death induced by the 1-MPSG compound. ...
[CuI(2,9-dimethyl-1,10-phenanthroline)P(p-OCH 3 -Ph) 2 CH 2 SarcosineGlycine] (1-MPSG), highly stable in physiological media phosphino copper(I) complex—is proposed herein as a viable alternative to anticancer platinum-based drugs. It is noteworthy that, 1-MPSG significantly and selectively reduced cell viability in a 3D spheroidal model of human lung adenocarcinoma (A549), in comparison with non-cancerous HaCaT cells. Confocal microscopy and an ICP-MS analysis showed that 1-MPSG effectively accumulates inside A549 cells with colocalization in mitochondria and nuclei. A precise cytometric analysis revealed a predominance of apoptosis over the other types of cell death. In the case of HaCaT cells, the overall cytotoxicity was significantly lower, indicating the selective activity of 1-MPSG towards cancer cells. Apoptosis also manifested itself in a decrease in mitochondrial membrane potential along with the activation of caspases-3/9. Moreover, the caspase inhibitor (Z-VAD-FMK) pretreatment led to decreased level of apoptosis (more pronouncedly in A549 cells than in non-cancerous HaCaT cells) and further validated the caspases dependence in 1-MPSG-induced apoptosis. Furthermore, the 1-MPSG complex presumably induces the changes in the cell cycle leading to G2/M phase arrest in a dose-dependent manner. It was also observed that the 1-MPSG mediated intracellular ROS alterations in A549 and HaCaT cells. These results, proved by fluorescence spectroscopy, and flow cytometry, suggest that investigated Cu(I) compound may trigger apoptosis also through ROS generation.
... Copper(II) compounds, on the other hand, have been intensively studied; however, the corresponding ones of Cu(I) have been scarcely tested as antimicrobial, antiviral, antifungal and anticancer drugs due to their significant lower stability in water media [6]. Moreover, copper(I) complexes are expected to be less toxic to normal cells in contrast to tumour ones, due to the physiological properties of copper as endogenous metal [7]. Antimony(III) compounds exhibit antiproliferative properties and have been tested in both normal and cancerous cells with promising results [8]. ...
Three known organo-antimony(III)–copper(I), mixed-metal small bioactive molecules (SBAMs) of formula [Cu(tpSb)3Cl] (1), [Cu2(tpSb)4Br2] (2) and [Cu2(tpSb)4I2] (3) (tpSb = triphenylstibine) were used for the clarification of their antiproliferative activity against human breast cancer cells: MCF-7 (hormone-dependent cells) and MDA-MB-231 (hormone-independent cells). The in vitro toxicity of 1–3 was studied against normal human foetal lung fibroblast cells (MRC-5). The genotoxicity of 1–3 was determined by the presence of micronucleus. The type of the cell death caused by 1–3 was determined using cell cycle arrest. The molecular mechanism of action of 1–3 was defined by their binding affinity towards CT-DNA (calf thymus DNA) using UV spectroscopy and viscosity measurements. Docking studies depict the interactions between 1–3 and DNA. Computations were also employed in order to rationalize the activity of these compounds. This is based on the contribution of metal aromaticity in the case of compounds 2 and 3 where the short Cu···Cu distance (2.7724(6) (2) and 2.7251(11) (3) Ǻ, respectively) suggests d¹⁰–d¹⁰ interaction between metal centres.
Graphic abstract
The known small bioactive molecules of formula [Cu(tpSb)3Cl] (1), [Cu2(tpSb)4Br2] (2) and [Cu2(tpSb)4I2] (3) (tpSb = triphenylstibine) were used for the clarification of their antiproliferative activity against human breast cancer cells: MCF-7 (hormone-dependent (HD) cells) and MDA-MB-231 (hormone-independent (HI) cells).Open image in new window
... The highly proliferative cells, such as tumor cells and trypanosomatid parasites, show many metabolic similarities that could lead to a correlation between antiparasitic and antitumor activities. In fact, several antitumoral drugs also show significant antiparasitic activity and vice-versa [34][35][36]. Although the antitumoral properties of these complexes have been preliminarily tested searching for a correlation of bioactivities, a more detailed examination of their potential in cancer therapy to afford a grounded conclusion about their eventual value is still lacking [37]. ...
The steady rise in the cancer burden and grim statistics set a vital need for new therapeutic solutions. Given their high efficiency, metallodrugs are quite appealing in cancer chemotherapy. This work examined the anticancer activity of an anti-trypanosomal ruthenium-based compound bearing the 5-nitrofuryl pharmacophore, [RuII(dmso)2(5-nitro-2-furaldehyde semicarbazone)] (abbreviated as RuNTF; dmso is the dimethyl sulfoxide ligand). The cytotoxicity of RuNTF was evaluated in vitro against ovarian adenocarcinoma, hormone-dependent breast adenocarcinoma, prostate carcinoma (grade IV) and V79 lung fibroblasts human cells. The activity of RuNTF was similar to the benchmark metallodrug cisplatin for the breast line and inactive against the prostate line and lung fibroblasts. Given the known role of serum protein binding in drug bioavailability and the distribution via blood plasma, this study assessed the interaction of RuNTF with human serum albumin (HSA) by circular dichroism (CD) and fluorescence spectroscopy. The fluorescence emission quenching from the HSA-Trp214 residue and the lifetime data upon RuNTF binding evidenced the formation of a 1:1 {RuNTF-albumin} adduct with log Ksv = (4.58 ± 0.01) and log KB = (4.55 ± 0.01). This is supported by CD data with an induced CD broad band observed at ~450 nm even after short incubation times. Importantly, the binding to either HSA or human apo-transferrin is beneficial to the cytotoxicity of the complex towards human cancer cells by enhancing the cytotoxic activity of RuNTF.
... Since a number of copper(I) complexes emit red uorescence at room temperature, it is possible for their effective evaluation of the cellular uptake. 62 Interestingly, the cellular uptake plays an important role in the treatment of micromolecular drug. 63 In this respect, the cellular uptake was studied aer EAC cells were explored to 12.5 mM of copper(I) complexes (1-6) for 24 h, the cells were stained with DAPI staining and observed under uorescence microscope (Fig. 13 & S11 †). ...
A series of six new bis(thiosemicarbazone)copper(I) complexes of the type [Cu(L1–6)2Cl] (1–6) have been synthesized and characterized. The molecular structure of the ligand L⁴ was determined by the single crystal XRD method. All the complexes adopted trigonal planar (Y-shaped) geometry. All the complexes strongly bind with CT-DNA via intercalative mode, which was further supported by molecular docking studies. Further, the complexes were effectively bind with BSA as observed by UV-Vis and fluorescence spectra. All the complexes effectively cleave pBR322 DNA through hydrolytic pathway as evidenced from T4 ligase experiments. All the complexes interact with the anticancer receptor focal adhesion kinase (FAK) via electrostatic, van der Waals, hydrogen bonding, σ–π and π–π interactions. In vitro cytotoxicity of the complexes were assessed by MTT assay against four cancer cell lines such as human breast adenocarcinoma (MCF-7), cervical (HeLa), epithelioma (Hep-2) and Ehrlich ascites carcinoma (EAC), and two normal cell lines namely normal human dermal fibroblasts (NHDF) and L6 myotubes with respect to the commercially used anticancer drug cisplatin. All the complexes induce apoptosis in EAC cells, which was confirmed by AO/EB, Hoechst 33258 and PI staining methods. The complexes block cell cycle progression of EAC cells in S phase (DNA synthesis). The cellular uptake studies confirmed the ability of the complexes to go into the cytoplasm and accumulation in the cell nuclei. In the in vivo anticancer studies, the complexes significantly reduce the tumour volume in female Swiss albino mice. Overall, our results ensure the role of thiosemicarbazone-based copper(I) complexes as prospective anticancer agents, induction of apoptosis and S phase arrest with the mitochondrial controlled pathway.
... Interaction with metal ions has important consequences for the solubility, pharmacokinetics and bioavailability of fluoroquinolones, and it is also involved in their mechanism of action [11][12][13][14]. Complexation can be a strategy to increase the range of antibiotics action or overcome antibiotics resistance [15]. ...
The stability of ternary copper(II) complexes of a heterocyclic ligand, L (L being 2,2′-bipyridine (bipy) or 1,10-phenanthroline (phen)) and the fluorescent antibacterial agent norfloxacin (NFX) as the second ligand was studied at pH 7.4 and different ionic strengths. Fluorescence quenching upon titration of NFX with the binary complexes allowed to obtain stability constants for NFX binding, Kb, as a function of ionic strength. The Kb values vary by more than two orders of magnitude when buffer concentration varies from 0.5 to 100 mM. It was observed that previously synthesized ternary complexes dissociate in buffer according with the obtained stability constants. This shows that equimolar solutions of NFX and binary complexes are equivalent to solutions of synthesized ternary complexes. The interaction of the ternary copper complexes with anionic SDS (sodium dodecyl sulfate) micelles was studied by fluorescence and electron paramagnetic resonance (EPR). Titration of NFX-loaded SDS micelles with the complexes Cu:L allowed to determine the stability constants inside the micelles. Fluorescence quenching demonstrated that SDS micelles increase the stability constants by factors around 50. EPR spectra gave details of the copper(II) local environment, and demonstrated that the structure of the ternary complexes inside SDS micelles is different from that in buffer. Mononuclear ternary complexes formed inside the micelles, while in buffer most ternary complexes are binuclear. The results show that anionic membrane interfaces increase formation of copper fluoroquinolone complexes, which can influence bioavailability, membrane diffusion, and mechanism of action of the antibiotics.
The interaction of 2-(thiophen-2′-yl)ethylphosphine, paraformaldehyde, and benzhydrylamine or 1-methylbenzylamine resulted in 1,5-diaza-3,7-diphosphacyclooctanes, which were used for the synthesis of P,P-bischelate copper(i) complexes. The obtained compounds were characterized by NMR spectroscopy, mass spectrometry, and elemental analysis. The study of the luminescent properties of the copper(i) complexes demonstrated that they are solid-state singlet luminophores. Their biological activity was investigated. They were shown to be inactive against gram-positive and gram-negative bacteria and exhibited a low cytotoxicity, which determined their potential use as luminescent sensors for biological applications.
In this work, we explored the ability of N-methylS methyl dithiocarbazate ([H2N-N(CH3)C(=S)SCH3]; DTCZ) to form coordination complexes with copper starting from different copper (II, I) sources. Data proved that the type of used salt affects the stoichiometry and structure of the obtained coordination complexes. Copper complexes of general empirical formula [Cu(DTCZ)Cl2] (1), [Cu(DTCZ)2NO3]NO3 (2), [Cu(DTCZ)2(OH2)]SO4 (3), [Cu(DTCZ)2]PF6 (4), [Cu(DTCZ)(PPh3)2]NO3 (5) and [Cu(DTCZ)2]Br (6) were synthesized in high yield and characterized by elemental analysis, UV-Vis and IR spectroscopy. Molecular structures of 1-6 and also of side-products [Cu(DTCZ)2SO4] (3a), [Cu(DTCZ)2](PF6)(OH) (4b) and [CuBr(C3H7NS2)]n (6a) were determined by single crystal X-ray diffraction (XRD). In all cases, DTCZ binds the metal in the neutral form through the hydrazine nitrogen (NH2) and thione sulphur (S) atom set, forming monosubstituted and disubstituted complexes having tetrahedral, square planar, or square pyramidal geometries, depending on the copper source. In addition, two one-dimensional (1D) coordination polymers and water channels have been observed in the crystal states.
The present work reports the synthesis of new N4-donor compounds carrying p-xylyl spacers in their structure. Different Schiff base aliphatic N-donors were obtained synthetically and subsequently evaluated for their ability to interact with two models of nucleic acids: calf-thymus DNA (CT-DNA) and the RNA from yeast Saccharomyces cerevisiae (herein simply indicated as RNA). In more detail, by condensing p-xylylenediamine and a series of aldehydes, we obtained the following Schiff base ligands: 2-thiazolecarboxaldehyde (L1), pyridine-2-carboxaldehyde (L2), 5-methylisoxazole-3-carboxaldehyde (L3), 1-methyl-2-imidazolecarboxaldehyde (L4), and quinoline-2-carboxaldehyde (L5). The structural characterisation of the ligands L1-L5 (X-ray, ¹H NMR, ¹³C NMR, elemental analysis) and of the coordination polymers {[CuL1]PF6}n (herein referred to as Polymer1) and {[AgL1]BF4}n, (herein referred to as Polymer2, X-ray, ¹H NMR, ESI-MS) is herein described in detail. The single crystal X-ray structures of complexes Polymer1 and Polymer2 were also investigated, leading to the description of one-dimensional coordination polymers. The spectroscopic and in silico evaluation of the most promising compounds as DNA and RNA binders, as well as the study of the influence of the 1D supramolecular polymers Polymer1 and Polymer2 on the proliferation of Escherichia coli bacteria, were performed in view of their nucleic acid-modulating and antimicrobial applications. Spectroscopic measurements (UV–Vis) combined with molecular docking calculations suggest that the thiazolecarboxaldehyde derivative L1 is able to bind CT-DNA with a mechanism different from intercalation involving the thiazole ring in the molecular recognition and shows a binding affinity with DNA higher than RNA. Finally, Polymer2 was shown to slow down the proliferation of bacteria much more effectively than the free Ag(I) salt.
The synthesis and characterization of a Cu(I) phosphine complex, as well as spectroscopic and simulation studies of its interaction with the DNA helix, are described. Based on X-ray single-crystal diffraction data, the monoclinic phase [Cu(PPh3)(L)(I)], L= 2-((pyridin-2-ylmethylene)amino)isoindoline-1,3-dione, with a tetrahedral molecular geometry was synthesised. The experimental results suggested that the complex could target DNA with a high affinity via an intercalation binding mode. The Stern–Volmer analysis based on fluorimetry approved that raising the temperature from 283 to 293 K causes the Ke to increase, confirmed a dynamic mechanism in the interaction while a further increase of temperature to 303 K, causes the opposite consequence which confirmed a static nature for the interaction at the high range of temperatures. Furthermore, a concluded positive cooperativeness at ambient temperature would be particularly important to achieve a significant impact of the complex on DNA strands even at low complex concentrations. According to competitive fluorescence tests the complex interacts with DNA at intercalation binding sites on DNA. The resulting entropy and enthalpy shifts identify the van der Waals forces as the interaction's primary binding mechanism. Docking study confirmed the insertion of aromatic ring into the DNA double helix.
In this work we show, using the example of a series of [Cu(Xantphos)(N^N)]⁺ complexes (N^N being substituted 5-phenyl-bipyridine) with different peripheral N^N ligands, that substituents distant from the main action zone can have a significant effect on the physicochemical properties of the system. By using the C≡C bond on the periphery of the coordination environment, three hybrid molecular systems with −Si(CH3)3, −Au(PR3), and −C2HN3(CH2)C10H7 fragments were produced. The Cu(I) complexes thus obtained demonstrate complicated emission behaviour, which was investigated by spectroscopic, electrochemical, and computational methods in order to understand the mechanism of energy transfer. It was found that the −Si(CH3)3 fragment connected to the peripheral C≡C bond changes luminescence to long-lived intra-ligand phosphorescence, in contrast to MLCT phosphorescence or TADF. The obtained results can be used for the design of new materials based on Cu(I) complexes with controlled optoelectronic properties on the molecular level, as well as for the production of hybrid systems.
Following the great impetus provided by the discovery of the anticancer activity of cisplatin [cis-diamminedichloridoplatinum(II)] in the 1960s, extensive search for alternative metal-based drugs with improved pharmacological properties has been attempted. Actually, the outstanding efficacy showed by clinically approved Pt(II) compounds is counterbalanced by severe toxic effects on normal tissues, and by the early appearance of drug resistance phenomena. Among non-Pt compounds, copper complexes are considered promising alternatives to platinum drugs as antitumor agents. In particular, the discovery of significant alterations in cancer cell copper metabolism and the different responses to copper between normal and tumor cells have paved the way for the development of copper-based anticancer drugs. This article aims to summarize the extant literature on the most well-studied classes of anticancer copper complexes, with special emphasis on research performed in the last 10 years, most relevant to the elucidation of the involved mechanisms of action and/or reporting on in vivo efficacy evaluations.
Two novel phosphine ligands, Ph2PCH2N(CH2CH3)3 (1) and Ph2PCH2N(CH2CH2CH2CH3)2 (2), and six new metal (Cu(I), Ir(III) and Ru(II)) complexes with those ligands: iridium(III) complexes: Ir(η5-Cp*)Cl2(1) (1a), Ir(η5-Cp*)Cl2(2) (2a) (Cp*: Pentamethylcyclopentadienyl); ruthenium(II) complexes: Ru(η6-p-cymene)Cl2(1) (1b), Ru(η6-p-cymene)Cl2(2) (2b) and copper(I) complexes: [Cu(CH3CN)2(1)BF4] (1c), [Cu(CH3CN)2(2)BF4] (2c) were synthesized and characterized using elemental analysis, NMR spectroscopy, and ESI-MS spectrometry. Copper(I) complexes turned out to be highly unstable in the presence of atmospheric oxygen in contrast to ruthenium(II) and iridium(III) complexes. The studied Ru(II) and Ir(III) complexes exhibited promising cytotoxicity towards cancer cells in vitro with IC50 values significantly lower than that of the reference drug—cisplatin. Confocal microscopy analysis showed that Ru(II) and Ir(III) complexes effectively accumulate inside A549 cells with localization in cytoplasm and nuclei. A precise cytometric analysis provided clear evidence for the predominance of apoptosis in induced cell death. Furthermore, the complexes presumably induce the changes in the cell cycle leading to G2/M phase arrest in a dose-dependent manner. Gel electrophoresis experiments revealed that Ru(II) and Ir(III) inorganic compounds showed their unusual low genotoxicity towards plasmid DNA. Additionally, metal complexes were able to generate reactive oxygen species as a result of redox processes, proved by gel electrophoresis and cyclic voltamperometry. In vitro cytotoxicity assays were also carried out within multicellular tumor spheroids and efficient anticancer action on these 3D assemblies was demonstrated. It was proven that the hydrocarbon chain elongation of the phosphine ligand coordinated to the metal ions does not influence the cytotoxic effect of resulting complexes in contrast to metal ions type.
The general and well-defined synthetic strategies to access mononuclear and binuclear homoleptic copper(I)-phosphines complexes were listed and discussed. Moreover, the synthetic protocols to obtain mononuclear and binuclear heteroleptic copper(I)-phosphine complexes containing halides, pseudohalides and/or N-containing ligands were covered, underlining a wide range of structurally varied phosphine and diimine ligands. The effect of the steric hinderance and electronic properties of the ligands on the geometrical structure of copper(I) were highlighted. The importance of this class of complexes are stemmed from their properties; their catalytic, photophysical and biological applications were highlighted with emphasis on the role of the phosphine and diimine ligands.
CuBr(PPh3)2(4,6-dimethylpyrimidine-2-thione) (Cu-L) was synthesized by stirring 15 CuBr(PPh3)3 and 4,6-dimethylpyrimidine-2-thione in dichloromethane. The crystal structure of Cu-16 L was obtained, and indicated that the complex adopts a distorted tetrahedral structure with several 17 intramolecular hydrogen bonds. Moreover, a centrosymmetric dimer is formed by the intermolec-18 ular hydrogen bonding of the bromine acceptor created by symmetry operation 1-x, 1-y, 1-z to the 19 methyl group (D3 = C42) of the pyrimidine-thione ligand. HSA-binding of Cu-L and its ligand were 20 evaluated, revealing that Cu-L binds to HSA differently than its ligand. The HSA-bindings were 21 modelled by molecular docking, which suggested that Cu-L binds to the II A domain while L binds 22 between the I B and II A domains. Anticancer activities toward OVCAR-3 and HeLa cell lines were 23 tested and indicated the significance of the copper centre in enhancing the cytotoxic effect; negligible 24 toxicities for L and Cu-L were observed towards a non-cancer cell line. The current study highlights 25 the potential of copper(I)-phosphine complexes containing thione ligands as therapeutic agents. 26
In this research paper, the synthesis process and characterization of a dinuclear Cu(I) phosphine complex, as well as spectroscopic and simulation analysis of its interaction with DNA helix, are presented. The monoclinic phase [Cu(PPh3)(L0.5)(I)]2 with a tetrahedral molecular geometry was elucidated based on X-ray single-crystal diffraction data. The significant association constant (6.88 × 10⁵) and remarkable hyperchromism as obtained from UV–Visible spectra indicated a high binding affinity of the Cu(I) complex for DNA, which is in accordance with both intercalation and groove binding modes. The results of competitive fluorescence experiments along with molecular docking simulation proved that the planar part of the complex can insert into the core of adenine nucleobases and compete with methylene blue for the intercalative binding sites, while the bulky substituent binds in the minor groove of DNA via replacement of Hoechst molecules at A-T rich regions. According to thermodynamic parameters (the negative values of ΔH° and ΔS°), it is quite clear that the interaction process is enthalpy-favored while disfavored by entropy and van der Walls and hydrophobic forces play a major role in stabilization of right-handed B-DNA form during the interaction, as shown in the circular dichroism spectra. Based on the above findings partial intercalation mode at A-T rich region of DNA was proposed. The cytotoxicity and apoptosis results on MCF-7 cell line indicated positive effect of the Cu(I) complex in controlling growth and viability of breast cancer more than cisplatin.
Gold(III) complex containing 2-pyridineethanol has been synthesized and characterized structurally by single crystal X-ray diffraction, vibrational spectroscopy, 1H NMR spectroscopy, electrochemical study, and DFT calculations. The Au(III) ion is four coordinated with one N–donor ligand (L) and three Cl anions. The Okuniewski's (τ’4=0.018) has been used to estimate the angular distortion from ideal square planar geometry. The vibrational spectroscopy studies, in the solid state and DMSO solution and cyclic voltammetry, have been performed to determine its stability and redox activity, respectively. A complete assignment of the IR and Raman spectra has been made based on the calculated potential energy distribution (PED). The theoretical calculations have been made for two functionals and several basis sets. The compound has been evaluated for its antiproliferative properties in a human lung adenocarcinoma cell line (A549), mouse colon carcinoma (CT26), human breast adenocarcinoma (MCF-7), human prostate carcinoma derived from the metastatic site in the brain (DU-145), and PANC-1 human pancreas/duct carcinoma cell line and non-tumorigenic cell lines: HaCat (human keratinocyte), and HEK293T (human embryonic kidney). Au(III) complex cytotoxicity is significantly against A549 and MCF-7 cells as in the reference drug: cisplatin. Studies of the interactions of Au(III) complex with DNA, HSA (human serum albumin) have been performed. The results from modeling docking simulations indicate that the title complex exerts anticancer effects in vitro based on different mechanisms of action to compare with cisplatin.
New benzimidazolium salts were synthesized as N-heterocyclic carbene precursors. These NHC precursors were metallated with Cu2O and CuI in acetone and water under reflux to give novel copper(I) complexes. The structures of these benzimidazolium salts and copper(I) complexes were characterized on the basis of elemental analysis, 1H NMR, 13C NMR, IR and LC–MS spectroscopic techniques. The (NHC)Cu(I) complexes 3–4 were tested against MCF7 and MDA-MB-231 cancer cells, Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA) and Candida albicans microorganisms, Leishmania major promastigotes and amastigotes, Toxoplasma gondii parasites and against Vero cell line in vitro. The synthesized copper NHC carbene complex 4b (1,3-bis(2,3,4,5,6-pentamdthylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-2-yl)copper(I) chloride) was the most active against MCF7 cancer cells (half growth Inhibition Concentrations (IC50) = 0.3 µg mL−1), as well as the most potent antimicrobial against E. coli (inhibition zone (IZ) = 23.3 mm), MRSA (IZ = 25.5 mm) and C. albicans (IZ = 28.5 mm) besides its antileishmanial activities against L. major promastigotes and amastigotes (IC50 < 0.04 µg mL−1). Compound 4c (1,3-bis(4-(tert-butyl)benzyl)-2,3-dihydro-1H-benzo[d]imida-zol-2-yl)copper(II) bromide) is the most potent anticancer against MDA-MB-231 cancer cells IC50 = 0.4 µg mL−1). Compound 4e (5,6-dimethyl-1,3-bis(2,4,6-trimethylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-2-yl)copper(I) chloride) is the best suitable antitoxoplasmal drug candidate due to its SI of 16.5. These candidates need further study to identify mode of action and drug standardization.
Biological activity against reference and multi-drug resistant (MDR) clinical strains of fluoroquinolones (FQs): ciprofloxacin (HCp), norfloxacin (HNr), lomefloxacin (HLm) and sparfloxacin (HSf), phosphine ligands derived from those antibiotics and 14 phosphino copper(I) and copper(II) complexes with 2,9-dimethyl-1,10-phenanthroline, 1,10-phenanthroline or 2,2′-biquinoline have been determined. Almost all phosphines showed excellent antibacterial activity relative to reference strains (S. aureus ATCC 6538, E. coli ATCC 25922, K. pneumoniae ATCC 4352, and P. aeruginosa ATCC 27853). In rare cases P. aeruginosa rods showed natural insensitivity to oxides, and their copper(II) complexes. Most of the studied compounds showed weak antibacterial activity against clinical multi-drug resistant strains (MDR P. aeruginosa 16, 46, 325, 355, MRD A. baumanii 483 and MDR S. aureus 177). However, phosphines Ph2PCH2Sf (PSf), Ph2PCH2Lm (PLm) and their copper(I) complexes were characterized by the best antibacterial activity. In addition, PSf compounds, in which the activities relative to P. aeruginosa MDRs were relatively diverse, paid particular attention in our studies. Genetic and phenotypic studies of these strains showed significant differences between the strains, indicating different profiles of FQs resistance mechanisms. This may prove that a change in the spatial conformation of the PSf derivatives relative to the native form of HSf increased its affinity for the target site of action in gyrase, leading to selective inhibition of the multiplication of MDR strains. In conclusion, differences in PSf activity within closely related P. aeruginosa strains may indicate its diagnostic and therapeutic potential.
The search for new antifungals is very important because the large genetic variation of pathogenic organisms has resulted in the development of increasingly effective defense mechanisms by microorganisms. Metal complexes...
In the current study, we have discuss two new copper(II) complexes with their excellent binding and cleavage affinity towards DNA and proteins. Crystal-structure analysis revealed that these two complexes of the general formula [Cu(ENox)bpyCl], 1 and [Cu(phen)2Cl], 2 (HENox = Enoxacin, bpy = 2,2’-bipyridine and phen = 1,10-phenanthroline) crystallized in chiral space group P-1 and C 2/c and they exhibited a distorted square pyramidal geometry around the copper atoms (τ = 0.008 and 0.88). Biological studies of the complexes towards calf thymus (CT) DNA and proteins (BSA/HSA) were explored by a series of spectroscopy techniques. All these measurements revealed that both complexes interact with CT DNA via intercalative mode with their excellent binding affinity and complex 2 exhibiting the highest DNA-binding constant (K_b) = 2.87×105, M−1. The interaction of the complexes with proteins (BSA/HSA) indicated that complexes have quenched the intrinsic fluorescence of proteins in a static quenching mode. Also, the ability of complexes to cleave the supercoiled plasmid DNA (pBR322) and proteins in the presence of activator-like H2O2 as revealed from Gel-electrophoresis and SDS-PAGE experiments and is consistent with their strong hydrophobic interaction towards proteins. Moreover, molecular docking (MD) analysis on the crystal structures of DNA, BSA and HSA were also employed in order to measure the ability complexes to bind to these target macromolecules. The in vitro cytotoxicity of the complexes was evaluated against breast cancer MCF-7 cells and the results suggested that both complexes exhibit superior anticancer activity.
Phosphonium salt (p-OCH3-Ph)2P(CH2OH)2Cl (MPOHC), derived phosphine ligands without and with SarGly (Sarcosine-Glycine) peptide carrier P(p-OCH3-Ph)2CH2OH (MPOH) and P(p-OCH3-Ph)2CH2SarGly (MPSG), respectively, and two copper(I) complexes [Cu(I)(dmp)(MPOH)] (1-MPOH; dmp = (2,9-dimethyl-1,10-phenanthroline)) and [Cu(I)(dmp)(MPSG)] (1-MPSG) were synthesized. The resulting compounds were characterized by elemental analysis, 1D and 2D NMR and UV-Vis absorption spectroscopies, mass spectrometry, cyclic voltammetry and by X-ray diffraction analysis. Cytotoxicity of all compounds was evaluated in vitro against colon, lung, breast, pancreatic, prostate tumor cell lines, as well as towards non-tumor cell lines: lung, kidney and keratinocyte. Stable in biological medium in the presence of atmospheric oxygen, Cu(I) complexes exerted a cytotoxic effect higher than that elicited by cisplatin against tested cancer cell lines. The introduction of methoxy group onto the phenyl rings of the phosphine ligand coordinated to the copper(I) ion resulted in a relevant increase of cytotoxicity in the case of breast, pancreatic and prostate tumor cell lines in vitro. Attachment of a peptide carrier significantly increased the selectivity towards cancer cells. Fluorescence spectroscopic data (calf thymus DNA: CT-DNA) titration), together with analysis of DNA fragmentation (gel electrophoresis) and molecular docking provided evidence for the multimodal interaction of copper compounds with DNA and showed their unusual low genotoxicity. Additionally, copper complexes were able to generate reactive oxygen species as a result of redox processes, proved by fluorescence spectroscopy and cyclic voltamperometry.
The ability of the studied FomA protein fragments of Fusobacterium nucleatum (Fn) with copper(II) ions (Cu(II)-Ac-KGHGNGEEGTPTVHNE-NH2 (1Cu) and its cyclic analogue Cu(II)-cyclo(KGHGNGEEGTPTVHNE) (2Cu)) to induce reactive oxygen species (ROS) generation, as a result of red-ox processes, was determined by UV-Vis, luminescence methods, spin trapping and cyclic voltamperometry. The contribution of ¹O2 and ˙OH to DNA degradation was proved using gel electrophoresis. Furthermore, the pronounced generation of ROS by mouse colon carcinoma cells (CT26) stimulated by both copper(II) complexes was confirmed. A fluorescence method allowed the total amounts of ROS generated inside the CT26 cells to be detected, while the spin trapping technique proved that free radicals mainly attached to the membrane surface. These last results are in agreement with the data obtained from the ICP-MS method, which demonstrates that 1Cu and 2Cu complexes are not efficiently accumulated inside the cell. Furthermore, the role of ROS in lipid peroxidation was established. The above-mentioned factors may clearly indicate the contribution of ROS generated by the studied copper(II) complexes to colonic cell damage, which can lead to a carcinogenesis process. This study may be an important step to recognize and understand the mechanism of colon cancer initiation.
Explanation of carcinogenesis processes may certainly contribute to the prevention and development of novel methods for cancer treatment. In this paper we considered the probable relationship between the presence of Fusobacterium nucleatum in intestines and its possible influence on the development of colorectal cancer. For this purpose, intracellular and/or extracellular generation of reactive oxygen species (ROS) by mouse colon carcinoma cells (CT26) were stimulated by two fragments of FomA adhesin from F. nucleatum and their complexes with copper(II): Cu(II)-Ac-KGHGNG-NH2 (1Cu) and Cu(II)-Ac-PTVHNE-NH2 (2Cu). Incubation of the cells with copper complexes was followed with ICP-MS technique. The overall generation of ROS was shown by means of fluorescence spectroscopy with two proper probes, whereas identification of ROS was achieved by the spin trapping technique and EPR measurements. As a result, an abundant production of the hydroxyl radicals, both inside and outside the cells, was observed upon the stimulation of the CT26 cells with the copper complexes. Clearly both compounds induced strong oxidation stress which triggered a radicals’ cascade that finally resulted in the pronounced lipid peroxidation. The later was evidenced with the measured level of malondialdehyde, a biomarker of the peroxidation process. By applying N-acetylcysteine antioxidant to the studied system the free radical mechanism of the lipid peroxidation process was confirmed. Hypothetically this mechanism can lead to intestines cells damages and further cancerogenesis processes.
Different studies about the anticancer potential of several medically used antibacterial fluoroquinolones have been established. Fluoroquinolone derivatives, like some anti‐cancer drugs, such as doxorubicin, can achieve antitumor activity via poisoning of type II human DNA topoisomerases. Interestingly, structural features required for the anticancer activity of quinolones have been determined. Most of the chemical modifications required to convert antibacterially acting fluoroquinolones into their anticancer analogs were at position 7 and the carboxylic group at position 3. This review highlights the antitumor potential of fluoroquinolones in general and summarizes the chemical modifications carried out on fluoroquinolones to become anticancer agents. Moreover, the review gives a quick recap on metal ion chelates with fluoroquinolones and their substantial role in topoisomerase poisoning and antitumor potential improvement. Hence, it should be highly interesting for researchers attempting to design and synthesize novel anticancer fluoroquinolone candidates. Fluoroquinolone derivatives can achieve the antitumor activity via poisoning of type II human DNA topoisomerases. This review summarizes the chemical modifications carried out on fluoroquinolones to become anticancer agents. It also gives an overview on metal ion chelates with fluoroquinolones and their role in topoisomerase poisoning and antitumor activity improvement.
Cytotoxicity of cationic (NHC)Cu(I)complexes bearing 2,2′-dipyridylamine (dpa)type ligands has been evaluated toward 4 cancer cell lines, and compared to the one of neutral (NHC)Cu(I)complexes. The high cytotoxicity of these novel cationic (NHC)Cu(I)complexes, combined with the straightforward synthesis, and versatility of dpa type ligands may offer new prospects in cancer research, toward the development of novel carrier linked prodrugs.
Abstract A large number of drugs are administered on different mucosal surfaces. However, due to the poor mucoadhesion of the current formulations, their bioavailability is often very low. The development of efficient mucoadhesive drug delivery systems is thus crucial for improving the performance of these drugs. The mucoadhesive properties of gold nanoparticles were investigated. First, two types of gold nanoparticles were synthesized: AuNP1 and AuNP2. AuNP1 only contain internal thiol groups on their metallic core, and AuNP2 contain both internal and peripheral thiol groups. Different protocols based on an adapted quantitative colorimetric method, UV-visible and fluorescence spectroscopies were then developed to gather information on their mucoadhesive properties. Moreover, a global correction factor for the inner filter effect in spectrofluorimetry was proposed, and the data obtained were compared to those commonly used in the literature. Mucins deeply interact with AuNP1, perturbing their core, whereas they remain at the periphery of AuNP2. The quantitative method suggests that a larger number of mucins interact with AuNP2. The establishment of this protocol could be applied to assess the mucoadhesive properties of other stable molecules. This mucoadhesive property of gold nanoparticles could be combined with their drug delivery ability in order to improve the medication administered on mucosa.
A series of six new bis(thiosemicarbazone)copper(I) complexes of the type [Cu(L1–6)2Cl] (1−6) were synthesized and characterized. The complexes adopted trigonal planar ′Y′ shaped geometry coordinating through two thione sulphur atoms of two ligand molecules and one chloride ion. All the complexes intercalatively bind with calf thymus DNA (CT−DNA) as evidenced by spectral and molecular docking studies. The absorption and emission spectral techniques confirmed the strong interaction of the complexes with BSA via static quenching mode. The complexes efficiently cleave pBR322 DNA via hydrolytic pathway, and significantly interact with epidermal growth factor receptor. All the complexes were assessed for their anti‐proliferative activity, in which the complexes 2, 3 and 4 containing methyl, methoxy and hydroxyl groups, respectively, showed significant activity. The complexes induce apoptosis in EAC cells as evidenced by acridine orange (AO)/ethidium bromide (EB), Hoechst 33258 and propidium iodide (PI) staining methods, and cell cycle analysis. Cellular uptake studies revealed the ability of the complexes to go into the cytoplasm and accumulation in the cell nuclei. The complexes are involved in the generation of reactive oxygen species (ROS), mitochondrial mediated and caspase‐dependent apoptosis. Further, using a female Swiss albino mice model, we found that the complexes 2 and 3 inhibited Ehrlich ascites carcinoma (EAC) tumour cell growth in vivo. The newly synthesized bis(thiosemicarbazone)copper(I) complexes effectively kills Ehrlich ascites carcinoma (EAC) cells via generation of ROS, mitochondrial mediated and caspase‐dependent pathway.
Novel half-sandwich ruthenium(II) complexes with aminomethyl(diphenyl)phosphine derived from fluoroloquinolones (RuPCp, RuPSf, RuPLm, RuPNr) were being investigated as alternatives to well-established metal-based chemotherapeutics. All compounds were characterized by elemental analysis, selected spectroscopic methods (i.e., absorption and fluorescence spectroscopy, ESI-MS, NMR, circular dichroizm), X-ray diffractometry, ICP-MS, and electrochemical techniques. To overcome low solubility, serious side effects connected with systemic cytotoxicity of ruthenium complexes, and acquiring the resistance of cancer cells, polymeric nanoformulations based on Pluronic P-123 micelles loaded with selected Ru(II) complexes were prepared and characterized. Resulting micelles (RuPCp_M, RuPNr_M) enabled efficient drug accumulation inside human lung adenocarcinoma (A549 tumor cell line), proved by confocal microscopy and ICP-MS analysis, allowing cytotoxic action. Studied complexes exhibited promising cytotoxicity in vitro with IC50 values significantly lower than the reference drug cisplatin. The fluorescence spectroscopic data (CT-DNA titration, cell staining in vitro) together with analysis of DNA fragmentation (pBR322 plasmid, comet assay) provided clear evidence for the interaction with DNA inducing apoptotic cell death.
The copper(II) ion binding by the Ac-KGHGNG-NH2 and Ac-PTVHNE-NH2 fragments of FomA adhesin from Fusobacterium nucleatum was studied using potentiometry, UV-Vis, CD, EPR and DFT techniques. The coordination pattern was described in a wide range of pH values. Ligands begin interactions with metal ions using imidazole nitrogen. At pH 6.8 (a value typical of the large intestine environment) the metal ion was coordinated by the 3N donor atoms {Nim, 2×N-amide} in both cases. However, the copper(II) ion was bound more effectively by the Ac-PTVHNE-NH2 peptide. The formation of reactive oxygen species (ROS) was studied by UV-Vis and fluorescence spectroscopies, as well as gel electrophoresis in the presence of H2O2 and/or ascorbic acid. The complexes generated ROS in highest amounts among all compounds. Moreover, they stimulated the CT26 cell line (mouse colon carcinoma) to produce ROS which lead to oxidative stress. It was also determined that such radicals took part in the plasmid degradation mechanism.
In this paper, we present a comparative study on the cytotoxic mode of action of copper(I) and copper(II) complexes with phosphine derivatives of fluoroquinolone antibiotics (ciprofloxacin HCp and norfloxacin HNr). The in vitro cytotoxic activity of four new compounds was tested against two selected cancer cell lines. All complexes exhibited much better cytotoxicity against both cell lines than unmodified fluoroquinolone antibiotics, their phosphines (PCp, PNr), chalcogenide derivatives (oxides: OPCp, OPNr; sulfides: SPCp, SPNr and selenides: SePCp, SePNr) and previously described by us complexes with phosphines derived from different fluoroquinolones: lomefloxacin (HLm) and sparfloxacin (HSf) as well as cisplatin. Apoptosis, observed at a great predominance, was induced by all studied complexes. Importantly, it was concluded that coordination compounds with Cu(I) ion ([CuI-PNr] and [CuI-PCp]) were much more active than those with Cu(II) ion ([OPNr-CuII], [OPCp-CuII]), even though the highest efficacy to produce reactive oxygen species, participating in overall cytotoxicity, was proved for copper(II) complexes among all studied compounds. Herein, we discuss not only results obtained for copper(I)/(II) complexes with phosphines derived from HNr and HCp but we also compare them to previously described data for complexes with HLm and HSf derivatives. This is the first insight into a structure-activity relationship of copper complexes with phosphine derivatives of fluoroquinolone antibiotics.
Cytotoxic effect of iodide or thiocyanate copper(I) complexes (1-PSf, 2-PSf, 3-PSf, 4-PSf) with a phosphine derived from sparfloxacin (HSf) and 2,9-dimethyl-1,10-phenanthroline (dmp) or 2,2’-biquinoline (bq) as diimine auxiliary ligands was proved in vitro on somatic (MRC-5) and neoplastic (MCF7) human cell lines. Differences in mode of action were investigated in-depth for selected the dmp and the bq complexes (1-PSf, 3-PSf, respectively) by elucidation of (i) efficiency to produce reactive oxygen species (ROS) in biological systems (cyclic voltammetry), (ii) their impact on mitochondrial membrane potential, (iii) potency to activation of caspases 3 and 9, and (iv) influence on the degree of DNA degradation (comet assay). It was concluded that the apoptosis of cancer cells is straightly connected with caspase-dependent mitochondrial pathway and supported by ROS production along with irreversible DNA fragmentations. Finally, it was demonstrated that the selected copper(I) complex encapsulated inside liposomes (1-PSf-L) exhibited the enhanced accumulation inside cancer cells. This resulted in its higher cytotoxicity against cancer cells with therapeutic index even ca. 60. Increased selective accumulation in active neoplasm with simultaneous enhanced bioavailability and reduced systemic toxicity of liposomal formulations of copper(I) complexes can result in development of new copper-based therapeutics and their successful implementation in anticancer chemotherapy.
The new class of cyclometalated copper(I) with NCN pincer and N-aryl-1,3,5-triaza-7-phosphaadamantane (PTA-PhR) ligands of formula [Cu(L)(PTA-PhR)](PF6), (R = Me (1), Et (2), iPr (3), HL=5-methoxy-1,3-bis (1-methyl-1H-benzo[d]imidazol-2-yl)benzene) have been synthesized by C−H activation and fully characterized. The cytotoxicity of complexes was evaluated against a panel of several human tumor cell lines. All the complexes showed in vitro antitumor activity comparable to that of the reference metallodrug cisplatin. Tests completed on cisplatin sensitive and resistant cell lines exhibited that against human ovarian 2008/C13* cell line pair, the resistance factor of copper complexes was roughly 4-5 lower than that of cisplatin. The thioredoxin reductase activity, reactive oxygen species (ROS) generation, and cellular apoptosis of the complexes have also been studied. Toxicity studies exhibited notable in vitro antimicrobial activity of the copper(I) complexes against Gram-positive and Gram-negative bacteria strains, which is much more active than furacillinum as standard drug. The interaction of complexes 1-3 with calf thymus DNA (CT DNA) was investigated using viscosity, fluorescence quenching, and electronic absorption spectroscopy. The DNA cleavage ability of complex 3 has been studied. Overall, the new designing of copper(I) complexes provided a useful strategy for the development of bioorganometallic anticancer drugs with multiple modes of action.
Five copper(II) complexes containing N,N',N''-trisubstituted guanidine ligands were synthesized and characterized by elemental analyses, and UV-Visible, FT-IR, EPR and mass spectroscopic techniques. The synthesized copper(II) complexes (1-5) bear the general formula [Cu{C6H5CONC(NR)NHCH2C6H5}2] where R = phenyl (1), 4-methylphenyl (2), 4-ethoxyphenyl (3), 2-methoxyphenyl (4) or 1-naphthyl (5). Four coordinated square planar geometry of the complexes was confirmed by single crystal X-ray diffraction study. The interaction of the Cu(II) complexes with calf thymus DNA (CT DNA) was explored using absorption and fluorescence spectroscopic methods. The results revealed that the complexes have an affinity constant for DNA in the order of 104 M-1 and the mode of interaction is non covalent intercalation. DNA cleavage study showed that the complexes cleaved DNA without any external agent. The interaction of Cu(II) complexes with bovine serum albumin (BSA) was also studied using absorption and fluorescence techniques. The cytotoxic activity of the Cu(II) complexes was probed in vitro against human breast (MCF7) and lung (A549) cancer cell lines. The complexes were also tested against mouse embryonic fibroblasts (NIH 3T3) cell lines. The complexes 1 and 3 have good cytotoxic activity which is comparable with cyclophosphamide drug. The complexes were less cytotoxic towards normal cell lines showing that they affect only cancer cell lines. Superoxide radical scavenging properties of the complexes were assessed using NBT assay. Copper(II) complexes showed appreciable superoxide radical scavenging activity with IC50 value ranging from 1.53 to 5.62 µM. Further molecular docking technique was employed to understand the binding of the complexes toward the molecular target DNA and human DNA topoisomerase I.
Two cationic γ-carbolines, 2-methyl-5H-pyrido[4,3-b]indolium iodide () and 2,5-dimethyl-5H-pyrido[4,3-b]indolium iodide (), were synthesized, and the DNA-binding properties of the cationic γ-carbolines were elucidated. Through a series of experiments, we proved that the two cationic γ-carbolines could strongly interact with DNA by intercalative binding. However, , with a methyl group substituting H atom of 5-NH, has shown a stronger intercalative interaction with DNA compared to . The dissociation of H from the 5-NH of resulted in better water solubility and less binding affinity to DNA. Atomic force microscopy (AFM) images of pBR322 showed that both and strongly interacted with DNA and induced conformational changes in DNA. Moreover, the CT-DNA circular dichroism (CD) spectra changes and the statistics of the node numbers of pBR322 in AFM images indicated that had more profound effects on DNA conformations compared to . Furthermore, our studies have shown that the interactions between cationic γ-carbolines and DNA were sensitive to ionic strength. Increased ionic strength in the buffer caused the DNA helix to shrink, and the base stacking would be more compact, which resulted in minimal intercalation of cationic γ-carbolines into DNA.
Tetrahedral copper(I) TpCuP complexes 1-15, where Tp is a N,N,N-tris(azolyl)borate and P is a tertiary phosphine, have been synthetized and characterized by means of NMR, ESI-MS, and XAS-EXAFS and X-ray diffraction analyses on the representative complex 1 and 10, respectively. All copper(I) complexes were evaluated for their antiproliferative activity against a panel of human cancer cell lines (including cisplatin- and multidrug resistant sublines). The two most effective complexes [HB(pz)3]Cu(PCN), 1 and [HB(pz)3]Cu(PTA), 2 showed selectivity toward tumor vs normal cells, inhibition of 26S proteasome activity associated with endoplasmic reticulum (ER) stress and unfolded protein response (UPR) activation. No biochemical hallmarks of apoptosis were detected and morphology studies revealed an extensive cytoplasmic vacuolization coherently with a paraptosis-like cell death mechanism. Finally, the antitumor efficacy of complex 1 was validated in the murine Lewis Lung Carcinoma (LLC) model.
Motivation:
Molecular simulation has historically been a low-throughput technique, but faster computers and increasing amounts of genomic and structural data are changing this by enabling large-scale automated simulation of, for instance, many conformers or mutants of biomolecules with or without a range of ligands. At the same time, advances in performance and scaling now make it possible to model complex biomolecular interaction and function in a manner directly testable by experiment. These applications share a need for fast and efficient software that can be deployed on massive scale in clusters, web servers, distributed computing or cloud resources.
Results:
Here, we present a range of new simulation algorithms and features developed during the past 4 years, leading up to the GROMACS 4.5 software package. The software now automatically handles wide classes of biomolecules, such as proteins, nucleic acids and lipids, and comes with all commonly used force fields for these molecules built-in. GROMACS supports several implicit solvent models, as well as new free-energy algorithms, and the software now uses multithreading for efficient parallelization even on low-end systems, including windows-based workstations. Together with hand-tuned assembly kernels and state-of-the-art parallelization, this provides extremely high performance and cost efficiency for high-throughput as well as massively parallel simulations.
Availability:
GROMACS is an open source and free software available from http://www.gromacs.org.
Supplementary information:
Supplementary data are available at Bioinformatics online.
ABSTRACT Neutral and cationic copper bis(thiosemicarbazone) complexes bearing methyl, phenyl and hydrogen, on the diketo-backbone of the ligand have been synthesized. All of them were characterized by spectroscopic methods and in three cases by X-ray crystallography. In vitro cytotoxicity studies revealed that they are cytotoxic unlike the corresponding zinc complexes. Copper complexes Cu(GTSC) and Cu(GTSCHCl) derived from glyoxal-bis(4-methyl-4-phenyl-3-thiosemicarbazone) (GTSCH2) are the most cytotoxic complexes against various human cancer cell lines, with a potency similar to that of the anticancer drug adriamycin and up to 1000 fold higher than that of the corresponding zinc complex. Tritiated thymidine incorporation assay revealed that Cu(GTSC) and Cu(GTSCHCl) inhibit DNA synthesis substantially. Cell cycle analyses showed that Cu(GTSC) and Cu(GTSCHCl) induce apoptosis in HCT116 cells. Complex Cu(GTSCHCl) caused distinct DNA cleavage and Topo IIα inhibition unlike Cu(GTSC). In vivo administration of Cu(GTSC) significantly inhibits tumor growth in HCT116 xenografts in nude mice.
Platinum-based anticancer drugs occupy a crucial role in the treatment of various malignant tumours. However, the efficacy and applicability of platinum drugs are heavily restricted by severe systemic toxicities and drug resistance. Different drug targeting and delivery (DTD) strategies have been developed to prevent the shortcomings of platinum-based chemotherapy. These approaches can be roughly categorized into two groups; namely, active and passive tactics. Active DTD is realized through specific molecular interactions between the drugs and cell or tissue elements, while passive DTD is achieved by exploiting the enhanced permeability and retention effect in tumour tissues. The principal methods for active DTD include conjugation of platinum drugs with selective targeting moieties or encapsulation of platinum drugs in host molecules. Bioactive substances such as hormones, carbohydrates, bisphosphonates, peptides and proteins are commonly used in active DTD. Passive DTD generally involves the fabrication of functionalized polymers or nanoparticles and the subsequent conjugation of platinum drugs with such entities. Polymeric micelles, liposomes, nanotubes and nanoparticles are frequently used in passive DTD. In some cases, both active and passive mechanisms are involved in one DTD system. This review concentrates on various targeting and delivery techniques for improving the efficacy and reducing the side effects of platinum-based anticancer drugs. The content covers most of the related literatures published since 2006. These innovative tactics represent current state-of-the-art developments in platinum-based anticancer drugs.
We present two new hybrid meta exchange- correlation functionals, called M06 and M06-2X. The M06 functional is parametrized
including both transition metals and nonmetals, whereas the M06-2X functional is a high-nonlocality functional with double
the amount of nonlocal exchange (2X), and it is parametrized only for nonmetals.The functionals, along with the previously
published M06-L local functional and the M06-HF full-Hartree–Fock functionals, constitute the M06 suite of complementary functionals.
We assess these four functionals by comparing their performance to that of 12 other functionals and Hartree–Fock theory for
403 energetic data in 29 diverse databases, including ten databases for thermochemistry, four databases for kinetics, eight
databases for noncovalent interactions, three databases for transition metal bonding, one database for metal atom excitation
energies, and three databases for molecular excitation energies. We also illustrate the performance of these 17 methods for
three databases containing 40 bond lengths and for databases containing 38 vibrational frequencies and 15 vibrational zero
point energies. We recommend the M06-2X functional for applications involving main-group thermochemistry, kinetics, noncovalent
interactions, and electronic excitation energies to valence and Rydberg states. We recommend the M06 functional for application
in organometallic and inorganometallic chemistry and for noncovalent interactions.
In this study, we present conformational energies for a molecular mechanical model (Parm99) developed for organic and biological molecules using the restrained electrostatic potential (RESP) approach to derive the partial charges. This approach uses the simple "generic" force field model (Parm94), and attempts to add a minimal number of extra Fourier components to the torsional energies, but doing so only when there is a physical justification. The results are quite encouraging, not only for the 34-molecule set that has been studied by both the highest level ab initio model (GVB/LMP2) and experiment, but also for the 55-molecule set for which high-quality experimental data are available. Considering the 55 molecules studied by all the force field models for which there are experimental data, the average absolute errors (AAEs) are 0.28 (this model), 0.52 (MM3), 0.57 (CHARMm [MSI]), and 0.43 kcal/mol (MMFF). For the 34-molecule set, the AAEs of this model versus experiment and nb initio are 0.28 and 0.27 kcal/mol, respectively. This is a lower error than found with MM3 and CHARMm, and is comparable to that found with MMFF (0.31 and 0.22 kcal/mol). We also present two examples of how well the torsional parameters are transferred from the training set to the test set. The absolute errors of molecules in the test set are only slightly larger than in the training set (differences of <0.1 kcal/mol). Therefore, it can be concluded that a simple "generic" force field with a limited number of specific torsional parameters can describe intra- and intermolecular interactions, although all comparison molecules were selected from our 82-compound training set. We also show how this effective two-body model can be extended for use with a nonadditive force field (NAFF), both with and without lone pairs. Without changing the torsional parameters, the use of more accurate charges and polarization leads to an increase in average absolute error compared with experiment, but adjustment of the parameters restores the level of agreement found with the additive model. After reoptimizing the psi, Phi torsional parameters in peptides using alanine dipeptide (6 conformational pairs) and alanine tetrapeptide (11 conformational pairs), the new model gives better energies than the Cornell et al. (J Am Chem Soc 1995, 117, 5179-5197) force field. The average absolute error of this model for high-level nb initio calculation is 0.82 kcal/mol for alanine dipeptide and tetrapeptide as compared with 1.80 kcal/mol for the Cornell et al. model. For nucleosides, the new model also gives improved energies compared with the Cornell et al. model. To optimize force field parameters, we developed a program called parmscan, which can iteratively scan the torsional parameters in a systematic manner and finally obtain the best torsional potentials. Besides the organic molecules in our test set, parmscan was also successful in optimizing the Psi, Phi torsional parameters in peptides to significantly improve agreement between molecular mechanical and high-level nb initio energies. (C) 2000 John Wiley & Sons, Inc.
The present study describes an investigation by fluorescence quenching, circular dichroism and UV-visible spectroscopy of the interaction between norfloxacin (NRF) and human serum albumin (HSA) in the presence of electromagnetic fields (EMFs). The results obtained from this study indicated that NRF had a strong ability to quench HSA at λex = 280 nm. In addition, a slight blue shift occurred, which suggested that the microenvironment of the protein became more hydrophobic after addition of NRF. The interaction between the NRF and HSA, whether in the absence or presence of an EMF, was considered to be a static quenching mechanism. Moreover, synchronous fluorescence demonstrated that the microenvironment around Trp became modified. Data of HSA-NRF in the presence of EMFs between 1 Hz–1 MHz confirmed the results of quenching and blue shifts. Corresponding Stern-Volmer plots were also drawn and the resultant Ksv and kq values were compared. Moreover, the binding parameters, including the number of binding sites, the binding constant and the distance, r, between donor and acceptor, were calculated based on Förster’s non-radiative energy transfer theory. According to far and near UV-CD, the formation of the complex caused changes of the secondary and tertiary structures of HSA. The obtained results are significant for patients who are subjected to high-frequency radiation as this was found to reduce the affinity of NRF to HSA.
Zinc complexes with the third-generation quinolone antibacterial drugs levofloxacin and sparfloxacin have been synthesized and characterized. The deprotonated quinolones act as bidentate ligands coordinated to zinc ion through the pyridone and a carboxylato oxygen atom. The crystal structures of [bis(aqua)bis(levofloxacinato)zinc(II)], 1, and [bis(sparfloxacinato)(1,10-phenanthroline)zinc(II)], 3, have been determined by X-ray crystallography. The biological activity of the complexes has been evaluated by examining their ability to bind to calf-thymus DNA (CT DNA) by UV spectroscopy and viscosity measurements. UV studies of the interaction of the complexes with DNA have revealed that they can bind to CT DNA probably by the intercalative binding mode which has also been verified by DNA solution viscosity measurements. The DNA binding constants have been also calculated. A competitive study with ethidium bromide (EB) showed that the complexes exhibit the ability to displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB for the intercalative binding site. The interaction of the complexes with human and bovine serum albumin proteins has been studied by fluorescence spectroscopy showing that the complexes exhibit good binding propensity to these proteins having relatively high binding constant values. The biological properties of the complexes have been evaluated in comparison to the previously reported Zn(II) complexes with the first- and second-generation quinolones oxolinic acid and enrofloxacin.
Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes for the treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and melanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects and intrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have entered clinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketing approval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individual nations. During this time there have been more failures than successes with the development of 14 drugs being halted during clinical trials. Currently there are four drugs in the various phases of clinical trial (satraplatin, picoplatin, Lipoplatin and ProLindac). No new small molecule platinum drug has entered clinical trials since 1999 which is representative of a shift in focus away from drug design and towards drug delivery in the last decade. In this perspective article we update the status of platinum anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued during clinical trials, and discuss the results in the context of where we believe the field will develop over the next decade.
Cobalt(II) complexes with the non-steroidal anti-inflammatory drug mefenamic acid in the presence or absence of nitrogen donor heterocyclic ligands (2,2'-bipyridine, 1,10-phenanthroline or pyridine) have been synthesized and characterized with physicochemical and spectroscopic techniques. The experimental data suggest that mefenamic acid acts as deprotonated monodentate ligand coordinated to Co(II) ion through a carboxylato oxygen. The crystal structures of tetrakis(methanol)bis-(mefenamato)cobalt(II), 1 and (2,2'-bipyridine)bis(methanol)bis(mefenamato)cobalt(II), 2 have been determined by X-ray crystallography. The EPR spectra of complexes 1 and 2 in frozen solution reveal that they retain their structures. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA and bis(methanol)bis(pyridine)bis-(mefenamato)cobalt(II) exhibits the highest binding constant. Competitive study with ethidium bromide (EB) has shown that the complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB. The cyclic voltammograms of the complexes recorded in dmso solution and in the presence of CT DNA in 1 : 2 dmso : buffer (containing 150 mM NaCl and 15 mM trisodium citrate at pH 7.0) solution have shown that they can bind to CT DNA by the intercalative binding mode. Mefenamic acid and its cobalt(II) complexes exhibit good binding propensity to human or bovine serum albumin protein having relatively high binding constant values. The antioxidant activity of the compounds has been evaluated indicating their high scavenging activity against hydroxyl free radicals and superoxide radicals.
There is a growing interest in structural studies of DNA by both experimental and computational approaches. Often, 3D-structural
models of DNA are required, for instance, to serve as templates for homology modeling, as starting structures for macro-molecular
docking or as scaffold for NMR structure calculations. The conformational adaptability of DNA when binding to a protein is
often an important factor and at the same time a limitation in such studies. As a response to the demand for 3D-structural
models reflecting the intrinsic plasticity of DNA we present the 3D-DART server (3DNA-Driven DNA Analysis and Rebuilding Tool). The server provides an easy interface to a powerful collection of tools for the generation of DNA-structural models
in custom conformations. The computational engine beyond the server makes use of the 3DNA software suite together with a collection
of home-written python scripts. The server is freely available at http://haddock.chem.uu.nl/dna without any login requirement.
Transcriptional regulation in papillomaviruses depends on sequence-specific binding of the regulatory protein E2 to several sites in the viral genome. Crystal structures of bovine papillomavirus E2 DNA targets reveal a conformational variant of B-DNA characterized by a roll-induced writhe and helical repeat of 10.5 bp per turn. A comparison between the free and the protein-bound DNA demonstrates that the intrinsic structure of the DNA regions contacted directly by the protein and the deformability of the DNA region that is not contacted by the protein are critical for sequence-specific protein/DNA recognition and hence for gene-regulatory signals in the viral system. We show that the selection of dinucleotide or longer segments with appropriate conformational characteristics, when positioned at correct intervals along the DNA helix, can constitute a structural code for DNA recognition by regulatory proteins. This structural code facilitates the formation of a complementary protein-DNA interface that can be further specified by hydrogen bonds and nonpolar interactions between the protein amino acids and the DNA bases.
Antifungal activity of new copper(II) complexes of 2-methylthionicotinate (2-MeSNic) of the composition Cu(2-MeSNic)2(MeNia)(2).4H2O (where MeNia is N-methylnicotinamide), and Cu(2-MeSNic)2(Nia)(2).2H2O (where Nia is nicotinamide) and Cu(2-MeSNic)2L2 (where L is isonicotinamide, iNia, or ethyl nicotinate, EtNic) were tested on various strains of filamentous fungi by the macrodilution method. Most sensitive against copper(II) adducts with bioactive ligands were Rhizopus oryzae and Microsporum gypseum (IC50 1.5-2.3 mmol/L). The adducts with Nia, MeNia and EtNic at 5 mmol/L induced morphological changes in growing hyphae of Botrytis cinerea, mainly their intensive branching attached to release of cytoplasm with partial growth inhibition. Inhibition of sporulation (> 90%) of Alternaria alternata by Cu(2-MeSNic)2.H2O was observed as a change in the color of the colonies. The highest resistance was marked by B. cinerea and Fusarium moniliforme (average IC50 values 4.25 and 3.13 mmol/L, respectively). The presence of all bioactive ligands in copper(II) complexes caused an increase in the inhibition effect against model fungi (except significant inhibition activity of EtNic on R. oryzae).
In this study, we present conformational energies for a molecular mechanical model (Parm99) developed for organic and biological molecules using the restrained electrostatic potential (RESP) approach to derive the partial charges. This approach uses the simple “generic” force field model (Parm94), and attempts to add a minimal number of extra Fourier components to the torsional energies, but doing so only when there is a physical justification. The results are quite encouraging, not only for the 34-molecule set that has been studied by both the highest level ab initiomodel (GVB/LMP2) and experiment, but also for the 55-molecule set for which high-quality experimental data are available. Considering the 55 molecules studied by all the force field models for which there are experimental data, the average absolute errors (AAEs) are 0.28 (this model), 0.52 (MM3), 0.57 (CHARMm [MSI]), and 0.43 kcal/mol (MMFF). For the 34-molecule set, the AAEs of this model versus experiment and ab initio are 0.28 and 0.27 kcal/mol, respectively. This is a lower error than found with MM3 and CHARMm, and is comparable to that found with MMFF (0.31 and 0.22 kcal/mol). We also present two examples of how well the torsional parameters are transferred from the training set to the test set. The absolute errors of molecules in the test set are only slightly larger than in the training set (differences of <0.1 kcal/mol). Therefore, it can be concluded that a simple “generic” force field with a limited number of specific torsional parameters can describe intra- and intermolecular interactions, although all comparison molecules were selected from our 82-compound training set. We also show how this effective two-body model can be extended for use with a nonadditive force field (NAFF), both with and without lone pairs. Without changing the torsional parameters, the use of more accurate charges and polarization leads to an increase in average absolute error compared with experiment, but adjustment of the parameters restores the level of agreement found with the additive model. After reoptimizing the Ψ, Φ torsional parameters in peptides using alanine dipeptide (6 conformational pairs) and alanine tetrapeptide (11 conformational pairs), the new model gives better energies than the Cornell et al. ( J Am Chem Soc 1995, 117, 5179–5197) force field. The average absolute error of this model for high-level ab initio calculation is 0.82 kcal/mol for alanine dipeptide and tetrapeptide as compared with 1.80 kcal/mol for the Cornell et al. model. For nucleosides, the new model also gives improved energies compared with the Cornell et al. model. To optimize force field parameters, we developed a program called parmscan, which can iteratively scan the torsional parameters in a systematic manner and finally obtain the best torsional potentials. Besides the organic molecules in our test set, parmscan was also successful in optimizing the Ψ, Φ torsional parameters in peptides to significantly improve agreement between molecular mechanical and high-level ab initio energies. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 1049–1074, 2000
In this paper, new copper(i) and copper(ii) complexes with phosphine derivatives of two fluoroquinolones (ciprofloxacin and norfloxacin) are presented. The synthesized compounds ([CuI-PCp], [CuI-PNr], [OPCp-CuII]+ and [OPNr-CuII]+) were characterized by elemental analysis and MS as well as by the NMR, EPR and IR spectroscopies. X-ray techniques were used to determine the crystal and molecular structures of [CuI-PCp]·CH2Cl2·CH3CN and OPCp-CuII]NO3·3H2O. For all the studied compounds, the ability to interact with DNA was determined using three different methods. The results of gel electrophoresis revealed that in the presence or absence of H2O2, the copper(i) complexes caused only single-stranded cleavage of the sugar-phosphate backbone of DNA. In turn, the copper(ii) complexes damaged the plasmid exclusively in the presence of the oxidant. The addition of H2O2 caused distinct changes in the plasmid structure, resulting in a complete disappearance of its native form. Forms II and III arising from single- and double-strand cleavage were detected. Studies of the interactions with calf thymus DNA in the presence of ethidium bromide (EB) showed that the tested complexes and phosphines interact with DNA in a partial intercalation mode, contrary to unmodified antibiotic and oxide derivatives, which do not displace EB from the system. Molecular docking (AutoDock Vina program) was performed using the synthetic double-stranded hexadecanucleotide (sequence: ATATCGCGATATCGCG). Data analysis showed that a majority of the compounds preferably bound to the minor or major grooves, however most of them were also able to intercalate with the DNA double helix.
In this paper we present new copper(I) iodide or copper(I) thiocyanate complexes with hydroxymethyldiphenylphosphine (PPh2(CH2OH)) or phosphine derivative of sparfloxacin, a 3rd generation fluoroquinolone antibiotic agent (PPh2(CH2-Sf)) and 2,9-dimethyl-1,10-phenanthroline (dmp) or 2,2’-biquinoline (bq) auxiliary ligands. The synthesized complexes were fully characterized by NMR and UV-Vis spectroscopies as well as by mass spectrometry. Selected structures were additionally analyzed by X-ray and DFT methods. All complexes proved to be stable in solution in the presence of water and atmospheric oxygen for several days. Cytotoxic activity of the complexes was tested against two cancer cell lines (CT26 - mouse colon carcinoma and A549 - human lung adenocarcinoma). The studies applying two different incubation times enabled preliminary estimation of the dependence of selectivity and mechanism of action on the type of diimine and phosphine ligands. The obtained results showed that the complexes with PPh2(CH2-Sf) are significantly more active than those with PPh2(CH2OH). On the other hand, the relative impact of diimine on cytotoxicity is less pronounced. However the dmp complexes are characterized by the strong inhibitory properties, while the bq ones are rather not. This confirms the interesting and promising biological properties of the investigated group of copper(I) complexes, which undoubtedly are worth of further biological studies.
We synthesized two derivatives of sparfloxacin (HSf): aminomethyl(diphenyl)phosphine (PSf) and its oxide (OPSf). The compounds were characterized by NMR spectroscopy, MS and elemental analysis. In addition, the molecular structures of the compounds were determined using DFT and X-ray (OPSf) analysis. The antibacterial activity of HSf and both derivatives was tested against four reference and fifteen clinical Gram-positive and Gram-negative strains of bacteria (sensitive or resistant to fluoroquinolones). The results showed that the activity of PSf was similar to or higher than the activity of HSf, while OPSf was found significantly less active. The compounds were also tested in vitro toward the following cancer cell lines: mouse colon carcinoma (CT26) and human lung adenocarcinoma (A549). Regardless of the cancer cell line, derivatization of HSf resulted in the gradual increase of cytotoxicity. OPSf exhibited the highest one (4 h - incubation time: IC50(CT26) = 51.0 ± 1.2; IC50(A549) = 74.9 ± 1.4 and 24 h: IC50(CT26) = 109.2 ± 8.8; IC50(A549) = 52.7 ± 9.2).
Non-viral gene delivery vectors are acquiring greater attention in the field of gene therapy by replacing the biological viral vectors. DNA-cationic polymer complexes are one of the most promising systems to find application in gene therapy. Hence, a complete insight of their biophysical characterization and binding energy profile is important in understanding the mechanism involved in non viral gene therapy. In this investigation, the interaction between calf thymus DNA (ctDNA) and imidazolium-based poly(ionic liquids) (PILs) also known as polyelectrolytes with three different alkyl side chains (ethyl, butyl and hexyl) in physiological conditions using various spectroscopic experiments with constant DNA concentration and varying polyelectrolyte concentrations is reported. UV-Visible absorption, fluorescence quenching studies, gel electrophoresis, circular dichroism (CD) and Fourier transform infrared spectroscopy (FTIR) have confirmed the binding of polyelectrolytes with DNA. UV-Vis absorption measurements and fluorescence quenching revealed that the binding between DNA and polyelectrolyte is dominated by electrostatic interactions. Additionally, CD and FTIR results indicated that the DNA retained its B-form with minor perturbation in the phosphate backbone without significant change in the conformation of its base pairs. Preference for alkyl side chains (KPIL-Ethyl Br < KPIL -Butyl Br < KPIL -Hexyl Br) towards efficient binding between polyelectrolyte and DNA was inferred from the binding and quenching constants calculated from the absorption and emission spectra, respectively. Further, in silico molecular docking studies not only validated the observed binding trend but also provided insight into the binding mode of the polyelectrolyte-DNA complex.
The research on copper(I,II) coordination compounds as antiproliferative agents has increased as demonstrated by the high number of papers published in this field in the period 2008-2012. The first consideration which stems from the presented data concerns the large variety of ligands used to synthesize potentially active copper drugs. The reported copper complexes (mostly copper(II)) comprised ligands of different hapticity, from monodentate to hexadentate, and characterized by different donor atoms (O, N, S, P, and C) which gave rise to different geometrical arrangements and, in some cases, dimeric and polymeric species. Regarding the copper oxidation state, there is no direct correlation between the antiproliferative activity and reduced or oxidized forms of the metal. However, the few reported copper(I) complexes, featured by phosphine or heterocyclic carbene ligands generally showed a potent cytotoxic activity. Most of the studies with copper complexes continue to consider DNA as the main biological target.
Cuprous bis-phenanthroline compounds possess metal-to-ligand charge transfer, MLCT, excited states. Phenanthroline ligands coordinated to Cu(I) that are disubstituted in the 2- and 9-positions with alkyl or aryl groups, abbreviated CuI(phen′)2+, have long-lived excited states at room temperature. The parent CuI(phen)2+ compound is non-emissive under the same conditions with a short excited state lifetime, τ<10 ns. Disubstitution in the 2,9-positions stabilizes the Cu(I) state and increases the energy gap between the MLCT and the ground state. The prototypical and most well studied compound is CuI(dmp)2+, where dmp is 2,9-(CH3)2-1,10-phenanthroline. In dichloromethane solution at room temperature, CuI(dmp)2+ displays broad MLCT absorption with λmax=454 nm, a broad unstructured emission with λmax=730 nm, and an excited state lifetime of 85 ns. The emission arises from two closely spaced MLCT excited states, separated in energy by 1800 cm−1, that behave as one state at room temperature. CuI(dmp)2+* excited states are quenched in the presence of Lewis bases and coordinating solvents. A 5-coordinate excited state complex, or exciplex, is proposed to account for temperature dependent quenching data. The substantial inner-sphere reorganizational energy changes that follow light excitation are novel features of these MLCT excited states. This review attempts to cover all the existing data reported on CuI(phen′)2+ excited states and contrast it with well-known MLCT behavior of (dπ)6 transition metal compounds.
Here, we report the antiproliferative/cytotoxic properties of 8-hydroxyquinoline (8-HQ) derivatives on HeLa cells in the presence of transition metal ions (Cu2+, Fe3+, Co2+, Ni2+). Two series of ligands were tested, the arylvinylquinolinic L1-L8 and the arylethylenquinolinic L9-L16, which can all interact with metal ions by virtue of the N,O donor set of 8-HQ; however, only L9-L16 are flexible enough to bind the metal in a multidentate fashion, thus exploiting the additional donor functions. L1-L16 were tested for their cytotoxicity on HeLa cancer cells, both in the absence and in the presence of copper. Among them, the symmetric L14 exhibits the highest differential activity between the ligand alone (IC50 = 23.7 μM) and its copper complex (IC50 =1.8 μM). This latter, besides causing a significant reduction of cell viability, associates to a considerable accumulation of the metal inside the cells. Metal accumulation is also observed when the cells are incubated with L14 complexed with other late transition metal ions (Fe3+, Co2+, Ni2+), although the biological response of HeLa cells is different. In fact, while Ni/L14 and Co/L14 exert a cytostatic effect, both Cu/L14 and Fe/L14 trigger a caspase-independent paraptotic process, that results from the induction of a severe oxidative stress and the unfolded protein response.
AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user.
Novel tetrahedral copper(I) mixed-ligand complexes of the type [Cu(X)(N∩N)(PCN)] 3-10, where X = Cl, Br; N∩N = 2,2'-bipyridine (bipy), 1,10-phenantroline (phen), 5,6-dimethyl-1,10-phenantroline (dmp) and dipyrido-[3,2-d:2',3'-f]-quinoxaline (dpq); PCN = tris-(2-cyanoethyl)phosphine have been synthetized and characterized by NMR, ESI-MS and X-ray diffraction on two representative examples, [CuCl(phen)(PCN)].DMF, 5.DMF and [CuBr(dpq)(PCN)].2DMF, 10.2DMF. Cu(I) complexes were evaluated for their in vitro antitumor properties against a panel of human cancer cell lines, including cisplatin and multi-drug resistant sublines. The most effective complex [CuCl(dpq)(PCN)], 9 exhibited nanomolar cytotoxicity towards both sensitive and resistant cancer cells but it significantly inhibited the growth of cultured normal cells. In vitro DNA assays and single cell gel electrophoresis revealed that 9 induced DNA fragmentation resulting in cell apoptosis. In parallel, FISH micronucleus assay attested high levels of genotoxicity following treatment of peripheral blood lymphocytes with complex 9, suggesting to carefully reconsider the potential risk posed by diimine metal complexes.
Herein, a series of CuI or CuNCS complexes with neocuproine (2,9-dimethyl-1,10-phenanthroline: dmp) and two tris(aminomethyl)phosphines derived from morpholine (P(CH2 N(CH2 CH2 )2 O)3 ) or thiomorpholine (P(CH2 N(CH2 CH2 )2 S)3 ) were tested as cytotoxic agents in vitro towards mouse colon carcinoma (CT26) and human lung adenocarcinoma (A549). The studies showed that the complexes exhibit potential antitumor properties, displayed by IC50 values below 10 μM towards the tested cell lines, in the case of 4 h incubation time with the examined compounds. Moreover a high antimicrobial activity of all the complexes was observed against S. aureus and C. albicans with MICs equal to 1-2 μg/ml. To gain insight into the molecular mechanism of biological activity of the complexes we investigated also their interactions with plasmid DNA (pUC18) and the human and bovine serum albumins (HSA and BSA, respectively). Gel electrophoresis experiments demonstrated that all the compounds were comparably efficient in DNA degradation process, however luminescence quenching showed surprising dependence on the interactions strength of the used compounds with the albumins. Apart from exceptionally effective [CuI(dmp)P(CH2 N(CH2 CH2 )2 O)3 ], the complexes with P(CH2 N(CH2 CH2 )2 O)3 quenched more strongly luminescence of BSA, while the complexes with P(CH2 N(CH2 CH2 )2 S)3 were more active in the quenching of HSA luminescence. This article is protected by copyright. All rights reserved.
The copper(i) iodide or copper(i) isothiocyanate complexes with 2,9-dimethyl-1,10-phenanthroline (dmp) and two interesting aminomethylphosphanes: P(CH2N(CH2CH2)2O)3 (1) and novel P(CH2N(CH2CH2)2S)3 (2): CuI(dmp)P(CH2N(CH2CH2)2O)3 (1I), which was presented in our previous papers, CuI(dmp)P(CH2N(CH2CH2)2S)3 (2I), CuNCS(dmp)P(CH2N(CH2CH2)2O)3 (1T) and CuNCS(dmp)P(CH2N(CH2CH2)2S)3 (2T) are discussed in this work. The chemical structures of three new complexes were determined in solution by means of NMR spectroscopy and in solid state using X-ray measurements. For all presented complexes the coordination geometry about the Cu(i) centre is pseudo-tetrahedral showing the small flattening and large rocking distortions. All compounds crystallize as the discrete dimers bound by [small pi]-stacking interactions between dmp rings, which strongly depend on the phosphane ligand. Investigated complexes exhibit orange photoluminescence in the solid state of highly diversified intensity, position of the luminescence band and the lifetimes. On the basis of TDDFT calculations, the CT bands observed in UV-Vis spectra are assigned to the two mixed transitions from the CuX (X = I or NCS) bond with a small admixture of the CuP bond to [small pi]* orbitals of the dmp ligand: (MX,MPR3)LCT. However, emission bands can be interpreted to be of (MX)LCT type.
A novel bulky phosphine derived from 2-piperazinopyridine P(CH2N(CH2CH2)2N-2-py)3 (1) and its chalcogenide derivatives (oxide, sulphide and selenide) have been synthesized and characterized by elemental analysis as well as NMR and mass spectra. Next, two new copper(I) iodide or isothiocyanate complexes with 1 and 2,9-dimethyl-1,10-phenanthroline (dmp) [CuI(dmp)(1)] (1I) and [CuNCS(dmp)(1)] (1T), have been also synthesized and characterized by elemental analysis and studied by NMR, mass, UV–Vis, IR and luminescence spectroscopies. The X-ray structure of the complex 1T•1.81(CH3COCH3) was determined. The coordination geometry about the Cu(I) centre is pseudo-tetrahedral with distortions resulting mostly from the molecular packing in the crystal cell. Both complexes exhibit orange photoluminescence in the solid state, which is much stronger for 1I than for 1T. Surprisingly, the luminescence spectra of both complexes at room and LN temperatures show large, composite bands with unprecedentedly small batochromic shift and negligible narrowing accompanying the temperature decrease. On the basis of TDDFT calculations we interpreted these bands as of (MX,MPR3)LCT type resulting mainly from the transitions from the copper – iodine (or isothiocyanate) bonds and a small admixture of copper-phosphine bonds to antibonding orbitals of dmp diimine.
The use of metal-organic complexes is a potentially fruitful approach for the development of novel enzyme inhibitors. They hold the attractive promise of forming stronger attachments with the target by combining the co-ordination ability of metals with the unique stereoelectronic properties of the ligand. We demonstrated that this approach can be successfully used to inhibit the protease of the human immunodeficiency virus (type 1). Several ligands bearing substituents designed to interact with the catalytic site of the enzyme when complexed to Cu2+ were synthesised. The inhibition pattern of the resulting copper(II) complexes was analysed. We showed that the copper(II) complex of N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide (C1) interacts with the active site of the enzyme leading to competitive inhibition. On the other hand, N2-pyridine-amide ligands and oxazinane carboxamide ligand were found to be poor chelators of the cupric ion under the enzymatic assay conditions. In these cases, the observed inhibition was attributed to released cupric ions which react with cysteine residues on the surface of the protease. While unchelated metal cations are not likely to be useful agents, metal chelates such as C1 should be considered as promising lead compounds for the development of targeted drugs.
The interaction of copper(II/I) complexes of a few 2,9-dimethyl-1,10-phenanthrolines with calf thymus DNA has been investigated using absorption and circular dichroic spectral and electrochemical techniques and viscometry. The observation of the usual hypochromism and the novel hyperchromism in the absorption spectra of [Cu-I(bcp)(2)](+) [bcp = 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline] and [Cu-I(dpsmp)(2)](3-)[dpsmp(2-)=2,9-dimethyl-4,7-bis(sulfonatophenyl)-1,10-phenanthroline] respectively in the presence of DNA and the increase in viscosity of DNA at low loadings of both these complexes have been interpreted in terms of bridging of a pair of DNA duplexes by the complex species. These tetrahedral copper(I) complexes, which lack minor groove binding because of substituents at the 4- and 7-positions of phen ring, are efficient in bridging the duplexes. The electrochemical behaviors of [Cu-I(dmp)(2)](+) [dmp = 2,9-dimethyl-1,10-phenanthroline] and [Cu-I(bcp)(2)](+) bound to DNA have been compared with that of the analogous sulfonated complex [CU(dpsmp)(2)](2-/3-). The DNA binding constants determined reveal that dpsmp(2-) complex is engaged in DNA binding less intimately than the bcp complex. While Coulombic interactions are clearly more important than other types of interactions for the former, nonclassical hydrophobic interactions for the latter. The Hill analysis of the absorbance data obtained as a function of added DNA reveals Hill coefficients greater than unity, which may be construed as evidence for cooperative binding of the copper complexes to B-DNA.
A novel water and air stable copper(I) complex, [CuI(2,2′-biquinoline)P(CH2N(CH2CH2)2O)3] (1bq), was synthesized and characterized by means of 1H, 13C{1H} and 31P{1H} NMR, ESI-MS and elemental analysis. The X-ray structure of 1bq shows that the coordination geometry about the Cu(I) center is pseudo-tetrahedral. 1bq was assayed for antibacterial (Escherichia coli – a Gram-negative rod and Staphylococcus aureus – a Gram-positive coccus) and antifungal (Candida albicans) activities. The activity of 1bq was lower than that of [CuI(2,9-dimethyl-1,10-phenanthroline)P(CH2N(CH2CH2)2O)3] (1N). 1bq also showed significantly lower cytotoxicity than 1N on MSC (mesenchymal stem cells) culture and the RK-13 cell line. Both 1bq and 1N complexes bind to HSA and BSA albumins in site I located in subdomain IIA, however 1bq interacts less strongly with these albumins than 1N. Surprisingly, investigation of the interactions of the studied complexes with pUC18 plasmid showed a comparable effectiveness of 1N and 1bq for DNA cleavage.
This study reports the structure-activity relationship of a series of 8-hydroxoquinoline derivatives (8-HQs) and focuses on the citotoxic activity of 5-Cl-7-I-8-HQ (clioquinol, CQ) copper complex (Cu(CQ)). 8-HQs alone caused a dose-dependent loss of viability of the human tumor HeLa and PC3 cells, but the coadministration of copper increased the ligands effects, with extensive cell death occurring in both cell lines. Cytotoxic doses of Cu(CQ) promote intracellular copper accumulation and extensive endoplasmic reticulum vacuolization that precede a non-apoptotic (paraptotic) cell death. The cytotoxic effect of Cu(CQ) was reproduced in normal human endothelial cells (HUVEC) at concentrations double than those effective in tumor cells, pointing to a potential therapeutic window for Cu(CQ). Finally, the results showed that the paraptotic cell death induced by Cu(CQ) does not require nor involve caspases, giving an indication for the current clinical assessment of clioquinol as an antineoplastic agent.
By combining absorption and light-scattering spectroscopy, including photon correlation and angular distribution of absolute scattered intensity, we have studied the modes of ethidium bromide binding to calf thymus DNA at constant temperature and pH. It is found that the fraction of total bound dye molecules per nucleotide, (T)theta(D), is dependent on the counterion concentration, C(S). (T)theta(D) decreases slightly as C(S) is raised. Furthermore, the data indicate two modes of dye binding: intercalation and outside binding. The analysis of the Scatchard plots by Manning's polyelectrolyte theory of site-binding equilibria suggests (1) (I)theta(D), the fraction of intercalated dye molecules per nucleotide, increases continually with (T)theta(D), (2) over the experimental accessible range of (T)theta(D), intercalation is the stronger mode of binding, and (3) dye binding appears to be saturated when (I)theta(D) almost-equal-to (T)theta(D). The light-scattering measurements gave useful data for the DNA radius of gyration, [S]z, the DNA radius of hydration, Rh, the second virial coefficient, A2, and the DNA translational diffusion coefficient, D(z,0). These data were analyzed in terms of the wormlike chain and the sliding rod model. It is found that each intercalated EBr molecule adds a length of 0.27 nm to the total contour length of CT-DNA. Interestingly, the DNA persistence length of bending, l(p), is smaller in the presence than in the absence of EBr This indicates that dye binding reduces the DNA rigidity due to a neutralization of phosphate groups. Finally, it was shown that the angular dependence of the apparent diffusion coefficient, D(app)(q2), is well simulated by the Rouse-Zimm polymer model comprised of a number of subchains and an apparent subchain diffusion coefficient D(plat) that scales as T/eta. In particular, it is found that the Rouse-Zimm subchain extension, (RZ)b(S), is twice the effective persistence length, l(p,eff), which is the weighted sum of the persistence length due to bending, twisting, and contraction/extension. A further result is that the ionic strength dependence of l(p) can be well described by Manning's theory of territorial counterion binding and that a process such as spontaneous transient opening of DNA base pairs becomes important, if at all, when the ionic strength tends to zero.
An experiment that consists of an introduction to the fluorescence technique with a concomitant illustration of relevant aspects of protein structure. Keywords (Audience): Upper-Division Undergraduate
Recent research suggests that anti-cancer drugs which intercalate into DNA interfere with the action of topoisomers when they bind to nuclear DNA, causing DNA breakage, chromosome damage and sister-chromatid exchange in cells. The cytotoxic action of these drugs appears to result from actual chromosome breakage, although alternative modes of action have not been ruled out. Cells in late S or early G2 phase of the cell cycle are most susceptible to DNA intercalators while non-replicating cells are much more resistant. It is not yet clear whether mutagenic potential is a necessary attribute for anti-cancer action.
Two novel dinuclear palladium(II) complexes, {[Pd(en)Cl]2(bpse)}(NO3)2 (1) and {[Pd(en)Cl]2 (bpsu)}(NO3)2 (2), (where en is ethylenediamine; bpse is bis(3-methyl-4-pyridyl) selenide; bpsu is bis(3-methyl-4-pyridyl) sulfide) have been synthesized. The complexes have been characterized by elemental analysis, IR, 1H NMR, and 13C NMR. They have been assayed for antitumor activity in vitro against the mice leukemia L1210 and the human coloadenocarcinoma HCT8 cell lines. The results show that compound 1 has a lower I.D.50 value against the two cancer cell lines as compared to compound 2; the compounds also shows a lower I.D.50 value than cisplatin against the HCT8 cell line, but a higher I.D.50 value than cisplatin against the L1210 cell line. Binding studies indicate that compound 1 possibly interacts with DNA by a nonintercalative mode. Kinetics of binding of the two compounds to DNA are firstly studied using ethidium bromide as a fluorescence probe with stopped-flow spectrophotometer under pseudo-first-order condition. The stronger binding of two steps in the process of the compounds interacting with DNA are observed, and the kobs and Ea of binding of the two steps (where kobs is the observed pseudo-first-order rate constant, Ea is the observed energy of activation) are obtained.
The proposed curative properties of Cu-based non-steroidal anti-inflammatory drugs (NSAIDs) have led to the development of numerous Cu(II) complexes of NSAIDs with enhanced anti-inflammatory activity and reduced gastrointestinal (GI) toxicity compared with their uncomplexed parent drug. These low toxicity Cu drugs have yet to reach an extended human market, but are of enormous interest, because many of today's anti-inflammatory drug therapies, including those based on the NSAIDs, remain either largely inadequate and/or are associated with problematic renal, GI and cardiovascular side effects. The origins of the anti-inflammatory and gastric-sparing actions of Cu-NSAIDs, however, remain uncertain. Their ability to influence copper metabolism has been a matter of debate and, apart from their frequently reported superoxide dismutase (SOD)-like activity in vitro, relatively little is known about how they ultimately regulate the inflammatory process and/or immune system. Furthermore, little is known of their pharmacokinetic and biodistribution profile in both humans and animals, stability in biological media and pharmaceutical formulations, or the relative potency/efficacy of the Cu(II) monomeric versus Cu(II) dimeric complexes. The following review will not only discuss the etiology of inflammation, factors influencing the metabolism of copper and historical overview of the development of the Cu-NSAIDs, but also outline the structural characteristics, medicinal and veterinary properties, and proposed modes of action of the Cu-NSAIDs. It will also compare the SOD, anti-inflammatory and ulcerogenic effects of various Cu-NSAIDs. If the potential opportunities of the Cu-NSAIDs are to be completely realized, a mechanistic understanding and delineation of their in vivo and in vitro pharmacological activity is fundamental, along with further characterization of their pharmacokinetic/pharmacodynamic disposition.
Homoleptic copper(I) bis(2,9-dialkyl-1,10-phenanthroline) units, as well as a range of related heteroleptic species, represent popular choices for building blocks in the construction of supramolecular edifices and photo- and electroactive devices. The photophysical properties of these traditionally underperforming luminescent complexes can be dramatically modified in a qualitatively predictable fashion through ligand design, the use of bichromophoric ligands, and by reconstitution of the primary coordination sphere. An overview of key excited-state processes established in these complexes is presented, with particular emphasis on recent developments and insights, as well as ramifications for developing successful strategies to prolong luminescence lifetimes and increase quantum yields.
The mixed-chelate copper(II) complexes Casiopeínas® have been tested in several models in vitro and in vivo, showing promising antitumoral results. However, their mechanism of action remains to be defined. Trying to get a deeper insight into their molecular mode of action, further analyses, including gel electrophoresis, atomic force microscopy and circular dichroism were carried out to study their interaction with DNA and some cytoskeleton proteins. Our results revealed that the interaction of Casiopeínas triggers DNA cleavage by a free radical mechanism. The tested complexes showed a differential response to reducing and scavenger agents. Differences on target preference were also evident using double stranded oligonucleotides as sequence competitors. Surprisingly, distamycin A, a minor groove binder, enhanced the Casiopeínas' action on DNA. On the other hand, the tested Casiopeínas produce strong changes in protein structure of tubulin, integrin and fibronectin. All together these results suggest a multiple mode of action for these metal-based drugs. In addition, since it has been proposed that antitumor drugs efficiently interacting with DNA could also show activity against Trypanosoma cruzi, etiologic agent of Chagas disease, we evaluated the activity of these compounds on this protozoan parasite. The tested complexes showed in vitro anti-T. cruzi activity similar to the anti-trypanosomal reference drug Nifurtimox.
The nickel(II) complexes with the quinolone antibacterial agents oxolinic acid, flumequine, enrofloxacin and sparfloxacin in the presence of the N,N'-donor heterocyclic ligand 2,2'-bipyridylamine have been synthesized and characterized. The quinolones act as bidentate ligands coordinated to Ni(II) ion through the pyridone oxygen and a carboxylato oxygen. The crystal structure of [(2,2'-bipyridylamine)bis(sparfloxacinato)nickel(II)] has been determined by X-ray crystallography. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that they bind to CT DNA with [(2,2'-bipyridylamine)bis(flumequinato)nickel(II)] exhibiting the highest binding constant to CT DNA. The cyclic voltammograms of the complexes have shown that in the presence of CT DNA the complexes can bind to CT DNA by the intercalative binding mode which has also been verified by DNA solution viscosity measurements. Competitive study with ethidium bromide (EB) has shown that the complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB. The complexes exhibit good binding propensity to human or bovine serum albumin protein having relatively high binding constant values. The biological properties of the [Ni(quinolonato)(2)(2,2'-bipyridylamine)] complexes have been evaluated in comparison to the previously reported Ni(II) quinolone complexes [Ni(quinolonato)(2)(H(2)O)(2)], [Ni(quinolonato)(2)(2,2'-bipyridine)] and [Ni(quinolonato)(2)(1,10-phenanthroline)]. The quinolones and their Ni(II) complexes have been tested for their antioxidant and free radical scavenging activity. They have been also tested in vitro for their inhibitory activity against soybean lipoxygenase.
Basis sets are some of the most important input data for computational models in the chemistry, materials, biology, and other science domains that utilize computational quantum mechanics methods. Providing a shared, Web-accessible environment where researchers can not only download basis sets in their required format but browse the data, contribute new basis sets, and ultimately curate and manage the data as a community will facilitate growth of this resource and encourage sharing both data and knowledge. We describe the Basis Set Exchange (BSE), a Web portal that provides advanced browsing and download capabilities, facilities for contributing basis set data, and an environment that incorporates tools to foster development and interaction of communities. The BSE leverages and enables continued development of the basis set library originally assembled at the Environmental Molecular Sciences Laboratory.
Platinum anticancer drugs have been used for three decades despite their serious side effects and the emerging of resistance phenomena. Recently, a phosphine copper(I) complex, [Cu(thp)(4)][PF(6)] (CP), gained special attention because of its strong antiproliferative effects. CP killed human colon cancer cells more efficiently than cisplatin and oxaliplatin and it overcame platinum drug resistance. CP preferentially reduced cancer cell viability whereas non-tumour cells were poorly affected. Colon cancer cells died via a programmed cell death whose transduction pathways were characterized by the absence of hallmarks of apoptosis. The inhibition of 26S proteasome activities induced by CP caused intracellular accumulation of polyubiquitinated proteins and the functional suppression of the ubiquitin-proteasome pathway thus triggering endoplasmic reticulum stress. These data, providing a mechanistic characterization of CP-induced cancer cell death, shed light on the signaling pathways involved in paraptosis thus offering a new tool to overcome apoptosis-resistance in colon cancer cells.
Hydrophilic, monocationic [M(L)(4)]PF(6) complexes (M = Cu or Ag; L: thp = tris(hydroxymethyl)phosphine, L: PTA = 1,3,5-triaza-7-phosphaadamantane, L: thpp = tris(hydroxypropyl)phosphine) were synthesized by ligand exchange reaction starting from [Cu(CH(3)CN)(4)]PF(6) or AgPF(6) precursors at room temperature in the presence of an excess of the relevant phosphine. The related [Au(L)(4)]PF(6) complexes (L = thp, PTA or thpp) were synthesized by metathesis reactions starting from [Au(L)(4)]Cl at room temperature in the presence of equimolar quantity of TlPF(6). The three series of complexes [M(L)(4)]PF(6) were tested as cytotoxic agents against a panel of several human tumour cell lines also including a defined cisplatin resistant cell line. These investigations have been carried out in comparison with the clinically used metallodrug cisplatin and preliminary structure-activity relationships are presented. The best results in terms of in vitro antitumour activity were achieved with metal-thp species and, among the coinage metal complexes, copper derivatives were found to be the most efficient drugs. Preliminary studies concerning the mechanism of action of these [M(L)(4)]PF(6) species pointed to thioredoxin reductase as one of the putative cellular targets of gold and silver complexes and provided evidence that copper derivatives mediated their cytotoxic effect through proteasome inhibition.
The nickel(II) complexes with the second-generation quinolone antibacterial agent enrofloxacin in the presence or absence of the nitrogen-donor heterocyclic ligands 1,10-phenanthroline, 2,2'-bipyridine or pyridine have been synthesized and characterized. Enrofloxacin acts as bidentate ligand coordinated to Ni(II) ion through the ketone oxygen and a carboxylato oxygen. The crystal structure of (1,10-phenanthroline)bis(enrofloxacinato)nickel(II) has been determined by X-ray crystallography. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that they bind to CT DNA and bis(pyridine)bis(enrofloxacinato)nickel(II) exhibits the highest binding constant to CT DNA. The cyclic voltammograms of the complexes have shown that in the presence of CT DNA the complexes can bind to CT DNA by the intercalative binding mode which has also been verified by DNA solution viscosity measurements. Competitive study with ethidium bromide (EB) has shown that the complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB. The complexes exhibit good binding propensity to human or bovine serum albumin protein having relatively high binding constant values. The biological properties of the complexes have been evaluated in comparison to the corresponding Zn(II) enrofloxacinato complexes as well as Ni(II) complexes with the first-generation quinolone oxolinic acid.
Ciprofloxacin is an antibiotic that belongs to fluoroquinoles, characterized by broad spectrum of action against pathogens, especially Gram(-) aerobic bacilli. For a long time, it has been thought that ciprofloxacin has an effect only on bacterial cells. Now it is known, that this drug can significantly affect eukaryotic cells including human cancer cells. Its bactericidal action relay on inhibition of topoisomerase II, enzyme responsible for alterations in 3D structure of DNA during replication, transcription and chromatin condensation. Thanks to that, ciprofloxacin can induce cell cycle arrest and apoptosis of cancer cells. The effectiveness of ciprofloxacin was confirmed in several in vitro studies on tumor cell lines such as: human bladder cells, leukaemic cell lines, human osteosarcoma cells, human prostate cancer cells, human colorectal carcinoma cells and human non-small cell lung cancer cell line. Ciprofloxacin is particularly effective against non-small cell lung cancer mainly due to accumulation of ciprofloxacin in lung tissue after intravenous administration and its toxicity against lung cancer lines in vitro in a concentration and time-dependent manner.
We report here that dimethylsulfoxide (DMSO): suppresses radiation-induced transformation in vitro, even when DMSO treatments begin as late as 10 days post-irradiation (when cells are in the confluent, stationary phase of growth); inhibits the 12-O-tetradecanoylphorbol-13-acetate (TPA) enhancement of radiation-induced transformation in vitro; does not affect the expression of transformed cells as foci (when surrounded by non-transformed cells); and may be affecting radiation-induced transformation through its solvent properties (i.e. the 'Water Structure' theory), while its effects on the TPA enhancement of radiation transformation may be mediated by its free radical scavenging abilities. DMSO, dimethylformamide (DMF) and dimethylacetamide (DMA) are similar solvents which are all very effective in their ability to suppress radiation-induced transformation in vitro (at concentrations in the cellular media down to 0.01%). As DMSO is known to be an extremely effective OH. free-radical scavenging agent, while DMF and DMA are not as efficient at scavenging free radicals, our results suggest that properties other than free-radical scavenging ability may be important in the suppressive effects of these compounds on radiation-induced transformation in vitro. It is known that low concentrations of such basic aprotic solvents modify water structure so as to suppress the protic (H-bond donor) reactivity of water and enhance its basic (H-bond receptor) reactivity. These reactivity changes may well be responsible for the effects noted above. DMSO, DMF and DMA are also capable of suppressing the TPA enhancement of radiation transformation (at concentrations of the compounds of 0.1% or higher). For this effect, the ability of these compounds to scavenge OH. shows a general correlation with their ability to suppress the TPA enhancement of transformation, suggesting that the 'Radical Scavenger' theory may explain the ability of DMSO to suppress promotion in vitro.
The RNA genomes of a number of pathogenic RNA viruses, such as HIV-1, have extensive folded conformations with imperfect A-form duplexes that are essential for virus function and could serve as targets for structure-specific antiviral drugs. As an initial step in the discovery of such drugs, the interactions with RNA of a wide variety of compounds, which are known to bind to DNA in the minor groove, by classical or by threading intercalation, have been evaluated by thermal melting and viscometric analyses. The corresponding sequence RNA and DNA polymers, poly(A).poly(U) and poly(dA).poly(dT), were used as test systems for analysis of RNA binding strength and selectivity. Compounds that bind exclusively in the minor groove in AT sequences of DNA (e.g., netropsin, distamycin, and a zinc porphyrin derivative) do not have significant interactions with RNA. Compounds that bind in the minor grove in AT sequences of DNA but have other favorable interactions in GC sequences of DNA (e.q., Hoechst 33258, DAPI, and other aromatic diamidines) can have very strong RNA interactions. A group of classical intercalators and a group of intercalators with unfused aromatic ring systems contain compounds that intercalate and have strong interactions with RNA. At this time, no clear pattern of molecular structure that favors RNA over DNA interactions for intercalators has emerged. Compounds that bind to DNA by threading intercalation generally bind to RNA by the same mode, but none of the threading intercalators tested to date have shown selective interactions with RNA.
Electronic absorbance and fluorescence titrations are used to probe the interaction of chlorobenzylidine with DNA. The binding of chlorobenzylidine to DNA results in hypochromism, a small shift to a longer wavelength in the absorption spectra, and emission quenching in the fluorescence spectra. These spectral characteristics suggest that chlorobenzylidine binds to DNA by an intercalative mode. This conclusion is reinforced by fluorescence polarization measurements. Scatchard plots constructed from fluorescence titration data give a binding constant of 1.3 x 10(5) M(-1) and a binding site size of 10 base pairs. This indicates that chlorobenzylidine has a high affinity with DNA. The intercalative interaction is exothermic with a Van't Hoff enthalpy of -143 kJ/mol. This result is obtained from the temperature dependence of the binding constant. The interaction of chlorobenzylidine with DNA is affected by the pH value of the solution. The binding constant has its maximum at pH 3.0. Upon binding to DNA, the fluorescence from chlorobenzylidine is quenched efficiently by the DNA bases and the fluorescence intensity tends to be constant at high concentrations of DNA when the binding is saturated. The Stern-Volmer quenching constant obtained from the linear quenching plot is 1.6 x 10(4) M(-1) at 25 degrees C. The measurements of the fluorescence lifetime and the dependence of the quenching constant on the temperature indicate that the fluorescence quenching process is static. The fluorescence lifetime of chlorobenzylidine is 1.9 +/- 0.4 ns.