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Fast Hydrolysis and Strongly Basic Water Adducts Lead to Potent Os(II) Half-Sandwich Anticancer Complexes
Abstract and Figures
Complexes of the formula [Os(η6-arene)(C,N-phenylpyridine)Z] (where Z is chlorido or a tethered oxygen) undergo very fast Os-Z hydrolysis (<5 min), and the high basicity of the coordinated water molecule of the aqua adducts (Os-OH2; pKa > 8) very much contrasts with previously reported Os-aqua adducts bearing NN- and NO-chelating ligands (pKa < 6). The Os-Cl bond is unreactive in pure DMSO, yet the complexes readily form DMSO adducts upon aquation when dimethyl sulfoxide is present. Such a peculiar aqueous behavior is directly related to the negatively charged CN ligand. Potent Os-CN compounds (but not their Os-NN analogues) are particularly reactive; they bind to cysteine in vitro and decrease the activity of thioredoxin reductase (TrxR) in living cancer cells. By revealing some interesting structure-activity relationship on Os-CN vs Os-NN complexes, we start uncovering the molecular rationale for the successful biological applications of osmium(II) half-sandwich compounds.
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... Among these examples, there are Os-arenes bearing alcohols and acids reported by us, [6,9] and those bearing η 6 -biphenyl ligand, reported by Sadler. [10] The lack of structural variation is undoubtedly attributed to the limitations imposed by the synthetic methodology to attach the arene to the Os(II) core, most of which are not shared by Ru(II). ...
... In fact, the first purposely synthesised Os tether complexes have been recently reported by us. [6,9] Therefore, a synthetic method is needed that allows arenes to be functionalised through mild and less hazardous conditions, with accessible reagents and materials, and with a wide variety of possible substituents, including those that allow the formation of tether rings (e. g., N, [11c,25] O, [6,8,26] and S [27] donors). ...
Half‐sandwich Ru(II)‐ and Os(II)‐arene complexes have great potential for catalytic and biological applications. The possibility of fine‐tuning their chemical reactivity by including modifications in the ligands around the metal adds to their many advantages. However, structural modifications at the η⁶‐bound arene have had significant synthetic limitations, particularly in the design of Os(II)‐tethered complexes. For the first time, we have employed a practical C(sp³)‐C(sp²) coupling to obtain 28 new Ru(II) and Os(II) η⁶‐arene half‐sandwich complexes with a wide variety of arene functionalities, including those that enable the formation of tether rings, such as quinoline, and coumarin. The introduction of novel functional groups at the arene in Ru(II)‐ and Os(II) half‐sandwich complexes can broaden the synthetic scope of this type of organometallic complexes, and help to take full advantage of their structural diversity, for example, in intracellular catalysis.
... Thus, the involvement of the TrxR pathway is likely quite limited in the mechanism of action of this compound [118]. The last complex of the series, the osmium complex 39, also shows a significant cytotoxicity on MDA-MB-231 cells (IC 50 = 2.4 µM) and a decrease of about 30% of TrxR activity in cells (5 µM, 6 h), consistently with its ability to form a covalent adduct with cysteine [119]. ...
Cancers classified as multidrug-resistant (MDR) are a family of diseases with poor prognosis despite access to increasingly sophisticated treatments. Several mechanisms explain these resistances involving both tumor cells and their microenvironment. It is now recognized that a multi-targeting approach offers a promising strategy to treat these MDR tumors. Inhibition of thioredoxin reductase (TrxR), a key enzyme in maintaining redox balance in cells, is a well-identified target for this approach. Auranofin was the first inorganic gold complex to be described as a powerful inhibitor of TrxR. In this review, we will first recall the main results obtained with this metallodrug. Then, we will focus on organometallic complexes reported as TrxR inhibitors. These include gold(I), gold(III) complexes and metallocifens, i.e., organometallic complexes of Fe and Os derived from tamoxifen. In these families of complexes, similarities and differences in the molecular mechanisms of TrxR inhibition will be highlighted. Finally, the possible relationship between TrxR inhibition and cytotoxicity will be discussed and put into perspective with their mode of action.
Intracellular imaging of anticancer metallodrugs often relies on prelabeling with organic fluorophores, which significantly affects their physicochemical properties and intracellular distribution. On the other hand, the reported postlabeling strategies based on click‐chemistry reactions require cell fixation and permeabilization. Here, this study presents a postlabeling approach based on the catalyst‐free, inverse electron‐demand Diels–Alder reaction (iEDDA) between a strained fluorescein‐tagged bicyclononyne derivative (BCN‐FAM) and half‐sandwich Ir(III) complexes containing bidentate ligands comprising a tetrazine (Tz‐R,R’) entity. Five half‐sandwich Ir(III) complexes with formula [Cp*Ir(Tz‐R,R’)Cl]0/+ have been synthesized and fully characterized, including the X‐ray crystal structures of three of the five derivatives. Investigations of their stability and their reactivity in aqueous solution and in a model iEDDA reaction reveal the strong influence of the tetrazine ligand structure on the chemical properties of the corresponding complexes. A highly cytotoxic metallodrug candidate (Ir‐C,NPh,Me) is identified from biological studies, and chemical reactivity studies disclose an unusual preference for binding of methionine over cysteine. Postlabeling of Ir‐C,NPh,Me in live HeLa cells highlights its preferential accumulation within the nucleus, suggesting its retention through covalent modifications of nuclear proteins in good agreement with other half‐sandwich iridium(III) complexes.
Herein, the effects of a novel half-sandwich Os(II) complex on the aggregation of an amyloid model system, derived from the C-terminal domain of the nucleophosmin 1 protein (NPM1264–277), were investigated. The thioflavin T (ThT) binding assay revealed that the complex [(η⁶-toluene)Os(NHCglu)Cl2] (where NHCglu is the N-heterocyclic carbene ligand 1-methyl-3-{2,3,4,6-tetra-O-acetyl-1-glucosyl}imidazol-2-ylidene), hence named Os-Tolu, was able to repress amyloid aggregation in a dose-dependent way. Conformational studies through circular dichroism (CD) and Fourier transform infrared (FTIR) spectroscopies clearly indicated that this inhibitory effect occurred through the stabilization of α-helical structures of monomeric NPM1264–277, thus hampering self-recognition. Electrospray ionization mass spectrometry (ESI-MS) studies evidenced, through the formation of coordination adducts, direct interactions of the amyloid peptide with the Os-glucoconjugate complex that, in turn, promote chemical modifications of the sequence further disfavoring the self-assembly process. Noticeably, the presence of Os-Tolu completely repressed the formation of amyloid fibers in scanning electron microscopy (SEM) analysis and induced a slight rescue of cell viability, in contrast to its reduction caused by the amyloid model in human SH-SY5Y neuroblastoma cells. These data strongly support the hypothesis of expanding the use of osmium-based agents to neurodegenerative diseases, positioning them as potential neurodrugs.
Five metal-arene complexes of formula [MX2(η6-p-cymene)(diR(1-pyrenyl)phosphane)] (M = Os or Ru, X = Cl or I, R = isopropyl or phenyl) and symbolized as MRX2 were synthesized and fully characterized, namely OsiPrCl2, OsiPrI2, OsPhCl2, OsPhI2 and RuPhI2. Furthermore, nine cyclometalated half-sandwich complexes of formula [MX-(η6-p-cymene)(k2C-diR(1-pyrenyl)phosphane)] (M = Os or Ru, X = Cl or I, R = isopropyl or phenyl) or [M(η6-p-cymene)(kS-dmso)(k2C-diR(1-pyrenyl)phosphane)]PF6 (M = Os or Ru, R = isopropyl or phenyl) and symbolized as c-MRX were prepared; hence, c-OsiPrCl, c-OsiPrI, c-OsiPrdmso, c-OsPhCl, c-OsPhI, c-OsPhdmso, c-RuPhCl, c-RuPhI and c-RuPhdmso were obtained and fully characterized. The crystal structures of ten out of the fourteen complexes were solved. All complexes exhibit notable cytotoxic properties against A549 (Lung Adenocarcinoma) human cells, with IC50 values ranging from 48 to 1.42 μM. In addition, complex c-OsiPrdmso shows remarkable toxic behaviours agains other cell lines, namely MCF7 (breast carcinoma), MCF10A (non-tumorigenic epithelial breast) and MDA-MB-435 (melanoma) human cells, as illustrated by IC50 values of 4.36, 4.71 and 2.32 μM, respectively. Finally, it has been found that OsiPrI2 affects the cell cycle of A549 cells, impeding their replication (i.e., the cell cycle is blocked), whereas OsPhI2 (namely with phenyl groups instead of isopropyl ones) does not induce this effect.
Aquation is often acknowledged as a necessary step for metallodrug activity inside the cell. Hemilabile ligands can be used for reversible metallodrug activation. We report a new family of osmium(ii) arene complexes of formula [Os(η6-C6H5(CH2)3OH)(XY)Cl]+/0 (1-13) bearing the hemilabile η6-bound arene 3-phenylpropanol, where XY is a neutral N,N or an anionic N,O- bidentate chelating ligand. Os-Cl bond cleavage in water leads to the formation of the hydroxido/aqua adduct, Os-OH(H). In spite of being considered inert, the hydroxido adduct unexpectedly triggers rapid tether ring formation by attachment of the pendant alcohol-oxygen to the osmium centre, resulting in the alkoxy tethered complex [Os(η6-arene-O-κ1)(XY)] n+. Complexes 1C-13C of formula [Os(η6:κ1-C6H5(CH2)3OH/O)(XY)]+ are fully characterised, including the X-ray structure of cation 3C. Tether-ring formation is reversible and pH dependent. Osmium complexes bearing picolinate N,O-chelates (9-12) catalyse the hydrogenation of pyruvate to lactate. Intracellular lactate production upon co-incubation of complex 11 (XY = 4-Me-picolinate) with formate has been quantified inside MDA-MB-231 and MCF7 breast cancer cells. The tether Os-arene complexes presented here can be exploited for the intracellular conversion of metabolites that are essential in the intricate metabolism of the cancer cell.
The synthesis, characterisation and evaluation of the in vitro cytotoxicity of four indole-based half-sandwich metal complexes towards two ovarian cancer cell lines (A2780 and A2780cisR) and one normal prostate cell line (PNT2) are presented herein. Although capable of inducing catalytic oxidation of NADH and able to reduce NAD⁺ with high turnover frequencies, in cells and in the presence of sodium formate, these complexes also strongly interact with biomolecules such as glutathione. This work highlights that efficient out-of-cells catalytic activity might lead to higher reactivity towards biomolecules, thus inhibiting the in-cells catalytic processes.
Dinuclear metallodrugs offer much potential in the development of novel anticancer chemotherapeutics as a result of the distinct interactions possible with bio‐macromolecular targets and the unique biological activity that can result. Herein, we describe the development of isostructural homo‐dinuclear OsII–OsII and hetero‐dinuclear OsII–RuII organometallic complexes formed from linking the arene ligands of [M(η⁶‐arene)(C2O4)(PTA)] units (M=Os/Ru; PTA=1,3,5‐triaza‐7‐phosphaadamantane). Using these complexes together with the known RuII–RuII analogue, a chromatin‐modifying agent, we probed the impact of varying the metal ions on the structure, reactivity and biological activity of these complexes. The complexes were structurally characterised by X‐ray diffraction experiments, their stability and reactivity were examined by using ¹H and ³¹P NMR spectroscopy, and their biological activity was assessed, alongside that of mononuclear analogues, through MTT assays and cell‐cycle analysis (HT‐29 cell line). The results revealed high antiproliferative activity in each case, with cell‐cycle profiles of the dinuclear complexes found to be similar to that for untreated cells, and similar but distinct profiles for the mononuclear complexes. These results indicate these complexes impact on cell viability predominantly through a non‐DNA‐damaging mechanism of action. The new OsII–OsII and OsII–RuII complexes reported here are further examples of a family of compounds operating via mechanisms of action atypical of the majority of metallodrugs, and which have potential as tools in chromatin research.
We report the synthesis, characterization and cytotoxicity of six cyclometalated rhodium(III) complexes [CpXRh(C^N)Z]0/+, in which CpX = Cp*, Cpph, or Cpbiph, C^N = benzo[h]quinoline, and Z = chloride or pyridine. Three X‐ray crystal structures showing the expected “piano‐stool” configurations have been determined. The chlorido complexes hydrolyzed faster in aqueous solution, and reacted preferentially with 9‐ethyl guanine or glutathione compared to their pyridine analogues. The 1‐biphenyl‐2,3,4,5‐tetramethylcyclopentadienyl complex [CpbiphRh(benzo‐[h]quinoline)Cl] (3a) was the most efficient catalyst in coenzyme reduced nicotinamide adenine dinucleotide (NADH) oxidation to NAD⁺ and induced an elevated level of reactive oxygen species (ROS) in A549 human lung cancer cells. The pyridine complex [CpbiphRh(benzo[h]quinoline)py]⁺ (3b) was the most potent against A549 lung and A2780 ovarian cancer cell lines, being 5‐fold more active than cisplatin towards A549 cells, and acted as a ROS scavenger. This work highlights a ligand‐controlled strategy to modulate the reactivity and cytotoxicity of cyclometalated rhodium anticancer complexes.
An organoruthenium(II) complex with pyrithione (2‐mercaptopyridine N‐oxide) 1 a has previously been identified by our group as a compound with promising anticancer potential without cytotoxicity towards non‐cancerous cells. To expand the rather limited research on compounds of this type, an array of novel chlorido and 1,3,5‐triaza‐7‐phosphaadamantane (pta) organoruthenium(II) complexes with methyl‐substituted pyrithiones has been prepared. After thorough investigation of the aqueous stability of these complexes, their modes of action have been elucidated at the cellular level. Minor structural alterations in the ruthenium‐pyrithionato compounds resulted in fine‐tuning of their cytotoxicities. The best performing compounds, 1 b and 2 b, with a chlorido or pta ligand bound to ruthenium, respectively, and a methyl group at the 3‐position of the pyrithione scaffold, have been further investigated. Both compounds trigger early apoptosis, induce the generation of reactive oxygen species and G1 arrest in A549 cancer cells, and show no strong interaction with DNA. However, only 1 b also inhibits thioredoxin reductase. Wound healing assays and mitochondrial function evaluation have revealed differences between these two compounds at the cellular level.
We report the synthesis of halido Os(II) p-cymene complexes bearing bidentate chelating phenylazobenzothiazole (AZBTZ) ligands. Unlike the analogous phenylazopyridine (AZPY) complexes, AZBTZ-NMe2 is capable of both N,N-coordination to Os(II) and cyclometalation to form N,C-coordinated species. N,C-Coordination occurs via an azo nitrogen and an ortho carbon on the aniline ring, as identified by ¹H NMR and X-ray crystallography of [Os(p-cym)(N,N-AZBTZ-NMe2)Cl]PF6 (1a), [Os(p-cym)(N,N-AZBTZ-NMe2)Br]PF6 (2a), [Os(p-cym)(N,C-AZBTZ-NMe2)Br] (2b), and [Os(p-cym)(N,C-AZBTZ-NMe2)I] (3b). The N,C-coordinated species is more stable and is not readily converted to the N,N-coordinated complex. Analysis of the crystal structures suggests that their formation is influenced by steric interactions between the p-cym and AZBTZ-NMe2 ligands: in particular, larger monodentate halide ligands favor N,C-coordination. The complexes [Os(p-cym)(N,N-Me2-AZBTZ-NH2)Cl]PF6 (4) and [Os(p-cym)(N,N-Me2-AZBTZ-NH2)I]PF6 (5) were synthesized with methyl groups blocking the ortho positions on the aniline ring, forcing an N,N-coordination geometry. ¹H NMR NOE experiments confirmed hindered rotation of the arene ligand and steric crowding around the metal center. Complex 2b exhibited unexpected behavior under acidic conditions, involving regiospecific deuteration of the aniline ring at the meta position, as observed by ¹H NMR and high-resolution ESI-MS. Deuterium exchange occurs only under acidic conditions, suggesting an associative mechanism. The calculated partial charges on 2b show that the meta carbon is significantly more negatively charged, which may account for the regiospecificity of deuterium exchange.
Platinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η(5) -Cp(xbiph) )Ir(phpy)(Cl)] (1-Cl), which contains π-bonded biphenyltetramethylcyclopentadienyl (Cp(xbiph) ) and C^N-chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η(5) -Cp(xbiph) )Ir(phpy)(py)](+) (1-py) aquates slowly, and is more potent (in nanomolar amounts) than both 1-Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1-py from rapid reaction with intracellular glutathione. The high potency of 1-py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H2 O2 by catalytic hydride transfer from the coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy.
Metal complexes with N-heterocyclic carbene (NHC) ligands have been widely used in catalytic chemistry and are now increasingly considered for the development of new chemical tools and metal based drugs. Ruthenium complexes of the type (p-cymene)(NHC)RuCl(2) interacted with biologically relevant thiols and selenols, which resulted in the inhibition of enzymes such as thioredoxin reductase or cathepsin B. Pronounced antiproliferative effects could be obtained provided that an appropriate cellular uptake was achieved. Inhibition of tumor cell growth was accompanied by a perturbation of metabolic parameters such as cellular respiration.
Mammalian thioredoxin reductases (TrxR) are homodimers, homologous to glutathione reductase (GR), with an essential selenocysteine (SeCys) residue in an extension containing the conserved C-terminal sequence -Gly-Cys-SeCys-Gly. In the oxidized enzyme, we demonstrated two nonflavin redox centers by chemical modification and peptide sequencing: one was a disulfide within the sequence -Cys59-Val-Asn-Val-Gly-Cys64, identical to the active site of GR; the other was a selenenylsulfide formed from Cys497-SeCys498 and confirmed by mass spectrometry. In the NADPH reduced enzyme, these centers were present as a dithiol and a selenolthiol, respectively. Based on the structure of GR, we propose that in TrxR, the C-terminal Cys497-SeCys498 residues of one monomer are adjacent to the Cys59 and Cys64 residues of the second monomer. The reductive half-reaction of TrxR is similar to that of GR followed by exchange from the nascent Cys59 and Cys64 dithiol to the selenenylsulfide of the other subunit to generate the active-site selenolthiol. Characterization of recombinant mutant rat TrxR with SeCys498 replaced by Cys having a 100-fold lower kcat for Trx reduction revealed the C-terminal redox center was present as a dithiol when the Cys59-Cys64 was a disulfide, demonstrating that the selenium atom with its larger radius is critical for formation of the unique selenenylsulfide. Spectroscopic redox titrations with dithionite or NADPH were consistent with the structure model. Mechanisms of TrxR in reduction of Trx and hydroperoxides have been postulated and are compatible with known enzyme activities and the effects of inhibitors, like goldthioglucose and 1-chloro-2,4-dinitrobenzene.
A linear correlation between pH-meter readings in equivalent D2O and H2O solutions, determined experimentally, leads to a novel equation, which allows for a direct recalculation of pKa values measured in D2O into a H2O equivalent: pKH=0.929pKH*+0.42. The comparison of this equation with the previously used approach is discussed.
This work reports the synthesis and characterization of some novel osmium(II) complexes with potential as anticancer drugs tested in vitro and in vivo. The complexes have an structure [(η6-p-cym)Os(C^N)(X)]0/+, where the C^N ligand is deprotonated 2-phenylpyridine (ppy) or 4-(2-pyridin)benzaldehyde (ppy-CHO) and X are chloride, pyridine (py) or the pyridine derivative 4-NMe2-py. The in vitro cytotoxic studies showed that complexes [(η6-p-cym)Os(C^N)(4-NMe2-py)]+ (C^N = ppy 2a and ppy-CHO 5a) exerted effective antiproliferative activity towards both cisplatin-sensitive ovarian cancer cells (A2780) and cisplatin-resistant cells (A2780cis). The mechanism underlying the antiproliferative effects in vitro was studied showing a reduction of proteosynthesis up to 58 % and an increase of apoptosis modulated by caspase-3. Model animal Caenorhabditis elegans was used to estimate the effects of 2a and 5a and the in-house 4-NMe2-py Ru(II) analogue 5b in vivo. Compounds 2a, 5a and 5b were able to reduce tumor growth up 32.2 %, 19 % and 30 %, respectively in the tumoral strain JK1466 and presented low toxicity in both tumoral and wild-type strains. The mechanistic study using reporter gene expression showed that 2a, 5a and 5b were able to maintain the reactive oxygen species (ROS) levels in the animals by increased expression of the mitochondrial superoxide dismutase 3 (SOD-3), an indication that they were able to regulate oxidative stress genes specifically. Interestingly the three complexes showed a similar mechanism of action, suggesting that the identity of the metal ion does not matter and the effect are more related to the whole structure of the complex. Worthy of note, cisplatin treatment produced elevated ROS levels in the animals and induced the expression of glutathione transferase 4 (GST-4) suggesting different mechanisms of action for the two complexes. Altogether the results showed that osmium(II) complexes can be potential candidates in the search for novel chemotherapeutic drugs.
Six complexes of formula [Ir(η5:κ1-C5Me4CH2py)(C,N)]PF6, where C5Me4CH2py is 2-((2,3,4,5-tetramethylcyclopentadienyl)methyl)pyridine, and C,N is 2-phenylpyridine (1), 7,8-benzoquinoline (2), 1-phenylisoquinoline (3), 2-(p-tolyl)pyridine (4), 4-chloro-2-phenylquinoline (5), or 2-(2,4-difluorophenyl)pyridine (6), have been synthesized. The cyclopentadienyl ligand bears a tethered pyridine that binds to the metal center, resulting in an Ir(η5:κ1-C5Me4CH2pyN) tether-ring structure, as confirmed by the X-ray crystal structures of 1, 2, 4, 5, and 6. Nontether versions of 1 and 2 were synthesized to aid unambiguous correlation between structure and activity. While nontether complexes are highly potent toward MCF7 cancer cells (similar to cisplatin), complexes bearing the tether-ring structure, 1-6, are exceptionally more potent (1-2 orders of magnitude). Additionally, 1-6 disrupt mitochondrial membrane potential (ΔΨ
m
) and induce oxidative stress. Internalization studies strongly correlate intracellular accumulation and anticancer activity in tether and nontether complexes. We present a new class of organo-iridium drug candidates bearing a structural feature that results in a leap in anticancer potency.
The preparation of the tethered arene-ruthenium(II) complexes [RuCl2{η6:κ1(P)-C6H5(CH2)nOPR2}] (R = Ph, n = 1 (9a), 2 (9b), 3 (9c); R = iPr, n = 1 (10a), 2 (10b), 3 (10c)) from the corresponding phosphinite ligands R2PO(CH2)nPh (R = Ph, n = 1 (1a), 2 (1b), 3 (1c); R = iPr, n = 1 (2a), 2 (2b), 3 (2c)) is presented. Thus, in a first step, the treatment at room temperature of tetrahydrofuran solutions of dimers [{RuCl(-Cl)(6-arene)}2] (arene = p-cymene (3), benzene (4)) with 1-2a-c led to the clean formation of the corresponding mononuclear derivatives [RuCl2(η6-p-cymene){R2PO(CH2)nPh}] (5-6a-c) and [RuCl2(η6-benzene){R2PO(CH2)nPh}] (7-8a-c), which were isolated in 66-99% yield. The subsequent heating of 1,2-dichloroethane solutions of these compounds at 120 °C allowed the exchange of the coordinated arene. The substitution process proceeded faster with the benzene derivatives 7-8a-c, from which complexes 9-10a-c were generated in 61-82% yield after 0.5-10 h of heating. The molecular structures of [RuCl2(η6-p-cymene){iPr2PO(CH2)3Ph}] (6c) and [RuCl2{η6:κ1(P)-C6H5(CH2)nOPiPr2}] (n = 1 (10a), 2 (10b), 3 (10c)) were unequivocally confirmed by X-ray diffraction methods. In addition, complexes [RuCl2{η6:κ1(P)-C6H5(CH2)nOPR2}] (9-10a-c) proved to be active catalysts for the dehydrogenative coupling of hydrosilanes and alcohols under mild conditions (r.t.). The best results were obtained with [RuCl2{η6:κ1(P)-C6H5(CH2)3OPiPr2}] (10c), which reached TOF and TON values up to 117600 h-1 and 57000, respectively.
Experimental organometallic gold(I) compounds hold promise for anticancer therapy. This study reports the synthesis of two novel families of gold(I) complexes, including N1-substituted bis-N-heterocyclic carbene (NHCs) complexes of general formula [Au(N1-TBM)2]BF4 (N1-TBM = N1-substituted 9-methyltheobromin-8-ylidene) and mixed gold(I) NHC-alkynyl complexes, [Au(N1-TBM)alkynyl]. The compounds were fully characterised for their structure and stability in aqueous environment and in the presence of N-acetyl cysteine by nuclear magnetic resonance (NMR) spectroscopy. The structures of bis(1-ethyl-3,7,9-trimethylxanthin-8-ylidene)gold(I), (4-ethynylpyridine)(1,9-dimethyltheobromine-8-ylidene)gold(I) and of (2,8-Diethyl-10-(4-ethynylphenyl)-5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ4,5λ4-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinine)(1,3,7,9-tetramethylxanthin-8-ylidene)gold(I) were also confirmed by X-ray diffraction analysis. The compounds were studied for their properties as DNA G-quadruplexes (G4 s) stabilizers by fluorescence resonance energy transfer (FRET) DNA melting. Only the cationic [Au(N1-TBM)2]BF4 family showed moderate G4 stabilization properties with respect to the previously reported benchmark compound [Au(9-methylcaffein-8-ylidene)2]+ (AuTMX2). However, the compounds also showed marked selectivity for binding to G4 structures with respect to duplex DNA in competition experiments. For selected complexes, the interactions with G4 s were also confirmed by circular dichroism (CD) studies. Furthermore, the gold(I) complexes were assessed for their antiproliferative effects in human cancer cells in vitro, displaying moderate activity. Of note, among the mixed gold(I) NHC-alkynyl compounds, one features a fluorescent boron-dipyrromethene (BODIPY) moiety which allowed determining its uptake into the cytoplasm of cancer cells by fluorescence microscopy.
Half-sandwich ruthenium(II) complexes [(η6-p-cymene)Ru(C^N)-(X)]0/+ (X = Cl, py or 4-NMe2-py) containing a cyclometalated 2‐ppy or 1‐ppz with a non-coordinated CHO group as a handle for further functionalization have been synthesized...
The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the RuII(arene) pharmacophore and even less with an OsII(arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M-CNHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal-NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η6-p-cymene)ruthenium(II) 1bI was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future.
A series of six osmium(II) complexes of the type [(η6-p-cymene)Os(C^N)X] (X = chlorido or acetato) containing benzimidazole C^N ligands with an ester group as a handle for further functionalization have been synthesized. They exhibit IC50 values in the low micromolar range in a panel of cisplatin (CDDP) resistant cancer cells (approximately 10 more cytotoxic than CDDP in MCF-7), decrease levels of intracellular ROS and reduce NAD+ coenzyme, and inhibit tubulin polymerization. This discovery could open the door to a new large family of osmium(II)-based bioconjugates with diverse modes of action.
This work describes the preparation and characterization of seven neutral and one cationic water-soluble Ru(II)-carbonyls bearing from one to three PTA ligands (per Ru atom), namely, the four monocarbonyls, cis,cis,trans-RuCl2(CO)(dmso−S)(PTA)2 (6), trans-RuCl2(CO)(PTA)3 (7), cis,mer-RuCl2(CO)(PTA)3 (8), and trans,trans,trans-RuCl2(CO)(OH2)(PTA)2 (10), the three dicarbonyls, trans,trans,trans-RuCl2(CO)2(PTA)2 (11), [RuCl2(CO)2(PTA)]2 (12), and cis,cis,trans-RuCl2(CO)2(PTA)2 (13), and the cationic monocarbonyl complex cis-[RuCl(CO)(PTA)4](Cl) (17). The X-ray structures of 6−8, 10, 11, 13, and 17 are also reported.
Five complexes of formula [Ru(η6-C6H5CH2COOH)(XY)Cl]Cl/Na (XY = ethylenediamine (1), o-phenylenediamine (2), phenanthroline (3), and oxalato (4)) and [Ru(η6:κ1-C6H5CH2COO)(tmen)]Cl (tmen = N, N, N', N'-tetramethylethylenediamine, 5C) have been synthesized and fully characterized. Five new X-ray crystal structures ([Ru(η6-C6H5CH2COOH)(μ-Cl)Cl]2, 1, 3, 4, and 5C·PF6) have been determined, which are the first examples of ruthenium(II) structures with phenylacetic acid as arene ligand. Furthermore, 5C·PF6 is the first example of a five-membered tether ring with a Ru(η6:κ1-arene:O) bond. The tether ring in these complexes opens in acidic pH (<5) and closes reversibly in aqueous solution. The chlorido open-form undergoes aquation, and the aqua adduct can be observed (prior to ring closure) by NMR. The speciation has an attractive complexity in the pH range 0-12, showing interconversion of the three species (chlorido, aqua, and closed tether), dependent on the proton concentration and the nature of the XY chelating ligand. The closed tether version of 3, complex 3C, with σ-donor/π-acceptor phenanthroline as chelating ligand, opens up more readily (pH 4), while the tether ring in complex 5C hardly opens even at pH as low as 1. We have determined the p Ka of the pendant carboxylic group and that of the aqua adduct (ca. 3 and ca. 7, respectively), which can be finely tuned by the appropriate choice of XY. Complexes 1 and 2, which predominate in their inactive (closed-tether) form in intracellular conditions, show some cytotoxic activity (IC50 130 and 117 μM, respectively) in A2780 ovarian cancer cells. Complex 1 catalyzes the reduction through transfer hydrogenation of pyruvate to lactate and NAD+ to NADH in the presence of formate as H-source. Co-incubation with sodium formate decreases the IC50 value of 1 in A2780 cancer cells significantly.
Gold(III) compounds have received increasing attention in cancer research. Three gold complexes of general formula [AuIIIL]Cl, where L is benzil bis(thiosemicarbazonate), compound 1, benzil bis(4-methyl-3-thiosemicarbazonate), compound 2, or benzil bis(4-cyclohexyl-3-thiosemicarbazonate), compound 3, have been synthesized and fully characterized, including the X-ray crystal structure of compound 3, confirming square-planar geometry around the gold(III) centre. Compound 1 showed moderate cytotoxicity and accumulation in MCF7 breast cancer cells but did not inhibit thioredoxin reductase (TrxR) activity and did not induce reactive oxygen species (ROS) production. Compound 2, the least cytotoxic, was found to be capable of modestly inhibiting TrxR activity and produced low levels of ROS in the MCF7 cell line. The most cytotoxic compound, 3, had the highest cellular accumulation and its distribution pattern showed a clear preference for the cytosol and mitochondria of MCF7 cells. It readily hampered intracellular TrxR activity leading to a dramatic alteration of the cellular redox state and to the induction of cell death.
Anticancer metallodrugs based on ruthenium and osmium are among the most investigated and advanced non-platinum metallodrugs. Inorganic drug discovery with these agents has undergone considerable advances over the past two decades and has currently two representatives in active clinical trials. As many ruthenium and osmium metallodrugs are prodrugs, a key question to be addressed is how the molecular reactivity of such metal-based therapeutics dictates the selectivity and the type of interaction with molecular targets. Within this frame, this review introduces the field by the examples of the most advanced ruthenium lead structures. Then, global structure–activity relationships are discussed for ruthenium and osmium metallodrugs with respect to in vitro antiproliferative/cytotoxic activity and in vivo tumor-inhibiting properties, as well as pharmacokinetics. Determining and validating global mechanisms of action and molecular targets are still major current challenges. Moreover, significant efforts must be invested in screening in vivo tumor models that mimic human pathophysiology to increase the predictability for successful preclinical and clinical development of ruthenium and osmium metallodrugs.
The potential use of organometallic ruthenium complexes as anticancer drugs is well known. Here we show a family of activatable tethered ruthenium(II) arene complexes of general formula [Ru(η⁶:κ¹-C₆H₅(C₆H₄)NH₂)(XY)]n+ (closed tether-ring) bearing different chelating XY ligands (XY = aliphatic diamine, phenylenediamine, oxalato, bis(phosphino)ethane). The activation of these complexes (closed-to-open tether conversion) occurs in methanol and dimethylsulfoxide at different rates, and to different reaction extents at equilibrium. Most importantly, Ru complex activation (cleavage of the Ru-N-tether bond) occurs in aqueous solution when the proton concentration is high (upon N-tether protonation). The activation dynamics can be modulated by rational variation of the XY chelating ligand. The electron-donating capability and steric hindrance of XY have a direct impact on the Ru-N bond reactivity, with XY = N,N'-dimethyl, N,N'-diethyl, and N,N,N',N'-tetramethylethylenediamine affording complexes more prone to activation. Such activation in acidic media is fully reversible, and proton concentration also governs the deactivation rate; i.e., tether ring closure slows down as the pH decreases. Interaction of a closed-tether complex and its open-tether counterpart with 5'-GMP indicates selectivity of the active (open) complex towards nucleobase interaction. This work presents ruthenium tether complexes as exceptional pH-dependent switches with potential exploitation in cancer research.
An axial chiral version of the 2,6-dimesitylphenyl group attached to sulfur is reported. Its multistep preparation starts from (S)-binol, and the thiol group is established by a racemization-free thermal Newman-Kwart rearrangement. The new chiral thiolate ligand decorated with one mesityl group is used in the synthesis of a tethered ruthenium chloride complex. Its spectroscopic characterization revealed solvent-dependent epimerization at the ruthenium center. The major diastereomer is crystallographically characterized. Chloride abstraction with tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF4) yields the corresponding coordinatively unsaturated ruthenium complex with the Ru-S bond exposed. Si-H bond activation at this Ru-S bond proceeds in syn fashion but with moderate facial selectivity (d.r. = 70:30), generating diastereomeric chiral-at-ruthenium hydrosilane adducts. Their application to catalytic imine hydrosilylation led to promising enantioinduction (40% ee), thereby providing proof of concept for asymmetric catalysis involving cooperative Si-H bond activation.
Herein we report the synthesis, anticancer potency in vitro, biomolecule interaction, and preliminary mode of action studies of a series of cyclometalated 1,2,3-triazole-derived ruthenium(II) (2a-e) and osmium(II) (3a-e) organometallics of the general form [(η(6)-p-cym)RuCl(κ(2)-C^N-L)] with varying substituents in postion 1 of the 1,2,3-triazole moiety. These cyclometalates were characterized by standard analytical methods and their structures unambiguously assigned by single crystal X-ray crystallography. The anticancer activity of these novel compounds was tested in the human tumor cell lines A549 (non-small cell lung cancer), SW480 (colon adenocarcinoma), and CH1/PA-1 (ovarian teratocarcinoma), and preliminary structure-activity relationships were derived from the obtained data sets. Various representatives exhibit promising antineoplastic effects with IC50 values down to the low micromolar range. The compounds readily formed stable DMSO adducts after aquation in DMSO-containing solution, but employing DMSO as solubilizer in cytotoxicity assays had no pronounced effect on the cytotoxicity, compared to analogous experiments with DMF for most compounds. We isolated and characterized selected DMSO adducts as triflate salts and found that they show activities in the same range as the parent chlorido metalacycles in MTT assays with the use of DMSO. Osmium(II) cyclometalates exhibited higher antiproliferative activities than their ruthenium(II) counterparts. The IC50 values within each metal series decreased with increasing lipophilicity, which was attributed to higher cellular accumulation. Investigations on their mode of action revealed that the prepared organometallics were unable to inhibit topoisomerase IIα. Still, the most cytotoxic representatives 2b and 3b showed pronounced effects on cell cycle distribution.
A series of novel C,N-cyclometalated benzimidazole ruthenium(II) and iridium(III) complexes of the types [(eta6-p-cymene)RuCl(kappa2-N,C-L)] and [(eta5-C5Me5)IrCl(kappa2-N,C-L)] (HL = methyl 1-butyl-2-arylbenzimidazole carboxylate) with varying substituents (H, Me, F, CF3, MeO, NO2, and Ph) in the R4 position of the phenyl ring of 2-phenyl-benzimidazole chelating ligand of the ruthenium (3a-3g) and iridium complexes (4a-4g) have been prepared. The cytotoxic activity of the new ruthenium(II) and iridium(III) compounds have been evaluated in a panel of cell lines (A2780, A2780cisR, A427, 5637, LCLC, SISO and HT29) in order to investigate structure-activity relationships. Phenyl substitution at the R4 position shows increased potency in both Ru and Ir complexes (3g and 4g, respectively) as compared to their parent compounds (3a and 4a) in all cell lines. In general, ruthenium complexes are more active than the corresponding iridium complexes. The new ruthenium and iridium compounds increased caspase-3 activity in A2780 cells, as shown for 3a,d and 4a,d. Compound 4g is able to increase the production of ROS in A2780 cells. Furthermore, all the new compounds are able to overcome the cisplatin resistance in A2780cisR cells. In addition, some of the metal complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926 at 0.5 muM, being the ruthenium derivatives 3g (Ph) and 3d (CF3) the best-performers. QC calculations performed on some ruthenium model complexes showed only moderate or slight electron depletion at the phenyl ring of the C,N-cyclometalated ligand and the chlorine atom on increasing the electron withdrawing effect of the R substituent.
The synthesis and characterization of two families of cyclometalated Ru(II) complexes with the new (C-sp2,N-indole)(-) motif formed by activation of the C-H bonds of 2-phenylindole ligands of the general formula {(4'-R'-C6H4)-3-NOMe-5-R-2-6-R-3-(C6H2N)}are presented. The novel ruthenacycles show a remarkable cytotoxic activity in MCF7 and MDA-MB231 breast cancer cell lines, which clearly exceeds those of the trans and cis isomers of [PtCl2(L)(DMSO)] derived from the same ligands and even that of cisplatin.
The dinuclear complexes [(p-cymene)RuCl2](2) and [(cyclopentadienyl)MCl2](2) (M = Ru, Rh, Ir) are important starting materials in organometallic chemistry. The standard synthesis of these complexes involves heating of an alcoholic solution of Ru-III, Rh-III, or Ir-III salts with precursors of the -ligands for several hours under reflux. Microwave heating allows these complexes to be obtained within a few minutes without compromising the yields. Furthermore, the microwave-assisted syntheses require less solvent and, in some cases, lower amounts of ligand precursors.
Treatment of the osmium hydrido alkenylcarbyne complex [OsH{≡CC(PPh3)═CHPh}(PPh3)2Cl2]BF4 (1) with allenoates (CH2═C═CHCOOR, R = Me, Et) in the presence of excess AgBF4 leads to the insertion products 2/3. The reactions of complex 1 with substituted allenoates, i.e., diethyl 2-vinylidenesuccinate (CH2═C═C(CH2COOEt)(COOEt)) and ethyl penta-2,3-dienoate (CH(CH3)═C═CH(COOEt)), result in the formation of [3 + 2] annulation products 4 and 6, respectively. Mechanisms of the reactions have been proposed with the isolation of the key intermediates. The results reveal that the divergent pathways for these reactions are mainly of steric origin.
The ligands 2-pyridin-2-yl-1H-benzimidazole (HL(1)), 1-methyl-2-pyridin-2-ylbenzimidazole (HL(2)), and 2-(1H-imidazol-2-yl)pyridine (HL(3)) and the proligand 2-phenyl-1H-benzimidazole (HL(4)) have been used to prepare five different types of new ruthenium(II) arene compounds: (i) monocationic complexes with the general formula [(η(6)-arene)RuCl(κ(2)-N,N-HL)]Y [HL = HL(1), HL(2), or HL(3); Y = Cl or BF4; arene = 2-phenoxyethanol (phoxet), benzene (bz), or p-cymene (p-cym)]; (ii) dicationic aqua complexes of the formula [(η(6)-arene)Ru(OH2)(κ(2)-N,N-HL(1))](Y)2 (Y = Cl or TfO; arene = phoxet, bz, or p-cym); (iii) the nucleobase derivative [(η(6)-arene)Ru(9-MeG)(κ(2)-N,N-HL(1))](PF6)2 (9-MeG = 9-methylguanine); (iv) neutral complexes consistent with the formulation [(η(6)-arene)RuCl(κ(2)-N,N-L(1))] (arene = bz or p-cym); (v) the neutral cyclometalated complex [(η(6)-p-cym)RuCl(κ(2)-N,C-L(4))]. The cytototoxic activity of the new ruthenium(II) arene compounds has been evaluated in several cell lines (MCR-5, MCF-7, A2780, and A2780cis) in order to establish structure-activity relationships. Three of the compounds with the general formula [(η(6)-arene)RuCl(κ(2)-N,N-HL(1))]Cl differing in the arene moiety have been studied in depth in terms of thermodynamic dissociation constants, aquation kinetic constants, and DNA binding measurements. The biologically most active compound is the p-cym derivative, which strongly destabilizes the DNA double helix, whereas those with bz and phoxet have only a small effect on the stability of the DNA double helix. Moreover, the inhibitory activity of several compounds toward CDK1 has also been evaluated. The DNA binding ability of some of the studied compounds and their CDK1 inhibitory effect suggest a multitarget mechanism for their biological activity.
Ruthenium(II) arene compounds have been modified with the naphthalimide group, tethered via the arene ligand, i.e. {dichloro[η6-N-(phenylalkyl)(4-dimethylamino)-1,8-naphthalimide](pta)ruthenium(II)} (alkyl = methyl, ethyl, propyl, pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane), or via an imidazole group, i.e. {dichloro(η6-arene)(N-[3-(imidazol-1-yl)propyl]-1,8-naphthalimide)ruthenium(II)} (arene = p-cymene, toluene). All the compounds are reasonably cytotoxic (ca. 2–49 μM) toward cancer cells, and the arene-linked compounds also display selectivity in that they are less cytotoxic toward model healthy cells. Mechanistic studies show that the ruthenium center does not readily react with DNA but preferentially binds to proteins. In contrast, the naphthalimide group is a strong DNA intercalator, and combined, the complexes might be expected to simultaneously cross-link DNA and proteins.
Organometallic IrIII cyclopentadienyl complexes [(η5-Cpx)Ir(CN)Cl] {Cpx = Cp*, CN = 2-(p-tolyl)pyridine (1), 2-phenylquinoline (2), 2-(2,4-difluorophenyl)pyridine (3), Cpx = tetramethyl(phenyl)cyclopentadienyl (Cpxph), CN = 2-phenylpyridine (4), and Cpx = tetramethyl(biphenyl)cyclopentadienyl (Cpxbiph), CN = 2-phenylpyridine (5)} have been synthesized and characterized. The X-ray crystal structures of 2 and 5 have been determined and show typical “piano-stool” geometry. All the complexes hydrolyzed rapidly in aqueous solution (<5 min) even at 278 K. The pKa values of the aqua adducts 1A–5A are in the range 8.31–8.87 and follow the order 1A > 2A > 4A > 5A ≈ 3A. Hydroxo-bridged dimers {[(η5-Cpx)Ir]2(μ-OD)3}+ (Cpx = Cp*, 6; Cpxph, 7; Cpxbiph, 8) are readily formed during pH titrations at ca. pH 8.7. Complexes 1 and 3–5 bind strongly to 9-ethylguanine (9-EtG), moderately strongly to 9-methyladenine (9-MeA), and hence preferentially to 9-EtG when in competition with 9-MeA. The extent of guanine and adenine binding to complex 2 was significantly lower for both purines due to steric hindrance from the chelating ligand. All complexes showed potent cytotoxicity, with IC50 values ranging from 6.5 to 0.7 μM toward A2780 human ovarian cancer cells. Potency toward these cancer cells increased with additional phenyl substitution on Cp*: Cpxbiph > Cpxph > Cp*. Cpxbiph with complex 5 exhibited submicromolar activity (2× as active as cisplatin). These data demonstrate how the aqueous chemistry, nucleobase binding, and anticancer activity of C,N-bound IrIII cyclopentadienyl complexes can be controlled and fine-tuned by the modification of the chelating and cyclopentadienyl ligands.
Slipped under the radar? (1) H NMR spectroscopic examination revealed that [Ru(η(6) -arene)Cl2 (L)] (L=N-heterocyclic ligands) complexes readily undergo ligand exchange reaction in DMSO, a popular medium for preparing stock solutions for biological screening. It is therefore highly important for researchers to study stability in DMSO before reporting on the biological activity of such type of complexes.
The preparation of a series of half-sandwich
ruthenium complexes, [RuCl2(η6-p-cymene)(P*)] (P* = SPMeRR′)
and [RuCl2(κ-P*-η6-arene)], containing P-stereogenic
phosphines is reported. The borane-protected Pstereogenic
phosphines have been obtained by addition of
the (H3B)PMe2R (R = t-Bu (1), Cy (2), Fc (3))/sec-BuLi/
(−)-sparteine adduct to benzyl halides, carbonyl functions, and
epoxides with yields between 40 and 90% and ee values in the
70−99% range. Those containing an aryl secondary function
have been used in the preparation of [RuCl2(η6-p-cymene)-
(P*)] complexes. Borane deprotection has been performed
using HBF4, except for (H3B)PRMe(CH2SiMe2Ph) phosphines, where DABCO was used to avoid partial cleavage of the CH2−
Si bond. In the case of (H3B)P(t-Bu)Me(CH2C(OH)Ph2) (1l) the dehydrated phosphine was obtained. The tethered complexes
were obtained by p-cymene substitution in chlorobenzene at 120 °C, except for ferrocenyl-containing complexes, which
decomposed upon heating. The presence of substituents in the aryl arm of some of the phosphines introduces new chiral
elements in the tethered [RuCl2(κ-P*-η6-arene)] compounds. Full characterization of all compounds both in solution and in the
solid state has been carried out. Crystal structure determinations of four phosphine−borane molecules confirm the S
configuration at the phosphorus atom (1a,e,l and 2d). Moreover, the crystal structure of one p-cymene complex (5i) and four
tethered complexes reveal the strain of the compounds with two atoms in the tether (7c,g,l and 8i). Tethering has a marked
effect on the catalytic performance transfer hydrogenation of acetophenone and on the nature of hydridic species originating
during the activation period. The chiral induction attains 58% ee with complexes with the bulkiest substituents in the pendant
arm of the phosphine. Three of the prepared complexes can interact with DNA and present a reasonable cytotoxicity toward
cancer cells. Intercalation of the free aromatic pendant arm of the phosphines seems to be fundamental for such interactions.
Conversion of 4'-(2,5-dihydrophenyl)butanol or N-trifluoroacetyl-2,5-dihydrobenzylamine with MCl3 center dot nH(2)O (M-Ru, Os) affords the corresponding dimeric eta(6)-arene complexes in good to excellent yields. Under similar reaction conditions, the amine functionalized arene precursor 2,5-dihydrobenzylamine yields the corresponding Ru(II) complex. For osmium, HCl induced oxidation leads to formation of [OsCl6](2-) salts. However, under optimized reaction conditions, conversion of the precursor 2,5-dihydrobenzylamine chloride results in clean formation of eta(6)-arene Os(II) complex. X-ray structures of [(eta(6)-benzyl ammonium)(dmso) RuCl2] and (2,5-dihydrobenzyl ammonium) 4[OsCl6](2)confirm the spectroscopic data. High stability towards air and acid as well as enhanced solubility in water is observed for all eta(6)-arene complexes. (C) 2010 Elsevier B.V. All rights reserved.
A library of 29 organoosmium compounds has been built up with known and novel cyclometalated compounds obtained with C-N, NCN, and CNN ligands. All compounds have been tested for their in vitro cytotoxic properties against A172, a tumor cell line derived from a human glioblastoma, this affording a contrasted picture of the activities of the compounds gathered in this study. Some compounds displayed good to excellent activities, some of them showing IC in the nanomolar range. The level of activity was tentatively correlated to several physicochemical properties of the compounds such as their E(Os) redox potential and their lipophilicity (log P). A parallel with related ruthenium derivatives was tentatively proposed.
Golden times for metal-based drugs? Alkynyl triphenylphosphine gold(I) complexes display interesting biological properties and show high potential for future drug development. They are strong inhibitors of the enzyme thioredoxin reductase, trigger antiproliferative effects in tumor cells, and influence tumor cell metabolism, mitochondrial respiration, and angiogenesis in zebrafish embryos.
The isomerisation between the three known isomers of the [OsCl2(dmso)4] complex — trans-[OsCl2(dmso-S)4] (1), cis,fac-[OsCl2(dmso-S)3(dmso-O)] (2), and cis-[OsCl2(dmso-S)4] (3) — has been investigated by NMR spectroscopy, X-ray crystallographic analysis, and DFT calculations. We show that the two dmso-linkage isomers 2 and 3 equilibrate slowly at room temperature in solutions of both dimethyl sulfoxide (DMSO) and light-protected chloroform. Although crystals of 2 precipitate from DMSO solutions, crystals of 3 were obtained from chloroform solutions. Compound 2 isomerises to 1 after exposure to sunlight, while 1 transforms into 2 in hot DMSO solution. The molecular energies were calculated by DFT methods, which show that in the gas phase there are small differences in the total energies (Et), with 1 exhibiting the lowest energy, in contrast with its low population in solution. This result indicates that the stability of each isomer in solution is not simply determined by Et, but that the solvent plays an important role. In fact, quantum chemical calculations for the isomerisation process 1 ⇄ 2 show a marked increase in the equilibrium constant with increasing the solvent polarity. The calculation of the metal−dmso binding energies, in combination with the X-ray data, shows a significantly higher strength of Os−S bonds with respect to Ru−S bonds, which explains the different behaviour of otherwise analogous osmium−dmso and ruthenium−dmso complexes. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
(η6-Arene)ruthenium(II) complexes of the type [{[η6-C6H5(CH2)nCOOH]Ru(µ-Cl)Cl}2] (2a, n = 1; 3, n = 3) with tethered carboxylate groups can be obtained by dehydrogenation of the appropriate cyclohexadiene with RuCl3·3H2O. Formation of a κO-coordinated chelate in weakly acidic solution is observed by means of a 1H NMR titration for both [{η6-C6H5(CH2)3COOH}Ru(aq)](OTf)2 (3a′) and [{η6-C6H5(CH2)3COOH}Ru(phen)(aq)](OTf)2 (5′). Sandwich complexes of the type [{η6-C6H5(CH2)3COOH}Ru(η6-amino acid)](OTf)2 [amino acid = AcpheOH (6), ActyrOEt (7), ActrpOH (8)] can be prepared by treating [{η6-C6H5(CH2)3COOH}Ru(acetone)3](OTf)2 with the appropriate aromatic bioligand in CF3COOH (6/8) or CH2Cl2 (7). Chemospecific η6-labelling of the C-terminal indole function is observed for the peptide HphetrpOH in the analogous complex 9. Quantitative formation of 8 can also be achieved in aqueous solution in the presence of a 3:1 excess of the {η6-C6H5(CH2)3COOH}RuII fragment. This can also be employed for the N-terminal labelling of amino acids and peptides in its sandwich complex [(η6-C6Me6)Ru{η6-C6H5(CH2)3COOH}](OTf)2 (10). Coupling reactions by the carbodiimide method with EDC afford water-stable complexes of the type [(η6-C6Me6)Ru{η6-C6H5(CH2)3C(O)R}](OTf)2 [R = trpOMe (11), pheOMe (12), glyglyOEt (13)] in good yields. X-ray structures of [(η6-C6H5CH2COOC2H5)RuCl(phen)](OTf) (4b′) and 10 are reported. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
The thioredoxin system plays a key role in regulating the overall intracellular redox balance. It basically comprises the small redox protein thioredoxin (Trx), nicotinamide adenine dinucleotide phosphate, in its reduced form (NADPH), and thioredoxin reductase (TrxR), a large homodimeric selenzoenzyme controlling the redox state of thioredoxin. Details of the thioredoxin system are provided herein, particular emphasis being given to the protein chemistry of thioredoxin reductases. Several lines of evidence point out today that the thioredoxin system represents an effective “druggable” target for the development of new anticancer agents. Accordingly, a number of established anticancer agents were retrospectively found to be potent inhibitors of thioredoxin reductases and to induce severe oxidative stress. During the last decade a variety of gold compounds, either gold(I) or gold(III), were reported to manifest outstanding antitumor properties, forming a promising class of experimental anticancer agents. In turn, recent studies have revealed that several cytotoxic gold compounds, either gold(I) or gold(III), are potent TrxR inhibitors. Details of their mechanism of selenoenzyme inhibition are currently under investigation, in our laboratory, and some new results will be anticipated here; notably, preferential gold targeting of active site selenolate could be experimentally supported. Based on the numerous experimental evidences now available, both at the molecular and cellular level, we propose that the relevant cytotoxic actions produced by gold compounds are mainly the result of potent inhibition of thioredoxin reductase; the alterations of mitochondrial functions, elicited by profound TrxR inhibition, would eventually lead to cell apoptosis. A general and unitary framework is thus offered to interpret the mode of action of cytotoxic gold compounds, according to which they should be primarily considered as antimitochondrial drugs. The peculiar properties of gold compounds highlighted in this review might be further exploited for the obtainment of newer and selective anticancer agents.
Anthracene derivatives of ruthenium(II) arene compounds with 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (pta) or a sugar phosphite ligand, viz., 3,5,6-bicyclophosphite-1,2-O-isopropylidene-α-d-glucofuranoside, were prepared in order to evaluate their anticancer properties compared to the parent compounds and to use them as models for intracellular visualization by fluorescence microscopy. Similar IC(50) values were obtained in cell proliferation assays, and similar levels of uptake and accumulation were also established. The X-ray structure of [{Ru(η(6)-C(6)H(5)CH(2)NHCO-anthracene)Cl(2)(pta)] is also reported.
The novel steroidal conjugate 17-α-[2-phenylpyridyl-4-ethynyl]-19-nortestosterone (LEV-ppy) (1) and the steroid-C,N-chelate ruthenium(II) conjugate [Ru(η(6)-p-cymene)(LEV-ppy)Cl] (2) have been prepared. At 48 h incubation time, complex 2 is more active than cisplatin (about 8-fold) in T47D (breast cancer) and also shows an improved efficiency when compared to its nonsteroidal analogue [Ru(η(6)-p-cymene)(ppy)Cl] (ppy = phenylpyridine) (3) in the same cell line. The act of conjugating a levonorgestrel group to a ruthenium(II) complex resulted in synergistic effects between the metallic center and the steroidal ligand, creating highly potent ruthenium(II) complexes from the inactive components. The interaction of 2 with DNA was followed by electrophoretic mobility. Theoretical density functional theory calculations on complex 2 show the metal center far away from the lipophilic steroidal moiety and a labile Ru-Cl bond that allows easy replacement of Cl by N-nucleophiles such as 9-EtG, thus forming a stronger Ru-N bond. We also found a minimum energy location for the chloride counteranion (4(+)·Cl(-)) inside the pseudocavity formed by the α side of the steroid moiety, the phenylpyridine chelating subsystem, and the guanine ligand, i.e., a host-guest species with a rich variety of nonbonding interactions that include nonclassical C-H···anion bonds, as supported by electrospray ionization mass spectra.
Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.
Iodido osmium(II) complexes [Os(η(6)-arene)(XY)I](+) (XY = p-hydroxy or p-dimethylaminophenylazopyridine, arene = p-cymene or biphenyl) are potently cytotoxic at nanomolar concentrations toward a panel of human cancer cell lines; e.g., IC(50) = 140 nM for [Os(η(6)-bip)(azpy-NMe(2))I](+) toward A2780 ovarian cancer cells. They exhibit low toxicity and negligible deleterious effects in a colon cancer xenograft model, giving rise to the possibility of a broad therapeutic window. The most active complexes are stable and inert toward aquation. Their cytotoxic activity appears to involve redox mechanisms.
Double trouble: A hybrid organic-inorganic (organometallic) inhibitor was designed to target glutathione transferases. The metal center is used to direct protein binding, while the organic moiety acts as the active-site inhibitor (see picture). The mechanism of inhibition was studied using a range of biophysical and biochemical methods.
Chlorido osmium(II) arene [(eta(6)-biphenyl)Os(II)(X-pico)Cl] complexes containing X = Br (1), OH (2), and Me (3) as ortho, or X = Cl (4), CO(2)H (5), and Me (6) as para substituents on the picolinate (pico) ring have been synthesized and characterized. The X-ray crystal structures of 1 and 6 show typical "piano-stool" geometry with intermolecular pi-pi stacking of the biphenyl outer rings of 6. At 288 K the hydrolysis rates follow the order 2 > 6 > 4 > 3 > 5 > 1 with half-lives ranging from minutes to 4.4 h illustrating the influence of both electronic and steric effects of the substituents. The pK(a) values of the aqua adducts 3A, 4A, 5A, and 6A were all in the range of 6.3-6.6. The para-substituted pico complexes 4-6 readily formed adducts with both 9-ethyl guanine (9EtG) and 9-ethyl adenine (9EtA), but these were less favored for the ortho-substituted complexes 1 and 3 showing little reaction with 9EtG and 9EtA, respectively. Density-functional theory calculations confirmed the observed preferences for nucleobase binding for complex 1. In cytotoxicity assays with A2780, cisplatin-resistant A2780cis human ovarian, A549 human lung, and HCT116 colon cancer cells, only complexes 4 (p-Cl) and 6 (p-Me) exhibited significant activity (IC(50) values < 25 microM). Both of these complexes were as active as cisplatin in A2780 (ovarian) and HCT116 (colon) cell lines, and even overcome cisplatin resistance in the A2780cis (ovarian) cell line. The inactivity of 5 is attributed to the negative charge on its para carboxylate substituent. These data illustrate how the chemical reactivity and cancer cell cytotoxicity of osmium arene complexes can be controlled and "fine-tuned" by the use of steric and electronic effects of substituents on a chelating ligand to give osmium(II) arene complexes which are as active as cisplatin but have a different mechanism of action.
The novel luminescent gold(I) complex [N-(N',N'-dimethylaminoethyl)-1,8-naphthalimide-4-sulfide](triethylphosphine)gold(I) was prepared and investigated for its primary biological properties. Cell culture experiments revealed strong antiproliferative effects and induction of apoptosis via mitochondrial pathways. Biodistribution studies by fluorescence microscopy and atomic absorption spectroscopy showed the uptake into cell organelles, an accumulation in the nuclei of tumor cells, and a homogeneous distribution in zebrafish embryos. In vivo monitoring of vascularisation in developing zebrafish embryos revealed a significant anti-angiogenic potency of the complex. Mechanistic experiments indicated that the inhibition of thioredoxin reductase (based on the covalent binding of a gold triethylphosphine fragment) might be involved in the pharmacodynamic behavior of this novel gold species.
The reaction of electron-rich carbene-precursor olefins containing two imidazolinylidene moieties [(2,4,6-Me(3)C(6)H(2)CH(2))NCH(2)CH(2)N(R)Cdbond;](2) (2a: R=CH(2)CH(2)OMe, 2 b R=CH(2)Mes), bearing at least one 2,4,6-trimethylbenzyl (R=CH(2)Mes) group on the nitrogen atom, with [RuCl(2)(arene)](2) (arene=p-cymene, hexamethylbenzene) selectively leads to two types of complexes. The cleavage of the chloride bridges occurs first to yield the expected (carbene) (arene)ruthenium(II) complex 3. Then a further arene displacement reaction takes place to give the chelated eta(6)-mesityl,eta(1)-carbene-ruthenium complexes 4 and 5. An analogous eta(6)-arene,eta(1)-carbene complex with a benzimidazole frame 6 was isolated from an in situ reaction between [RuCl(2)(p-cymene)](2), the corresponding benzimidazolium salt and cesium carbonate. On heating, the RuCl(2)(imidazolinylidene) (p-cymene) complex 8, with p-methoxybenzyl pendent groups attached to the N atoms, leads to intramolecular p-cymene displacement and to the chelated eta(6)-arene,eta(1)-carbene complex 9. On reaction with AgOTf and the propargylic alcohol HCtbond;CCPh(2)OH, compounds 4-6 were transformed into the corresponding ruthenium allenylidene intermediates (4-->10, 5-->11, 6-->12). The in situ generated intermediates 10-12 were found to be active and selective catalysts for ring-closing metathesis (RCM) or cycloisomerisation reactions depending on the nature of the 1,6-dienes. Two complexes [RuCl(2)[eta(1)-CN(CH(2)C(6)H(2)Me(3)-2,4,6)CH(2)CH(2)N- (CH(2)CH(2)OMe)](C(6)Me(6))] 3 with a monodentate carbene ligand and [RuCl(2)[eta(1)-CN[CH(2)(eta(6)-C(6)H(2)Me(3)-2,4,6)]CH(2)CH(2)N-(CH(2)C(6)H(2)Me(3)-2,4,6)]] 5 with a chelating carbene-arene ligand were characterised by X-ray crystallography.
The osma(II)cycles [Os(phpy)(LL)(2)]PF(6) (LL = 1,10-phen (3a) and 4,4'-Me(2)-2,2'-bpy (3b)) are made from [(eta(6)-C(6)H(6))Os(micro-Cl)Cl](2) (1) either via transmetalation using the [Hg(phpy)(2)] organomercurial in MeOH or via the sp(2)-C-H bond cleavage of 2-phenylpyridine (phpyH) in MeCN to afford [(eta(6)-C(6)H(6))Os(phpy)Cl] or [(eta(6)-C(6)H(6))Os(phpy)(MeCN)]PF(6), respectively. The latter two react cleanly with LL to give 3a and 3b, the M(II/III) redox potentials of which equal 30 and -100 mV (vs Ag/AgCl), respectively. The electrochemically made Os(III) species oxidize rapidly reduced glucose oxidase. The second-order rate constant equals 1.1 x 10(7) M(-)(1) s(-)(1) for 3a at 25 degrees C, pH 7.