Metal-Based Drugs (Met Base Drugs)

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  Article: Synthesis, structure, electrochemistry, and cytotoxic properties of ferrocenyl ester derivatives.

  Li Ming Gao, Ramón Hernández, Jaime Matta, Enrique Meléndez
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  ABSTRACT: A series of ferrocenyl ester complexes, varying the lipophilic character of the pendant groups, was prepared and characterized by spectroscopic and analytical methods. The syntheses of Fe(C(5)H(4)CO(2)CH(3))(2), Fe(CpCOOCH(3)) (CpCOO CH(2)CH(3)), and Fe(CpCOOCH(2)CH(3))(2) are reported. The solid-state structure of Fe(C(5)H(4)CO(2)CH(3))(2) has been determined by X-ray crystallography. Fe(C(5)H(4)CO(2)CH(3))(2) has the cyclopentadienyl rings virtually in an eclipsed conformation with the pendant groups not completely opposite to each other. Cyclic voltammetry characterization showed that the functionalized ferrocenes oxidize at potentials, E(pa), higher than ferrocene as a result of the electro withdrawing effect of the pendant groups on the cyclopentadienyl ligand. The cytotoxicities of Fe(C(5)H(4)CO(2)CH(2)CH(2)OH)(2), Fe(C(5)H(4)CO(2)CH(2)CH=CH(2))(2), Fe(C(5)H(4)CO(2)CH(3))(2), Fe(CpCOOCH(3))(CpCOOCH(2)CH(3)), and Fe(CpCOOCH(2)CH(3))(2) in colon cancer HT-29 and breast cancer MCF-7 cell lines were measured by the MTT biological viability assay and compared to ferrocene and ferrocenium. Fe(C(5)H(4)CO(2)CH(2)CH=CH(2))(2) showed the best IC(50) values, 180(10) muM for HT-29 and 190(30) muM for MCF-7 cell lines, with cytotoxicities similar to ferrocenium. The cytotoxic data suggest that as we increase the lipophilic character of the functionalized ferrocene, the cytotoxicity improves approaching to the cytotoxic activity of ferrocenium.
  Metal-Based Drugs 02/2009; 2009:420784.
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  Article: Synthetic polymers as drug-delivery vehicles in medicine.

  Eberhard W Neuse
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  ABSTRACT: Cancerous diseases present a formidable health problem worldwide. While the chemotherapy of cancer, in conjunction with other treatment modalities, has reached a significant level of maturity, efficacious use of such agents is still restricted by numerous pharmacological deficiencies, such as poor water solubility, short serum circulation lifetimes, and low bioavailability resulting from lack of affinity to cancer tissue and inadequate mechanisms of cell entry. More critically still, most drugs suffer from toxic side effects and a risk of drug resistance. The class of platinum anticancer drugs, although outstandingly potent, is particularly notorious in that respect. Among the countless methods developed in recent years in an effort to overcome these deficiencies, the technology of polymer-drug conjugation stands out as a particularly advanced treatment modality. The strategy involves the bioreversible binding, conjugating, of a medicinal agent to a water-soluble macromolecular carrier. Following pharmacokinetic pathways distinctly different from those of the common, nonpolymeric drugs, the conjugate so obtained will act as a prodrug providing safe transport of the bioactive agent to and into the affected, that is, cancerous cell for its ultimate cell-killing activity. The present treatise will acquaint us with the pharmacological fundamentals of this drug delivery approach, applied here specifically to the metalorganic platinum-type drug systems and the organometallic ferrocene drug model. We will see just how this technology leads to conjugates distinctly superior in antiproliferative activity to cisplatin, a clinically used antitumor agent used here as a standard. Polymer-drug conjugation involving metal-based and other medicinal agents has unquestionably matured to a practical tool to the pharmaceutical scientist, and all indications point to an illustrious career for this nascent drug delivery approach in the fight against cancer and other human maladies.
  Metal-Based Drugs 02/2008; 2008:469531.
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  Article: Synthesis and photophysical properties of tetra- and octasubstituted phosphorous oxide triazatetrabenzcorrole photosensitizers.

  Edith M Antunes, Tebello Nyokong
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  ABSTRACT: The synthesis of phosphorous oxide triazatetrabenzcorroles (TBC) tetra- (9, 11) or octa- (13) substituted on the ring with halogenated functional groups is reported. The complexes are not aggregated in dimethylsulfoxide (DMSO) and show solubility in solvents such as pyridine. The Q band absorption spectra of the complexes are red-shifted compared to unsubstituted PTBC. The latter complex shows a large triplet lifetime (1.7 milliseconds), higher than for MPc derivatives. The chlorinated derivatives show good triplet yields (Phi(T) approximately 0.46 and 0.36) and relatively long lifetimes (256 and 452 microseconds), respectively, for 11 and 13.
  Metal-Based Drugs 02/2008; 2008:498916.
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  Article: Synthesis and cytotoxicity studies of titanocene C analogues.

  Megan Hogan, James Claffey, Eoin Fitzpatrick, Thomas Hickey, Clara Pampillón, Matthias Tacke
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  ABSTRACT: From the carbolithiation of 6-N,N-dimethylamino fulvene (3) and 2,4[bis(N,N-dimethylamino)methyl]-N-methylpyrrolyl lithium (2a), N-(N',N'-dimethylaminomethyl)benzimidazolyl lithium (2b), or p-(N,N-dimethylamino)methylphenyl lithium (2c), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl(4') resulting in N,N-dimethylamino-functionalised titanocenes 5a-c. When these titanocenes were tested against a pig kidney epithelial cell line (LLC-PK), the IC50 values obtained were of 23, and 52 muM for titanocenes 5a and 5b, respectively. The most cytotoxic titanocene in this paper, 5c with an IC50 value of 13 muM, was found to be approximately two times less cytotoxic than its analogue Titanocene C (IC50=5.5 muM) and almost four times less cytotoxic than cisplatin, which showed an IC50 value of 3.3 muM when tested on the LLC-PK cell line.
  Metal-Based Drugs 02/2008; 2008:754358.
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  Article: Investigation of Zinc bis(1,4-didecylbenzo)-bis(2,3-pyrido) Porphyrazine for Application as Photosensitizer in Photodynamic Therapy of Cancer.

  Keiichi Sakamoto, Eiko Ohno-Okumura, Taku Kato, Masaki Watanabe, Michael J Cook
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  ABSTRACT: The phthalocyanine analogue containing nonperipheral long alkyl-substituted benzenoid rings and pyridine rings, zinc bis(1,4-didecylbenzo)-bis(2,3-pyrido) porphyrazine, was synthesized. Zinc bis(1,4-didecylbenzo)-bis(2,3-pyrido) porphyrazine reacted with dimethyl sulfate and monochloroacetic acid to produce their quaternized products and diethyl sulfate to produce the sulfo-substituted products. All quaternized and sulfo-substituted showed amphiphilic character. Identical peaks in cyclic voltammograms appeared for these products before and after quaternization. During the evaluation of zinc bis(1,4-didecylbenzo)-bis(2,3-pyrido) porphyrazine for its photodynamic therapy of cancer (PDT) efficacy by cancer cell culture, the light exposed dimethyl sulfate quaternized zinc bis(1,4-didecylbenzo)-bis(2,3-pyrido) porphyrazines in IU-002 cells produce cell disruption that can be detected as a decrease in fluorescence.
  Metal-Based Drugs 02/2008; 2008:392090.
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  Article: Phthalocyanine-based molecularly imprinted polymers as nucleoside receptors.

  Luigia Longo, Giuseppe Vasapollo
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  ABSTRACT: A molecularly imprinted polymer (MIP) for tri-O-acetyladenosine (TOAA), PPM(TOAA), was prepared by the combined use of methacrylic acid (MAA) and Zn(II)tetra(4'-methacryloxyphenoxy) phthalocyanine as functional monomers. This MIP exhibited a higher binding ability for TOAA compared to the MIP prepared using only MAA, PM(TOAA), in batch rebinding tests. Scatchard analysis gave a higher association constant of PPM(TOAA) for TOAA (2.96x104 M-1) than that of PM(TOAA) (1.48x104 M-1). The MIP prepared using only the zinc-phthalocyanine, PP(TOAA), did not show any binding capacity for TOAA. This means that the phthalocyanine in the MIP contributes to higher affinities, although it barely interacts with TOAA. Since selectivity for this kind of MIPs is more important than binding affinity, the binding of TOAA and a structurally related compound, tri-O-acetyluridine (TOAU), on the polymers was investigated. Both PPM(TOAA) and PM(TOAA) exhibited binding affinities for TOAA while they did not show any binding capacity for TOAU.
  Metal-Based Drugs 02/2008; 2008:281843.
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  Article: Synthesis, structural, and biological studies of some schiff bases and their metal complexes.

  A P Mishra, Monika Soni
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  ABSTRACT: New bidentate or tridentate Schiff bases and their VO(II) and Co(II) complexes formed by the condensation of methyl isobutyl ketone with nicotinamide (mna)/2-amino-4-chlorophenol (map) and 2-hydroxy acetophenone with nicotinamide (han)/isoniazide (hai). Physicochemical characterization has been carried out to determine the structure of the complexes. The FAB mass and thermal data show degradation pattern of the complexes. XRD analysis reveals that all the studied complexes crystallize as tetragonal crystal system. Some of the complexes have been screened for their antimicrobial activity by the well diffusion technique using DMSO as solvent on different species of pathogenic bacteria/fungi, that is, E. coli, S. aureus, S. fecalis, A. niger, T. polysporum, and their antimicrobial potency have been discussed. It has been found that all the complexes are antimicrobially active and show higher activity than the free ligand. Metal chelation affects significantly the antimicrobial/bioactive behavior of the organic ligands.
  Metal-Based Drugs 02/2008; 2008:875410.
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  Article: Nuclear Factor-kappa B as a Resistance Factor to Platinum-Based Antineoplasic Drugs.

  Vilma Maldonado Lagunas, Jorge Meléndez-Zajgla
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  ABSTRACT: Platinum drugs continue to be major chemotherapy drugs for cancer treatment. Nevertheless, acquired or intrinsic resistance to these compounds is common in human tumors. One important mechanism for this resistance is the avoidance of cells entering the apoptotic pathway. Nuclear factor-kappa B (NF-kappa B, NF-kappaB) is a pleiotropic transcription factor key in determining the death threshold of human cells. This factor is important in the final response of cells to platinum drugs, as exemplified by in vitro and in vivo models showing that inhibition of NF-kappaB sensitizes cancer cells to the effects of these drugs. New approaches focusing on the inhibition of NF-kappaB could help to minimize or even eliminate intrinsic or acquired resistance to platinum drugs.
  Metal-Based Drugs 02/2008; 2008:576104.
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  Article: Kinetic and high-pressure mechanistic investigation of the aqua substitution in the trans-aquaoxotetracyano complexes of re(v) and tc(v): some implications for nuclear medicine.

  J Mattheus Botha, Andreas Roodt
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  ABSTRACT: A kinetic study of the aqua substitution in the [TcO(OH(2))(CN)(4)](-) complex by different thiourea ligands (TU = thiourea, NMTU = N-methyl thiourea, NNDMTU = N, N'-dimethylthiourea) yielded second-order formation rate constants (25 degrees C) as follows [NNDMTU, NMTU, TU, respectively]: k(f) = 11.5 +/- 0.1, 11.38 +/- 0.04, and 7.4 +/- 0.1 M(-1)s(-1), with activation parameters: Delta H(#) (k(f) ) : 55 +/- 2, 42 +/- 3, 35 +/- 5 kJ mol(-1); DeltaS(#) (k(f) ) : - 40 +/- 8, - 84 +/- 11, - 110 +/- 17 J K(-1)mol(-1). A subsequent high-pressure investigation of the aqua substitution in the [ReO(OH(2))(CN)(4)](-) and [TcO(OH(2))(CN)(4)](-) complexes by selected entering ligands yielded DeltaV(#) (k(f) ) values as follows: Re(V): -1.7 +/- 0.3(NCS(-)), -22.1 +/- 0.9 (TU) and for Tc(V): -3.5 +/- 0.3(NCS(-)), -14 +/- 1 (NNDMTU), and -6.0 +/- 0.5 (TU) cm(3)mol (-1), respectively. These results point to an interchange associative mechanism for the negative NCS(-) as entering group but even a pure associative mechanism for the neutral thiourea ligands.
  Metal-Based Drugs 02/2008; 2008:745989.
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  Article: Synthesis, Characterization, and In Vitro Photodynamic Activity of Novel Amphiphilic Zinc(II) Phthalocyanines Bearing Oxyethylene-Rich Substituents.

  Jian-Yong Liu, Xiong-Jie Jiang, Wing-Ping Fong, Dennis K P Ng
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  ABSTRACT: Three novel zinc(II) phthalocyanines substituted with one or two 3,4,5-tris(3,6,9-trioxadecoxy)benzoxy group(s) have been prepared and spectroscopically characterized. These compounds are highly soluble and remain nonaggregated in N,N-dimethylformamide. Upon excitation, they exhibit a relatively weak fluorescence emission and high efficiency to generate singlet oxygen compared with the unsubstituted zinc(II) phthalocyanine. These amphiphilic photosensitizers formulated with Cremophor EL are highly photocytotoxic against HT29 human colon adenocarcinoma and HepG2 human hepatocarcinoma cells. The mono-alpha-substituted analogue 4 is particularly potent with IC50 values as low as 0.02 muM. The higher photodynamic activity of this compound can be attributed to its lower aggregation tendency in the culture media as shown by absorption spectroscopy and higher cellular uptake as suggested by the stronger intracellular fluorescence, resulting in a higher efficiency to generate reactive oxygen species inside the cells.
  Metal-Based Drugs 02/2008; 2008:284691.
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  Article: Arsenic-based antineoplastic drugs and their mechanisms of action.

  Stephen John Ralph
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  ABSTRACT: Arsenic-based compounds have become accepted agents for cancer therapy providing high rates of remission of some cancers such as acute promyelocytic leukemia (APL). The mechanisms by which arsenic-containing compounds kill cells and reasons for selective killing of only certain types of cancer cells such as APLs have recently been delineated. This knowledge was gained in parallel with increasing understanding and awareness of the importance of intracellular redox systems and regulation of the production of reactive oxygen species (ROS) by controlling mitochondrial function. Many of the targets for the arsenic-containing compounds are mitochondrial proteins involved in regulating the production of ROS. Inhibition of these proteins by disulfide linkage of vicinal thiol groups often leads to increased production of ROS and induction of apoptotic signalling pathways. Sensitivity or resistance to the actions of arsenic-containing compounds on cancer cells and normal cells depends on the levels of transport systems for their uptake or efflux from the cells as well as their redox defence mechanisms. The exact mechanisms of arsenic toxicity as well as its anticancer properties are likely to be related and these aspects of arsenic metabolism are covered in this review. Greater understanding of the mechanisms of action of arsenic will help determine the risks of human exposure to this chemical. Novel organic arsenic-containing compounds and the lessons learned from studying their selective sensitivity in targeting dividing endothelial cells to inhibit angiogenesis raise the future possibility for designing better targeted antineoplastic arsenic-containing compounds with less toxicity to normal cells.
  Metal-Based Drugs 02/2008; 2008:260146.