Copper Imidazole Derivatives Complexes

The strong anti-tumour activity of the trans-bis (acetato) bis (imidazole) copper(II) complex [Cu(O2CMe)2(HIm)2], against the mouse cancer cell line B16 melanoma is well known.51 A similar complex [Cu(O2CMe)2L2] (1), where L = 1-methyl-4,5-diphenylimidazole, has been synthesized and its effects on the induction of cell division delays, on Sister Chromatid Exchanges (SCEs) and on the suppression of Mitotic Indices (MIs) were examined as well.52 SCEs have been proposed as a very sensitive method for detecting mutagens and/or carcinogens and furthermore as a method of evaluating chemotherapy in vitro and in vivo.53,54

The crystal structure of complex 1 indicates that two L molecules (via the pyridine-type N atoms) and two acetate ligands (via the carboxylate O atoms) are coordinated to the metal ion, forming a nearly square-planar arrangement. The Cu atom is six-coordinate with the ligand atoms forming a distorted octahedron. As expected, the structure of 1 shows a remarkable similarity to that of the anti-tumour complex [Cu(O2CMe)2(HIm)2].

The effect of complex 1 on the plasmid pKS DNA was examined, looking for the change of the conformational forms of the plasmid from the closed circular supercoiled (form I) to the open circular relaxed (form II). The unwinding effect of complex 1 is clearly observed when the plasmid is incubated with low concentrations (0.1 or 0.2 mM) of the compound (Figure 12.4), as seen from the progressive increase of the amount of the relaxed DNA (form II). Concentrations of the complex above 0.5 mM cause scissions on both forms of DNA, as shown by the appearance of a reduced amount of DNA in the gel.

Complex 1 induced small but non-significant changes in SCEs. By contrast, the complex induced a reduction of the proliferation rate index (PRI), an indicator of the cytostatic effect, and a reduction of MIs, an indicator of the cytotoxic effect, on human lymphocytes in cultures.

The obtained results show that concentrations of complex 1 between 0.77 x 10~7 and 1.54 x 10~6 M produced cytogenetic damage in culture human

Figure 12.4 Agarose gel electrophoretic patterns of plasmid bluescript KS incubated with different concentrations of 1 (in mM). Lane l: kDNA/Hind III markers; lane c: intact pKS. Form III: catenanes or knott forms of DNA

Figure 12.4 Agarose gel electrophoretic patterns of plasmid bluescript KS incubated with different concentrations of 1 (in mM). Lane l: kDNA/Hind III markers; lane c: intact pKS. Form III: catenanes or knott forms of DNA

lymphocytes. This DNA damage was observed by the induction of SCEs and the reduction of PRIs and MIs, indicating high cytostatic and cytotoxic action of 1. Thus, the vulnerability of cells to 1 may be interpreted as having some relevance to the treatment of human cancer.

Chelating donor ligands as N,N'-1,10-phenanthroline (phen) are potent in vitro inhibitors of the growth of Candida albicans, a commensal of the human body considered to be an important fungal pathogen which is often fatal in immuno-compromised patients.55,56 Phen itself and its metal complexes represent a novel set of highly active anti-fungal agents whose mode of action is significantly different from that of the state-of-the-art polyene and azole prescription. Additionally, benzimidazole and many of its derivatives exhibit a variety of biological actions, including anti-bacterial, -viral, -cancer and -fungal activity.57

The compound 2-(4'-thiazolyl)benzimidazole, {thiabendazole (TBZH) (1)}, (Scheme 12.7), with structural features common to phen and benzimidazole is non-toxic to humans and used as a fungicide in agriculture. Reactions of 1 with copper(II) acetate, chloride, nitrate and butanedioate yields [Cu(TBZH)2 (H2O)2] (2), [Cu(TBZH)2Cl]Cl• H2O • EtOH (3), [Cu(TBZH)2(NO3)2] (4) and [Cu(TBZH)(O2C CH2CH2 CO2)] (5), respectively. The molecular structure of complex 3 comprises a five-coordinate copper centre with the metal bound to two chelating TBZH ligands and one chloride ion. The geometry is best described as trigonal bipyramidal.58

The chemotherapeutic potential (IC50) of 1, 3 and 4 towards the human squamous carcinoma tongue cell line, CAL-27, and the malignant melanoma (melanocyte) skin cell line, SK-MEL-31, was determined. TBZH was capable of killing both cancer lines only at higher concentrations with IC50 value of 91.7 and 136.9 mg/ml, for the tongue and skin cell line, respectively. In the case of compounds 3 and 4, the IC50 values were almost identical (33.1 and 31.9 mg/ml, respectively) in the CAL-27 cell line and 39.1 and 30.7 mg/ml, respectively, in the SK-MEL-31 cell line. These doses were found to be significantly lower than that for the metal-free TBZH.

To date TBZH is the first N,N'-donor ligand that, in vitro, exhibits poor anticandida activity on its own but when complexed to a copper(II) centre becomes relatively potent.

Structure of thiabendazole

Scheme 12.7

Copper-Polycarboxylate Complexes 233

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