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Abstract
Six platinum(IV) compounds derived from an oxaliplatin analogue containing the unsaturated cyclic diamine trans-1,2-diamino-4-cyclohexene (DACHEX), in place of the 1,2-diaminocyclohexane, and a range of axial ligands, were synthesized and characterized. The derivatives with at least one axial chlorido ligand demonstrated solvent-assisted photoreduction. The electrochemical redox behavior was investigated by cyclic voltammetry; all compounds showed reduction potentials suitable for activation in vivo. X-ray photoelectron spectroscopy (XPS) data indicated an X-ray-induced surface reduction of the Pt(IV) substrates, which correlates with the reduction potentials measured by cyclic voltammetry. The cytotoxic activity was assessed in vitro on a panel of human cancer cell lines, also including oxaliplatin-resistant cancer cells, and compared with that of the reference compounds cisplatin and oxaliplatin; all IC50 values were remarkably lower than those elicited by cisplatin and somewhat lower than those of oxaliplatin. Compared to the other Pt(IV) compounds of the series, the bis-benzoate derivative was by far (5–8 times) the most cytotoxic showing that low reduction potential and high lipophilicity are essential for good cytotoxicity. Interestingly, all the complexes proved to be more active than cisplatin and oxaliplatin even in three-dimensional spheroids of A431 human cervical cancer cells.
Highlights
The clinical efficacy demonstrated by the three platinum-based drugs currently approved by the U.S Food and Drug Administration, has prompted over the years an intense research activity aiming to identify new metal-based anticancer drugs with enhanced efficacy, lower toxicity, and a broader spectrum of activity [1,2]
It was found that the 1,2-GG intrastrand crosslinks formed by kiteplatin are removed by DNA repair systems with lower efficiency than those formed by cisplatin and are more effective in inhibiting DNA polymerases such as the model prokaryotic DNA polymerase I (KF−) of the A-family and the eukaryotic translesion DNA polymerase η (Pol η) of the Y-family human DNA polymerases [7,8,9]
Based on the preliminary results obtained for the Pt(II) complex [Pt(OXA)(DACHEX)], which proved to have a cytotoxic activity better than that of cisplatin and comparable to or better than that of oxaliplatin and to be active against LoVo and LoVo-OXP cells, in this paper we have extended the investigation to corresponding Pt(IV) derivatives having different ligands in the axial positions
Summary
The clinical efficacy demonstrated by the three platinum-based drugs currently approved by the U.S Food and Drug Administration (cisplatin, carboplatin, and oxaliplatin), has prompted over the years an intense research activity aiming to identify new metal-based anticancer drugs with enhanced efficacy, lower toxicity, and a broader spectrum of activity [1,2]. The third generation drug oxaliplatin has, in spite of two ammines, a chelating aliphatic diamine (1R,2R-diaminocyclohexane, 1R,2R-DACH) as carrier ligand. In the search for alternatives capable of bypassing the resistance; the Pt(II) complex [PtCl2(cis-1,4-DACH)], named kiteplatin, carrying a structural isomer of the 1R,2R-diaminocyclohexane ligand present in oxaliplatin, has emerged as a valid alternative encompassing a very promising anticancer activity [6]. It was found that the 1,2-GG intrastrand crosslinks formed by kiteplatin are removed by DNA repair systems with lower efficiency than those formed by cisplatin and are more effective in inhibiting DNA polymerases such as the model prokaryotic DNA polymerase I (KF−) of the A-family and the eukaryotic translesion DNA polymerase η (Pol η) of the Y-family human DNA polymerases [7,8,9]
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