No abstract

The reaction of p-isopropylbenzaldehyde thiosemicarbazone [p-is.TSCN], 1, with palladium(II) acetate and potassium tetrachloroplatinate yielded two tetrameric orthopalladated isomers, [Pd(p-is.TSCN)]4 (complexes 2 and 3), and the platinum analogue [Pt(p-is.TSCN)]4 (complex 4), respectively. All of these complexes contain the thiosemicarbazone bonded as a terdentate ligand to the metallic atom, through the thiol sulfur, the azomethinic nitrogen and the ortho carbon of the p-isopropylphenyl ring to which the imine group is attached to as deduced from the study of the IR, NMR, and XRD spectra of complexes 2 and 4. Complexes 2 and 4 crystallize in the centrosymmetric monoclinic space group C2/c, with Z = 8. Unit cell parameters for complex 2 are as follows: a = 25.742(5) A, b = 19.560(4) A, c = 24.199(5) A, beta = 101.70(3)o. Unit cell parameters for complex 4 are as follows: a = 25.8728(19) A, b = 19. 5053(14) A, c = 24.0899(16) A, beta = 101.305(2)o. As can be deduced from the NMR study, the palladated isomers 2 and 3 interconvert in DMSO which may be a consequence of the existence in both complexes of a flexible eight-membered ring with alternating Pd-S atoms. The testing of the cytotoxic activity of these compounds against several human and murine cell lines sensitive and resistant to cisplatin (cis-DDP) suggests that compounds 2, 3, and 4 may be endowed with important anticancer properties since they elicit IC50 values in the microM range as does the clinically used drug cis-DDP, and, moreover, they display cytotoxic activity in tumor lines resistant to cis-DDP. The analysis of the interaction of these novel tetrameric cyclometalated compounds with DNA suggests that they form DNA interhelical cross-links.

The investigation of cis-PtI 2 (NH 3 ) 2 , the diiodido analogue of cisplatin (cisPtI 2 hereafter), has been unjustly overlooked so far mainly because of old claims of pharmacological inactivity. Some recent -but still fragmentary -findings prompted us to reconsider more systematically the chemical and biological profile of cisPtI 2 in comparison with cisplatin. Its solution behaviour, interactions with DNA and cytotoxic properties versus selected cancer cell lines were thus extensively analysed through a variety of biophysical and computational methods. Notably, we found that cisPtI 2 is highly cytotoxic in vitro toward a few solid tumour cell lines and that its DNA platination pattern closely reproduces that of cisplatin; cisPtI 2 is also shown to completely overcome resistance to cisplatin in a platinum resistant cancer cell line. The differences in the biological actions of these two Pt complexes are most likely related to slight but meaningful differences in their solution behaviour and reactivity. Overall, a very encouraging and unexpected pharmacological profile emerges for cisPtI 2 with relevant implications both in terms of mechanistic knowledge and of prospective clinical application. An ab initio DFT study is also included to support the interpretation of the solution behaviour of cisPtI 2 under physiological and slightly acidic pH conditions.

Six diiodido-diamine platinum(II) complexes, either cis or trans configured, were prepared, differing only in the nature of the amine ligand (isopropylamine, dimethylamine, or methylamine), and their antiproliferative properties were evaluated against a panel of human tumor cell lines. Both series of complexes manifested pronounced cytotoxic effects, with the trans isomers being, generally, more effective than their cis counterparts. Cell cycle analysis revealed different modes of action for these new Pt(II) complexes with respect to cisplatin. The reactivity of these platinum compounds with a number of biomolecules, including cytochrome c, two sulfur containing modified amino acids, 9-ethylguanine, and a single strand oligonucleotide, was analyzed in depth by mass spectrometry and NMR spectroscopy. Interestingly, significant differences in the reactivity of the investigated compounds toward the various model biomolecules were observed: in particular we observed that trans complexes preferentially release their iodide ligands upon biomolecule binding, while the cis isomers may release the amine ligands with retention of iodides. Such differences in reactivity may have important mechanistic implications and a relevant impact on the respective pharmacological profiles.

Cisplatin resistance observed in some human tumors has prompted research in platinum derivatives that can circumvent this effect. Despite initial works reporting lack of activity of trans-platinum derivatives, complexes with the general formula PtCl2(L)(L') exhibit cytotoxic activity in cisplatin-sensitive and -resistant cell lines. Here we reported the chemical and biological properties of seven platinum complexes with PPh3 or PMe2Ph in trans to several amines. They show important antitumoral properties in tumor cell lines. Among the compounds, those with a replacement of an ammine ligand in the inactive trans-DDP by a phosphine ligand have an important enhancement of their cytotoxic activity. In SKOV3, no G1 nor G2/M accumulation was observed after treatments, and apoptosis was launched probably by a mechanism independent of classical checkpoints activation. Our data indicate that our compounds are not cross-resistant with cisplatin and might be promising agents in the treatment of tumors unresponsive to cisplatin.