Trend in cytotoxic activity of a series of cis-[APtCl2] (A = ethylenediamine methylated at different positions) complexes

The study of a series of cis-[APtCl(2)] complexes (A = ethylenediamine, en, methylated at different positions) was carried out to evaluate the effect of different methyl substitutions on the cytotoxic properties of the resulting derivatives. As expected, differentially methylated complexes were found to differ widely in their cytotoxic effects on human cultured ovarian carcinoma cells (A2780). Molecular mechanics (MM) calculations have been performed to assess the relationship between differential diamine methylation and the repulsive energy of the corresponding complexes when interacting with DNA. Compounds that bind DNA at high energetic cost relative to cisplatin, due to the steric hindrance of additional methyl groups, have shown high values for IC50 (concentration inhibiting tumour cell growth by 50%). Semi-quantitative analyses with a DNA electrochemical biosensor confirm that the interaction between cis-[APtCl(2)] complexes and ds-DNA deposed onto the electrode is stronger for the non-methylated derivative with respect to the fully methylated congener. In addition, MM calculations were used to investigate the interactions between DNA and cis-[(P-L-A) PtCl2]complexes [A = en group linked to an antiestrogen-like pharmacophore, P, via a -(CH2)(n)- spacer (n = 2, 4, 6, 8 and 10), L]. (c) 2008 Elsevier B.V. All rights reserved.