DNA interstrand cross-linking efficiency and cytotoxic activity of novel cadmium(II) - Thiocarbodiazone complexes

We have prepared mono- and binuclear complexes of Zn-II and Cd-II with bis( 2-pyridyl aldehyde) thiocarbodiazone (H2L1) and bis(methyl 3-pyridyl ketone ) thiocarbodiazone (H2L2). Cytotoxicity data against the ovarian tumor cell line A2780cisR (acquired resistance to cisplatin) indicate that the mononu clear complex Cd/H2L2 (1) and the binuclear complex Cd-2/H2L1 (4) are able to circumvent cisplatin resistance and that their cytotoxic activity does: not substantially vary after depletion of intracellular levels of glutathio ne. Moreover, DNA binding studies show that complexes 1 and 4 have higher e fficiency than cisplatin at forming DNA interstrand cross-links in both nak ed pBR322 plasmid and A2780cisR cellular DNA. Interestingly, methiocarbodia zone ligands alone do not show the biological properties::of complexes 1 an d 4. Altogether these results suggest that DNA interstrand cross-link forma tion by compounds 1 and 4 might be related with their cytotoxic activity in cisplatin-resistant cells. We think that compounds 1 and 4 may represent a novel structural lead for the development of cadmium cytotoxic a gents cap able of improving antitumor activity in cisplatin-resistant tumors.