Studies on the anti-proliferative effects of novel DNA-intercalating bipyridyl-thiourea-Pt(II) complexes against cisplatin-sensitive and -resistant human ovarian cancer cells

Six bipyridyl complexes of platinum(II) with thiourea, with different substituents on thiourea moiety [Pt(bipy)(R,R0NCSNR00,R000)2]Cl2(bipy = 2,20-bipyridine: R = R0 =R00 =R000 = H; R = Me, R0 =R00 =R000 =H;R=n-Bu, R0 =R00 =R000 = H; R = Et, R0 =H,R00 = Et,R000 =H; R=p-tolyl, R0 =R00 =R000 = H; R = phenyl, R0 =H, R00 = phenyl, R000 = H), rationally designed to intercalate into DNA,have been tested against a cisplatin (cDDP)-sensitive human ovarian carcinoma cell line (2008) and its -resistant variant (C13*). We showhere that the anti-proliferative efficacy of these drugs was dependent on molecular structure, since it increased with ancillary ligand bulkinessand hydrophobicity of substituents on thiourea moiety. In particular, the presence of two phenyl groups on thiourea moiety confersan outstanding cytotoxicity. The increasing cell growth inhibition along the series of complexes partially paralleled with drug accumulation,particularly in resistant cells, but not with drug intercalation into DNA since all compounds exerted comparable ethidium bromidedisplacement ability. The cDDP-resistant phenotype seems, at least in part, to be involved in the action of these compounds, since the levelof cross-resistance established for most complexes appeared to be in agreement with the observed impairment of drug accumulation in theresistant subline. These findings indicate that resistance to alkylating agents such as cDDP confers low level of cross-resistance to this classof DNA intercalators, which, however, depending on substituents on thiourea moiety may present remarkable cell growth inhibition evenof resistant cells.