EVALUATION OF NOVEL AMMINE AMINE PLATINUM(IV) DICARBOXYLATES IN L1210MURINE LEUKEMIA-CELLS SENSITIVE AND RESISTANT TO CISPLATIN, TETRAPLATIN OR CARBOPLATIN/

Seventeen alkylamine ammine dicarboxylatodichloroplatinum(Iv) complexe s of general structure c,t,c-[PtCl2(OCOR(1))(2)NH3(RNH(2))], where R = aliphatic or alicyclic and R(1) = aliphatic or aromatic, have been ev aluated against L1210 cell lines with acquired resistance to cisplatin (10-fold), tetraplatin (34-fold) or carboplatin (14-fold) using an in vitro growth-delay assay. All of these compounds overcame cisplatin, tetraplatin and carboplatin resistance. Potency increased as the numbe r of carbon atoms in the axial aliphatic ligands (R(1)) increased, for example comparing JM216 (R = cyclohexyl, R(1) = CH3, IC50 = 1.2 mu M) with JM274 (R = cyclohexyl, R(1) = n-C4H9, IC50 = 0.05 mu M) against the parent sensitive line (L1210/S). The most active compounds were th ose possessing aromatic ligands at R(1), regardless of whether R = ali phatic or alicyclic, for example JM244 (R = n-C3H7, R(1) = C6H5, IC50 = 0.028 mu M) and JM2644 (R = c-C6H11, R(1) = C6H5, IC50 = 0.031 mu(M) against L1210/S. For an alicyclic alkylamine series in which R is var ied from c-C3H7 to C-C7H13, with R(1) = n-C3H7 for each compound, cyto toxic potency was maximised at c-C6H11 (JM221, IC50 = 0.06 mu M agains t L1210/S). Preliminary biochemical studies, at equitoxic doses, compa ring JM221 (0.1 mu M) with cisplatin (0.6 mu M) identified five times more platinum associated with JM221 treated cells and 1.5 times more p latinum bound to the DNA of JM221-treated cells. The lipophilic proper ties of some of these platinum(IV) dicarboxylates may contribute to bo th the potency and circumvention of resistance by these compounds.