Dinuclear alkyldiamine platinum antitumor compounds: A structure-activity relationship study

Six related dinuclear trans-platinum complexes, with the formula [{trans-Pt Cl2(NH3)(L)}(2)(mu -H2N(CH2)(n)NH2)](2+) (L = pyridine, 2-picoline, 4-picol ine; n = 4, 6) and chloride or nitrate anions, are compared with known cyto toxic dinuclear compounds (L = NH3; n =,4, 6) that overcome cisplatin resis tance. The cytotoxicity of the compounds was determined in L1210 murine leu kemia and L1210/2, a cisplatin-resistant derivative. Unlike the L = NH3 com pounds, the substituted n = 4 compounds are more susceptible,toward the res istance mechanisms in L1201/2. The n = 6 compounds, however, have comparabl e IC50 values in both cell lines. In general, the substituted compounds are less cytotoxic than their NH3 counterparts. After incubation with equimola r concentrations; the amount of platinum bound to cellular DNA was determin ed. The compounds show comparable binding, except for the sterically hinder ed 2-picoline compounds that bind significantly less. The amounts of platin um bound to DNA do not correlate with the cytotoxicity data. As DNA is cons idered to be the cellular target of platinum antitumor drugs, structural de tails of the DNA adducts probably account for the differences in cytotoxic activity.