CYTOTOXIC DIAMINE-PLATINUM(II) COMPLEXES WITH METHYLSULFINYL CARBOXYLATES AS THE LEAVING GROUPS - SYNTHESIS, CHARACTERIZATION, AND REACTIVITY TOWARD CHLORIDE-IONS, 5'-GMP, AND 9-METHYLGUANINE

Compounds of formula [Pt(diam)(Soa)]NO3, 3, and [Pt(diam)(Sob)]NO3, 4, (Soa, (methylsulfinyl)acetate; Sob, 2-(methylsulfinyl)benzoate; diam, chelating diamines: 1,2-ethylenediamine, en; (+/-)-, R,R-, S,S-, and meso-1,2-diaminocyclohexane, dach; 1,1-bis(aminomethyl)cyclohexane, damch) have been synthesized. IR, NMR, and FAB-mass spectroscopy suggest that the Soa and Sob anions are chelated to Pt through the S atom and the carboxylate group. Such a mode of coordination was confirmed for compounds 3 by the X-ray crystal structure determination of [Pt(en)(Soa)]NO3. This compound crystallizes in space group R3 (No. 146) with cell constants a = 15.139(3) angstrom and c = 12.886(2) angstrom. The structure was refined using 1001 independent reflections with I > 3sigma(I), giving a final R value of 0.018. In the complex cation Pt is in a square planar environment with en (Pt-N, 2.019(8) and 2.055(8) angstrom) and Soa (Pt-S, 2.184(2) angstrom, and Pt-O, 2.025(6) angstrom) chelated to Pt. The reactivities of 3 and 4 toward Cl-, 5'-GMP, and 9-methylguanine have been investigated by H-1 NMR spectroscopy at 40-degrees-C and complex concentration 10(-2) mol L-1 in D2O. Compounds 3 react readily with Cl- by displacement of the carboxylate group, yielding [PtCl(diam)(Soa-S)] (with monodentate S-coordinated Soa) which reacts with excess chloride to give [PtCl2-(diam)] at a very slow rate (for the en derivative formation of [PtCl2(en)] <20% after 24 h in 0.15 mol L-1 NaCl). In the case of compounds 4, t1/2 for complete replacement of Sob to give [PtCl2(diam)] in 0.15 mol L-1 NaCl is >24 h, but the concentration of the intermediates with S-coordinated monodentate Sob remains very low throughout the course of the reaction, indicating that the Sob chelate ring is more inert toward ring opening. Reactions of 3 and 4 toward 5'-GMP are rather fast: formation of [Pt(dach)(GMP)2]2- is complete in 3 and 1 h respectively (Pt/GMP = 1/2). These reactions proceed via the formation of intermediates with one N(7)-bound GMP and one monodentate Soa, coordinated to Pt via the S atom, or Sob probably bound to Pt via the O (sulfinyl) atom. Reactions with 9-methylguanine are slower and occur with a similar mechanism. The first step of the reaction of 5 with 2 mol of GMP is displacement of Cl by GMP. Formation of [Pt(en)(GMP)2]2- is complete in 75 min. Complexes 3 and 4 are moderately cytotoxic toward L1210 leukemia cells; the dach and damch derivatives are cytotoxic also against the L1210 cisplatin-resistant line. The cytotoxicities of the dach complexes depend not only on the absolute configuration of the diamine, but also on the configuration of the leaving group.