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.
Pasini, A., Dalfonso, G., Manzotti, C., Moret, M., Spinelli, S., Valsecchi, M. (1994). CYTOTOXIC DIAMINE-PLATINUM(II) COMPLEXES WITH METHYLSULFINYL CARBOXYLATES AS THE LEAVING GROUPS - SYNTHESIS, CHARACTERIZATION, AND REACTIVITY TOWARD CHLORIDE-IONS, 5'-GMP, AND 9-METHYLGUANINE. INORGANIC CHEMISTRY, 33(18), 4140-4148 [10.1021/ic00096a044].
CYTOTOXIC DIAMINE-PLATINUM(II) COMPLEXES WITH METHYLSULFINYL CARBOXYLATES AS THE LEAVING GROUPS - SYNTHESIS, CHARACTERIZATION, AND REACTIVITY TOWARD CHLORIDE-IONS, 5'-GMP, AND 9-METHYLGUANINE
MORET, MASSIMO;
1994
Abstract
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.
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