REACTION OF SYMMETRICALLY AND ASYMMETRICALLY SUBSTITUTED DERIVATIVES OF CISPLATIN WITH R(APG) - INFLUENCE OF THE NONLEAVING GROUPS ON STRUCTURES AND KINETICS

Reactions between symmetrically and asymmetrically substituted cis-platinum amine compounds with the dinucleotide r(ApG) have been studied. The symmetric cis-platinum amine compounds (general formulae cis-PtCl2(LL)2, L = NH3, alkylamine, also LL = ethylenediamine; these compounds contain a C2 symmetry element) gave only one A-N7-G-N7 adduct as a major reaction product. On the other hand, the asymmetrically substituted compounds (general formulae cis-PtCl2(LL')2, L = NH3, L' = alkylamine, also LL' = N,N-dimethylethylenediamine) gave two products (in different ratios), as detected and separated by HPLC. Product 1 has been assigned to a A-N7-G-N7 adduct having the substituted alkyl group(s) cis to the 3'G, whereas product 2 appears to have a structure with the alkylamine cis to the 5'A. The structures of the asymmetric adducts appear to deviate slightly from the cisplatinum adduct cis-Pt(NH3)2(ApG-N7,N7). Reaction velocity constants were measured under pseudo-first-order conditions, and for both the first and second binding steps the influence of the substituents was measured in the order NH3 greater-than-or-equal-to RNH2 >> R2NH. In the first step the binding selectivity for either the cis or trans side to the substituted amine was found to be quite low; however, the second step differs by a factor of 2-3 for the two reactions products. Steric hindrance appears to be important to explain the reactivity. On the other hand, the reaction velocity for the second step does not seem to be related to the rate of rotation (rotational barrier) around the Pt-GN7 bond. Rate constants for the first step vary from 0.017 (for Pt(diethylamine)2(2+)) to 0.277 M-1 s-1 (for Pt(en)2+); for the second step they vary from 4.5 x 10(-7) (for Pt(diethylamine)2(2+)) to 1.84 x 10(-4) s-1 (for Pt(en)2+). First-step rate constants of primary amine derivatives are nearly equal to that of cisplatin, while those of the asymmetric secondary amine derivatives are small. Second-step rate constants of secondary amine derivatives are small, and the bulkyness of the alkylamine groups may interfere with the rate of chelate formation.