PREPARATION, CHARACTERIZATION, CYTOTOXICITY, AND MUTAGENICITY OF A PAIR OF ENANTIOMERIC PLATINUM(II) COMPLEXES WITH THE POTENTIAL TO BIND ENANTIOSELECTIVELY TO DNA

The synthesis of a pair of enantiomeric Pt(II) complexes, [Pt(RR-eaP)C l2] and [Pt(S,S-eap)Cl2] (eap = N,N-diethyl-2,4-pentanediamine), desig ned to bind enantioselectively to GpG and ApG sequences of DNA is desc ribed. The in vitro cytotoxicity of each of the enantiomers toward mur ine leukemia and human bladder tumor cells has been measured. The RR e nantiomer was found to be more active in the leukemia cells, but the d ifference was not as great as expected (IC50; R,R 14 muM, S,S 33 muM). In the bladder tumor cell line, no significant difference in activity was found. The two enantiomers had similar mutagenicity in the Salmon ella reversion assay, but the R,R enantiomer was more cytotoxic in the bacterial cells. A structural analysis of the R,R enantiomer revealed that the ligand adopted an unexpected configuration, and a strain ene rgy minimization analysis showed that this was a consequence of intera ctions between the diamine ligand and the dichloro ligands. The signif icance of the structural preferences with respect to the lower than ex pected enantiospecificity is discussed. Crystals of [Pt(RR-eap)Cl2] ar e monoclinic; space group, P2(1)2(1)2(1); a = 7.909(5), b = 12.972(9), and c = 13.269(12) angstrom; Z = 4; and the structure was refined to R = 0.025 (1657F).