PREPARATION, DNA-BINDING, AND IN-VITRO CYTOTOXICITY OF A PAIR OF ENANTIOMERIC PLATINUM(II) COMPLEXES, [(R)-3-AMINOHEXAHYDROAZEPINE]DICHLORO-PLATINUM(II) AND (S)-3-AMINOHEXAHYDROAZEPINE]DICHLORO-PLATINUM(II) - CRYSTAL-STRUCTURE OF THE S-ENANTIOMER

A pair of enantiomeric Pt(II) complexes, [Pt(R-ahaz)Cl-2] and [Pt(S-ah az)Cl-2] (ahaz = 3-aminohexahydroazepine), has been investigated for t heir ability to bind enantioselectively to DNA. Improved synthetic pro cedures were developed for preparing both the ligands and the Pt compl exes. The structure of the complex of the S enantiomer was determined by X-ray crystallographic methods. Crystals of [Pt(S-ahaz)Cl-2] are or thorhombic, space group P2(1)2(1)2(1), with a = 6.917(1) Angstrom, b = 11.167(1) Angstrom, c = 12.373(2) Angstrom, Z = 4, and the structure was refined to R = 0.023 (1505F). Molecular modeling techniques were u sed to investigate the role of steric interactions between the ligand and DNA in influencing the bifunctional binding of the two enantiomers , and it was found that the S enantiomer should bind more readily. The binding of the S enantiomer, to calf thymus DNA, was indeed found to be slightly greater than that for the R enantiomer though slightly les s than that for cis-DDP. Assays of the proportion of monofunctional ad ducts showed that a substantially greater proportion of monofunctional adducts remained for the R enantiomer and cisplatin than for the S en antiomer. Each of the enantiomers was subjected to in vitro cytotoxici ty assays using cultures of human bladder (BL13/0), lung and resistant lung (PC9 and PC9cisR), and prostate (DU145) cancer cells. The R enan tiomer was found to be slightly more cytotoxic in,the bladder cell lin e and may be less cytotoxic in the lung cell line but there were no si gnificant differences in the resistant cell line nor in the prostate c ell line. The two enantiomers were taken up equally by the bladder can cer cells.