Preparation, Characterization, DNA Binding, and <i>in Vitro</i> Cytotoxicity of the Enantiomers of the Platinum(II) Complexes <i>N</i>-Methyl-, <i>N</i>-Ethyl- and <i>N</i>,<i>N</i>-Dimethyl-(<i>R</i>)- and -(<i>S</i>)-3-aminohexahydroazepinedichloroplatinum(II)

Abstract

A series of chiral diaminedichloroplatinum(II) complexes derived from [Pt(ahaz)Cl2] (ahaz = 3-aminohexahydroazepine) have been synthesized and tested for cytotoxic activity. Novel synthetic pathways were developed to produce the structural derivatives of the ahaz ligand, with alkyl substituents on the exocyclic nitrogen atom. The platinum(II) complexes of these ligands were synthesized and characterized by NMR and CD spectroscopy, confirming isomeric and enantiomeric purity. The crystal structures of three of these complexes, [Pt(S-meahaz)-Cl2], [Pt(R-etahaz)Cl2], and [Pt(S-dimeahaz)Cl2] (meahaz = N-methylahaz, etahaz = N-ethylahaz, dimeahaz = N,N-dimethylahaz), have been determined to establish the orientation of the protons and alkyl substituents on the nitrogen donor atoms. In vitro assays of the cytotoxic activity of the complexes have revealed a significant and reproducible enantioselective trend with the R-enantiomers more active than the S-enantiomers in all cell lines. Increasing the steric bulk on the amine groups was found to have only a modest effect on activity. No enantioselectivity was observed in the binding of R- and S-[Pt(etahaz)Cl2] to calf-thymus DNA.