The synthesis of a pair of enantiomeric Pt(II) complexes, [Pt(R,R-eap)Cl2] and [Pt(S,S-eap)Cl2] (eap = N,N-diethyl-2,4-pentanediamine), designed to bind enantioselectively to GpG and ApG sequences of DNA is described. The in vitro cytotoxicity of each of the enantiomers toward murine leukemia and human bladder tumor cells has been measured. The R,R enantiomer was found to be more active in the leukemia cells, but the difference was not as great as expected (IC50; R,R 14 microM, S,S 33 microM). In the bladder tumor cell line, no significant difference in activity was found. The two enantiomers had similar mutagenicity in the Salmonella 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 energy minimization analysis showed that this was a consequence of interactions between the diamine ligand and the dichloro ligands. The significance of the structural preferences with respect to the lower than expected enantiospecificity is discussed. Crystals of [Pt(R,R-eap)Cl2] are monoclinic; space group, P2(1)2(1)2(1); a = 7.909(5), b = 12.972(9), and c = 13.269(12) A; Z = 4; and the structure was refined to R = 0.025 (1657F).

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NMR studies show that the ternary octahedral D-cis-a-[Ru(RR-picchxnMe 2 )(phen)] 2+ cation binds with AT selectivity in the minor groove of [d(CGCGATCGCG) 2 ] and [d(ATATCGATAT) 2 ] duplexes through a non-intercalative interaction.

A study of the interaction with calf thymus DNA is described of a novel set of chiral ternary complex cations of general form [Ru(N4-tet)(phdi)]2+ (where N4 -tet is the chiral linear tetradentate R*R*-picchxn or R*-picchxnMe2). Individual equilibrium binding constants (KB) have been determined from spectroscopic titrations employing the hypochromism induced in the visible absorbance of the cations on interaction with the nucleic acid. These demonstrate both stereo- and enantioselectivity in the binding interactions. These KB data, together with induced circular dichroism and DNA thermal denaturation results, are all indicative of selective intercalation of the bidentate components of the cations into the nucleobase stack of the duplex. Supportive evidence for a secondary binding mode for the picchxn complexes is provided by the different mutagenicity profiles obtained for related cations.

Two novel substitutionally-inert diastereomeric ruthenium(II) cations of the form lambda- and delta-cis-beta-[Ru(RR-picchxn)(phen)]2+, where RR-picchxn is N,N'-dimethyl-N,N'-di(2-picolyl)-1R,2R-diaminocyclohexane and phen is 1,10-phenanthroline, have been studied with respect to their interactions with duplex DNA. NMR investigations show that both diastereomers bind to the oligonucleotide [d(CGCGATCGCG)]2 in the fast exchange regime and that binding predominantly takes place in the minor groove of the oligonucleotide, but that the governing interactions are significantly different for the two delta and lambda forms. Linear dichroism data support the latter interpretation, in that the relative orientations of cis-beta-[Ru(RR-picchxn)(phen)]2+ to calf thymus DNA also are observed to differ for the delta and lambda diastereomers. Interpretation of these data indicates the lambda form to be bound with the planar phen ligand closely parallel to the DNA base-pairs, but the average orientation of the phen ligand in the delta form deviates significantly from a parallel alignment.