Synthesis, characterisation and biological activity of chiral platinum(II) complexes

Four platinum(II) complexes of 1,10-phenanthroline (phen) and 3,4,7,8-tetramethyl-1,10-phenanthroline (3,4,7,8-Me₄phen), with the chiral ancillary ligands (1R,3S) and (1S,3R)-1,3-diamino-1,2,2-trimethylcyclopentane (R,S-tmcp and S,R-tmcp, respectively) have been synthesised and their biological activity quantified using an in vitro cytotoxicity assay against the L1210 murine leukaemia cell line. [Pt(R,S-tmcp)(3,4,7,8-Me₄phen)]Cl₂ and [Pt(S,R-tmcp)(3,4,7,8-Me₄phen)]Cl₂ showed an increase in biological activity over their non-methylated complexes, [Pt(R,S-tmcp)(phen)]Cl₂ and [Pt(S,R-tmcp)(phen)]Cl₂. Some chiral discrimination was observed in the in vitro cytotoxicity experiments with the complexes having (S,R) configuration showing higher biological activity in L1210 cells. Titrations of the metal complexes into ct-DNA and observation of the changes induced in the CD spectra were used to determine the binding constants. The binding of these metal complexes to the hexamer d(GTCGAC)₂ was studied using two-dimensional ¹H NMR spectroscopy. The addition of metal complexes to the hexamer produced upfield shifts of the metal complex of selected resonances, characteristic of intercalation for [Pt(tmcp)(phen)]Cl₂, whereas the [Pt(tmcp)(3,4,7,8-Me₄phen)]Cl₂ complexes only partially intercalate and in a “side-on” fashion. Through the observation of NOE cross-peaks, two-dimensional NMR experiments provided some insight into the site and groove preferences of these complexes when binding to DNA. Here, we report the biological activity of platinum(II) complexes containing an intercalator and a chiral diamine, which influences the degree to which the complexes can interact with DNA.