The crystal structure of [PtCl2(cis- 1,3-chxn)] (cis-1,3-chxn = (cis-cycloltexane-1,3 -diamine)) as the dimethylformamide solvate is reported. When [PtCl2(cis-1,3-chxn)] binds to d(GpG). two isomers are formed that are readily separated by HPLC. Both the HPLC and GFAAS studies of the products show that the isomers form in a I : I ratio. Competition experiments involving d(GpG) and the aquated and nonaquated forms of [PtCl2(cis-1,3-chxn)] and [PtCl2(NH3)(2)] showed that the slower binding of the former complex was due to slower aquation and not steric bulk. 1D and 2D NMR studies of the [Ptd(GpG)(cis-1,3-chxn)] isomers showed that both the dinucleotide and the diamine were highly fluxional, even at low temperatures, and this prevented formation of strong cross peaks in the NOESY and ROESY spectra and hence identification of the isomers. [PtCl2(cis-1,3-chxn)] was reacted with a 52-mer oligonucleotide having six GpG binding sites and the products were enzymatically digested and separated by HPLC. The two [Ptd(GpG)(cis-1,3-chxn)] stereoisomers were the only significant platinated products. again forming in a 1 : 1 ratio although it had been anticipated that stereoselectivity would be observed in the reaction with the 52-mer because of the potential for steric interactions with the cis-1,3-chxn ligand. Molecular modelling revealed that the observed lack of stereo selectivity was clue to the ability of the cis-1,3-chxn ligand to adopt a continuum of conformations that allow it to avoid severe steric clashes with the DNA.
- ANTITUMOR DRUG CIS-DIAMMINEDICHLOROPLATINUM(II)
- MAJOR DNA ADDUCT
- PLATINUM(II) COMPLEXES
- MOLECULAR MECHANICS