Investigations into the Interactions between DNA and Conformationally Constrained Pyridylamineplatinum(II) Analogues of AMD473

The syntheses of [PtCl2(amp)] (amp = 2-pyridylmethylamine) and enantiomerically pure [PtCl2(R-pea)] and [PtCl2(S-pea)] (pea = 1-(2-pyridyl)ethylamine) and the crystal structure of [PtCl2(R-pea)] are reported. The reactions of
[PtCl2(amp)] and of the enantiomers of [PtCl2(pea)] with d(GpG) and with a 52-base-pair oligonucleotide were
investigated. Each of the reactions with d(GpG) resulted in the formation of three platinated bifunctional d(GpG)
species in a ratio of 1:2:1. These species were shown to be a pair of isomers, one of which exists as a pair of
slowly interconverting rotamers that can be separated by HPLC but reequilibrate after 5 days at 37 °C. The pyridyl
moieties of the pyridylalkylamine ligands are constrained to lie in the coordination plane, and as a consequence,
the rotation about the Pt−N7 bond of the adjacent guanine is highly restricted. 2D NMR investigations were carried
out on the isomer of [Ptd(GpG)(amp)] that did not form separable rotamers and identified it as the isomer having
the pyridine adjacent to the 5‘-guanine of the d(GpG). The reaction of each of the three [PtCl2(py-R)] complexes
(py-R = amp or pea) with a 52-base-pair oligonucleotide resulted in the formation of the same three bifunctional
d(GpG) adducts in approximately the same ratios as the reactions with d(GpG), indicating that negligible
stereoselectivity results from interactions between the complexes and duplex DNA.