Investigations into the interactions between DNA and conformationally constrained pyridylamineplatinum(II) analogues of AMD473.
The syntheses of [PtCl(2)(amp)] (amp = 2-pyridylmethylamine) and enantiomerically pure [PtCl(2)(R-pea)] and [PtCl(2)(S-pea)] (pea = 1-(2-pyridyl)ethylamine) and the crystal structure of [PtCl(2)(R-pea)] are reported. The reactions of [PtCl(2)(amp)] and of the enantiomers of [PtCl(2)(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 degrees 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 [PtCl(2)(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.
Munk
Vivienne P
VP
Centre for Heavy Metals Research, School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia.
Diakos
Connie I
CI
Ellis
Leanne T
LT
Fenton
Ronald R
RR
Messerle
Barbara A
BA
Hambley
Trevor W
TW
D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry
D018736:DNA Adducts; D008024:Ligands; D009944:Organoplatinum Compounds; D011725:Pyridines; C110525:amminedichloro(2-methylpyridine)platinum(II); D004247:DNA