Guanine nucleobase adducts formed by a monofunctional complex: [Pt(N-(6-methyl-2-picolyl)-N-(2-picolyl)amine)Cl]Cl

Abstract

Monofunctional Pt(II) complexes bind to G residues in DNA and, if the carrier ligands are bulky, cause DNA structural distortions that lead to anticancer activity. We assessed the steric effects of the tridentate carrier ligand, N(H)6-Medpa (N-(6-methyl-2-picolyl)-N-(2-picolyl)amine), bearing a 6-methyl group and a 6′-proton projecting toward the nucleobase in Pt(N(H)6-Medpa)G adducts (G=9-ethylguanine, 3′-GMP, 5′-GMP, 5′-GTP). Pt(N(H)6-Medpa)G adducts form syn and anti rotamers with the guanine O6 and the central N–H of N(H)6-Medpa on the same or opposite side of the coordination plane, respectively. Pt(N(H)6-Medpa)G adducts have some properties (ease of rotamer interchange and extent of conversion to bis adducts, Pt(N(H)6-Medpa)G2) intermediate to properties reported for analogs having a tridentate ligand with zero or two methyl groups. However, in comparison, the syn rotamer of Pt(N(H)6-Medpa)G adducts has an unexpectedly high abundance. This result is attributable to guanine base canting, such that the 6-membered guanine ring is positioned away from the bulky 6-Me group. This canting both relieves electrostatic repulsion between the partially positive H6′ and the guanine H8 protons and creates a favorable electrostatic attraction between the H6′ proton and the partially negative guanine O6. This combined information provides insight useful for designing monofunctional anticancer agents.