title: 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.
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, United States.
authors.forename: Chase
authors.initials: C
authors.lastname: Andrepont
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, United States.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Marzilli
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, United States.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Pakhomova
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, United States. Electronic address: lmarzil@lsu.edu.
authors.forename: Luigi G
authors.initials: LG
authors.lastname: Marzilli
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry*; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D006147:Guanine
keywords: Monofunctional agent; NMR; Platinum(II) complex