Design, Synthesis and Evaluation of Novel Biarylpyrimidines ¿ a New Class of Ligand for Unusual Nucleic Acid Structures.

Abstract

Biarylpyrimidines are characterized as selective ligands for higher-order nucleic acid structures. A concise and efficient synthesis has been devised incorporating Suzuki biaryl cross-coupling of dihalopyrimidines. Two ligand series are described based on the parent thioether 4,6-bis[4-[[2-(dimethylamino)ethyl]mercapto]-phenyl]pyrimidine (la) and amide 4,6-bis(4[(2-(dimethylamino)ethyl)carboxamido]phenyl)pyrimidine (2a) compounds. In UV thermal denaturation studies with the poly(dA)·[poly(dT)]2 triplex structure, thioethers showed stabilization of the triplex form (¿Tm ¿ 20 °C). In contrast, amides showed duplex stabilization (¿Tm ¿ 15 °C) and either negligible stabilization or specific destabilization (¿Tm = -5 °C) of the triplex structure. Full spectra of nucleic acid binding preferences were determined by competition dialysis. The strongest interacting thioether bound preferentially to the poly(dA)·[poly(dT)]2 triplex, Kapp = 1.6 x 105 M-1 (40 x Kapp for CT DNA duplex). In contrast, the strongest binding amide selected the (T2G20T2)4 quadruplex structure, Kapp = 0.31 x 105 M-1 (6.5 x Kapp for CT DNA duplex).