Design, synthesis, and evaluation of novel biarylpyrimidines : A new class of ligand for unusual nucleic acid structures

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 (1a) 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 (ΔTm ≤ 20 °C). In contrast, amides showed duplex stabilization (ΔTm ≤ 15 °C) and either negligible stabilization or specific destabilization (ΔTm = −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 × 105 M-1 (40 × Kapp for CT DNA duplex). In contrast, the strongest bindin...