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 (1a) and amide 4,6-bis(4[(2-(dimethylamino)ethyl)carboxamido]phenyl)pyrimidine (2a) compounds. In UV thermal denaturation studies with the poly(dA) x [poly(dT)]2 triplex structure, thioethers showed stabilization of the triplex form (Delta Tm < or = 20 degrees C). In contrast, amides showed duplex stabilization (Delta Tm < or = 15 degrees C) and either negligible stabilization or specific destabilization (Delta Tm = -5 degrees 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) x [poly(dT)]2 triplex, K(app) = 1.6 x 10(5) M(-1) (40 x K(app) for CT DNA duplex). In contrast, the strongest binding amide selected the (T2G20T2)4 quadruplex structure, K(app) = 0.31 x 10(5) M(-1) (6.5 x K(app) for CT DNA duplex).
Subject(s)
Nucleic Acids/chemistry , Pyrimidines , Telomerase/antagonists & inhibitors , Binding Sites , DNA/chemistry , Drug Design , Humans , Ligands , Models, Molecular , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/classification , Pyrimidines/pharmacology , Sensitivity and Specificity , Spectrophotometry, Ultraviolet/methods , Structure-Activity Relationship , TemperatureABSTRACT
Biarylpyrimidines bearing omega-aminoalkyl substituents have been designed as ligands for high-order DNA structures: spectrophotometric, thermal and competition equilibrium dialysis assays showed that changing the functional group for substituent attachment from thioether to amide switches the structural binding preference from triplex to tetraplex DNA; the novel ligands are non-toxic and moderate inhibitors of human telomerase.