title: 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 (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).
authors.affiliation: School of Pharmacy, University of Bradford, Bradford, West Yorkshire BD7 1DP, UK. r.t.wheelhouse@brad.ac.uk
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wheelhouse
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Jennings
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Phillips
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pletsas
authors.forename: Peter M
authors.initials: PM
authors.lastname: Murphy
authors.forename: Nichola C
authors.initials: NC
authors.lastname: Garbett
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Chaires
authors.forename: Terence C
authors.initials: TC
authors.lastname: Jenkins
mesh_terms: D001665:Binding Sites; D004247:DNA / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009696:Nucleic Acids / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013056:Spectrophotometry, Ultraviolet / Q000379:methods; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors*; D013696:Temperature
chemical_list: D008024:Ligands; D009696:Nucleic Acids; D011743:Pyrimidines; D004247:DNA; D019098:Telomerase