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) 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).
Wheelhouse
Richard T
RT
School of Pharmacy, University of Bradford, Bradford, West Yorkshire BD7 1DP, UK. r.t.wheelhouse@brad.ac.uk
Jennings
Sharon A
SA
Phillips
Victoria A
VA
Pletsas
Dimitrios
D
Murphy
Peter M
PM
Garbett
Nichola C
NC
Chaires
Jonathan B
JB
Jenkins
Terence C
TC
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
D008024:Ligands; D009696:Nucleic Acids; D011743:Pyrimidines; D004247:DNA; D019098:Telomerase