Design, Synthesis and Evaluation of Novel Biarylpyrimidines ¿ a New Class of Ligand for Unusual Nucleic Acid Structures.
Wheelhouse, Richard T. Jenkins, Terence C. Jennings, Sharon A. Pletsas, Dimitrios
Wheelhouse, Richard T.
Jenkins, Terence C.
Jennings, Sharon A.
Pletsas, Dimitrios
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2006
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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).
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Wheelhouse, R.T., Jenkins, T.C., Jennings, S.A., Pletsas, D. et al (2006). Design, Synthesis and Evaluation of Novel Biarylpyrimidines ¿ a New Class of Ligand for Unusual Nucleic Acid Structures. Journal of Medicinal Chemistry. Vol. 49, No. 17, pp. 5187-5198.
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