PMID: 8583252Jan 1, 1995Paper

Improved synthesis of zebularine [1-(beta-D-ribofuranosyl)-dihydropyrimidin-2-one] nucleotides as inhibitors of human deoxycytidylate deaminase

Journal of Enzyme Inhibition
J J BarchiH Ford

Abstract

The 2'-deoxy (2a) and 2'-ara-fluoro (3a) derivatives of zebularine [1-(beta-D-ribofuranosyl)-dihydropyrimidin-2-one, 1a] were phosphorylated in high yield to the 5'-nucleotides 2b and 3b, respectively, and characterized by HPLC, enzyme degradation, 1H, 13C and 31P NMR, and high resolution mass spectral analysis. Their inhibitory activity against partially purified MOLT-4 deoxycytidylate deaminase (dCMPD) in the presence of the allosteric effector deoxycytidine triphosphate (dCTP) and Mg+2 ion was examined. Compounds 2b and 3b inhibited dCMPD with Ki values of 2.1 x 10(-8) M and 1.2 x 10(-8) M, respectively. The parent nucleotide, zebularine monophosphate 1b was ineffective at concentrations > 100 mumol. The effect of the nucleosides, 1a-3a, as well as tetrahydrouridine (THU) and 2'-deoxy THU (dTHU), on the cellular production of DNA precursors was examined in human MOLT-4 peripheral lymphoblasts. It was shown that 1a, 2a and 3a all elevated intracellular dCTP and TTP levels in whole cells with the most powerful effect elicited by 1a. The 2'-fluoro derivative 3a was chemically phosphorylated much more cleanly and higher yield than 2a, without the formation of diphosphorylated by-products. This compound was found to be infinitely...Continue Reading

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Citations

Jan 20, 2004·Molecular and Cellular Biology·Jonathan C ChengPeter A Jones
Mar 5, 2010·Fundamental & Clinical Pharmacology·Robert S JansenJos H Beijnen
Sep 22, 2016·Clinical Epigenetics·Inês GraçaCarmen Jerónimo
Mar 6, 2003·Journal of the National Cancer Institute·Jonathan C ChengEric U Selker
Feb 18, 2006·Nature Reviews. Drug Discovery·Christine B Yoo, Peter A Jones
May 29, 2003·The Journal of General Virology·Giorgio GribaudoSanto Landolfo
Jul 1, 2008·British Dental Journal·G W BellC H Malone

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