Synthesis and Biological Evaluation of 3,3-Difluoropyridine-2,4(1H,3H)-dione and 3-Deaza-3-fluorouracil Base and Nucleoside Derivatives

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• 作者：Morris J. Robins ; Hong Yang ; Karl Miranda ; Matt A. Peterson ; Erik De Clercq ; Jan Balzarini
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 14, 2009
• 年：2009
• 卷：52
• 期：9
• 页码：3018-3027
• 全文大小：177K
• 年卷期：v.52,no.9(May 14, 2009)
• ISSN：1520-4804

文摘

New 3-deaza-3-halouracil nucleosides including 3-deaza-3-fluorouridine and its 2′-deoxy and arabino analogues have been prepared by fluorination of protected precursors. The resulting 3,3-difluoropyridine-2,4(1H,3H)-dione derivatives underwent palladium-catalyzed hydrogenolysis of one C−F bond at atmospheric pressure, and deprotection gave the 3-deaza-3-fluorouracil compounds. Selective reaction of a stabilized Wittig reagent at C4 of the 3,3-difluoro-2,4-dione intermediates gave exocyclic alkenes that underwent hydrogenation accompanied by spontaneous elimination of hydrogen fluoride. Ammonolysis of the exocyclic carbethoxymethyl substituent and ester protecting groups gave 4-(carboxamidomethyl)-3-deaza-3-fluorouridine and its analogues. Grignard additions at C4 of the ribo and 2′-deoxy 3,3-difluoro-2,4-dione intermediates followed by deprotection gave the 3-deaza-3,3-difluoro-4-hydroxy-4-(substituted)uracil nucleosides. The cytostatic activity of 3-fluoro-3-deazauridine (CC₅₀ = 4.4−9.6 μM) in three cancer cell lines paralleled that of 3-deazauridine, whereas no significant inhibitory activity was observed with a variety of virus-infected cell cultures.