Synthesis and Antiviral Evaluation of 6-(Alkyl-heteroaryl)furo[2,3-d]pyrimidin-2(3H)-one Nucleosides and Analogues with Ethynyl, Ethenyl, and Ethyl Spacers at C6 of the Furopyrimidine Co

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• 作者：Morris J. Robins ; Ireneusz Nowak ; Vivek K. Rajwanshi ; Karl Miranda ; John F. Cannon ; Matt A. Peterson ; Graciela Andrei ; Robert Snoeck ; Erik De Clercq ; Jan Balzarini
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：August 9, 2007
• 年：2007
• 卷：50
• 期：16
• 页码：3897 - 3905
• 全文大小：146K
• 年卷期：v.50,no.16(August 9, 2007)
• ISSN：1520-4804

文摘

Sonogashira coupling strategies were employed to synthesize new furo[2,3-d]pyrimidin-2(3H)-one (FuPyrm)2'-deoxynucleoside analogues. Partial or complete reduction of ethyne-linked compounds afforded ethenyl-and ethyl-linked derivatives. Levels of inhibition of varicella-zoster virus (VZV), human cytomegalovirus(HCMV), a broad range of other DNA and RNA viruses, and several cancer cell lines were evaluated incell cultures. The anti-VZV potency decreased with increasing rigidity of the side chain at C6 of the FuPyrmring in the order dec-1-yn-1-yl < dec-1-en-1-yl < decan-1-yl. In contrast, compounds with a rigid ethynylspacer between C6 of the FuPyrm ring and a 4-alkylphenyl moiety were more potent inhibitors of VZVthan the corresponding derivatives with an ethyl spacer. Replacement of the phenyl moiety in 6-(4-alkylphenyl)derivatives with a pyridine ring (in either regioisomeric orientation) gave analogues with increased solubilityin methanol but reduced anti-VZV potency, and replacement with a pyrimidine ring reduced the anti-VZVactivity even further. The pyridine-ring-containing analogues were ~20-fold more potent inhibitors of VZVthan acyclovir but were ~6-fold less potent than BVDU and ~60-fold weaker than the most active 6-(4-pentylphenyl)-substituted prototype.