5-Alkynyl Analogs of Arabinouridine and 2'-Deoxyuridine: Cytostatic Activity against Herpes Simplex Virus and Varicella-Zoster Thymidine Kinase Gene-Transfected Cells

详细信息    查看全文

• 作者：Walter A. Cristofoli ; Leonard I. Wiebe ; Erik De Clercq ; Graciela Andrei ; Robert Snoeck ; Jan Balzarini ; Edward E. Knaus
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：June 14, 2007
• 年：2007
• 卷：50
• 期：12
• 页码：2851 - 2857
• 全文大小：81K
• 年卷期：v.50,no.12(June 14, 2007)
• ISSN：1520-4804

文摘

A group of arabinouridines (TMSEAU, EAU, IEAU-TA) and 2'-deoxyuridines (TMSEDU, EDU, IEDU)having a variety of substituents at the uracil C-5 position (trimethylsilylethynyl, TMSE; ethynyl, E; oriodoethynyl, IE), and the sugar C-2' position (2'-arabino OH in arabinouridine, AU; or 2'-deoxyribo H in2'-deoxyuridine, DU) were prepared to acquire antiviral structure-activity relationships. A broad-spectrumviral panel screen showed that these 5-alkynylarabino/deoxy-uridines exhibit moderate anti-HSV-1 activity,with no difference in potency between arabinouridines and 2'-deoxyuridines. The 2'-deoxyuridines TMSEDU,EDU, and IEDU, unlike the arabinouridines, exhibited potent antiviral activity against cytomegalovirus, butthey were also highly cytostatic. The abilities of the 5-alkynylarabino/deoxy-uridines to inhibit nontransfected(wild-type or thymidine kinase-deficient, tk^-) and viral gene transfected (HSV-1, HSV-2, or VZV thymidinekinase-positive, tk⁺) FM3A and OST (osteosarcoma) cells were determined. This group of 5-alkynylarabino/deoxy-uridines showed an enhanced ability to inhibit cells transfected with a viral thymidine kinase gene(HSV-1tk⁺, HSV-2tk⁺, VZVtk⁺) relative to wild-type or thymidine kinase-deficient (tk^-) cells.