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作者机构:Wayne State Univ Sch Med Dept Chem Dev Therapeut ProgramBarbara Ann Karmanos Canc In Detroit MI 48201 USA Univ Alabama Dept Pediat Birmingham AL 35294 USA Univ Michigan Sch Dent Dept Biol & Mat Sci Ann Arbor MI 48019 USA Yale Univ Sch Med Dept Pharmacol New Haven CT 06510 USA
出 版 物:《JOURNAL OF MEDICINAL CHEMISTRY》 (医药化学杂志)
年 卷 期:2003年第46卷第8期
页 面:1531-1537页
核心收录:
学科分类:1007[医学-药学(可授医学、理学学位)] 10[医学]
基 金:NCI NIH HHS [R01-CA44358] Funding Source: Medline NIAID NIH HHS [N01-AI85347, P01-AI46390] Funding Source: Medline
主 题:Aminopyrine Animals Antiviral Agents Cell Line Cercopithecus aethiops Cyclopropanes Enzyme-Linked Immunosorbent Assay Hepatitis B Virus Herpesviridae Human Mice Plaque Assay Purine Nucleosides Stereoisomerism Structure-Activity Relationship Support U.S. Gov't P.H.S.
摘 要:A series of 13 new (S,Z)-2-aminopurine methylenecyclopropane analogues was synthesized, and their antiviral activity was investigated. The nucleophilic displacement of chlorine of 2-amino-6-chloropurine derivative 5 with allyl-, propargyl-, cyclopropylmethyl-, isopropyl-, benzyl-, cyclohexyl-, and 2-hydroxyethylamine gave N-6-alkyl compounds 2a, 2b, 2c, 2d, 2e, 2f, and 2g. A similar reaction of 5 with allyl, cyclopropylmethyl, propyl, or pentyl alcohol catalyzed by K2CO3 afforded O-6-alkyl analogues 3a, 3c, 3h and 3i. Propane- and pentanethiol furnished S-6-alkyl compounds 4h and 4i. The N-6-alkyl derivatives 2a, 2b, O-6 analogues 3a, 3c, 3h, 3i, and S-6 compounds 4h, 4i which were highly effective in all CMV assays and exhibited the lowest cytotoxicity in proliferating HFF cells appear to be good candidates for in vivo assays. Activity of new analogues against HSV-1 or HSV-2 was restricted to BSC-1 and Vero cultures. Compounds 2c, 2b, 3a and 3h were effective against EBV in one of two assays (Daudi or H-1). Analogues 3a and 4i were the most active anti-VZV agents whereas compounds 3h, 3i, and 4h inhibited the replication of HBV in a micromolar concentration range.