L-碳环2'，3'-二脱氢-2'，3'-二脱氧核苷及2'，3'-二脱氧核苷的不对称合成与抗病毒活性

Asymmetric synthesis and antiviral activities of L-carbocyclic 2', 3'-didehydro-2',3'-dideoxy and 2',3'-dideoxy nucleosides.

作者信息

Wang P, Gullen B, Newton M G, Cheng Y C, Schinazi R F, Chu C K

机构信息

Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602, USA.

出版信息

J Med Chem. 1999 Aug 26;42(17):3390-9. doi: 10.1021/jm9901327.

DOI:10.1021/jm9901327

PMID:10464025

Abstract

Asymmetric syntheses of L-carbocyclic 2',3'-didehydro-2',3'-dideoxy- and 2',3'-dideoxypyrimidine and purine nucleoside analogues were accomplished, and their anti-HIV and anti-HBV activities were evaluated. The key intermediate, (1S, 4R)-1-benzoyloxy-4-(tert-butoxymethyl)cyclopent-2-ene (7), was prepared by benzoylation of the alcohol 2, selective deprotection of the isopropylidene group of 3, followed by thermal elimination via cyclic ortho ester or deoxygenation via cyclic thionocarbonate. The target compounds were also synthesized by thermal elimination via cyclic ortho esters from protected nucleosides. It was found that L-carbocyclic 2',3'-didehydro-2',3'-dideoxyadenosine (34) exhibited potent anti-HBV activity (EC(50) = 0.9 microM) and moderate anti-HIV activity (EC(50) = 2.4 microM) in vitro without cytotoxicity up to 100 microM.

摘要

完成了L-碳环2′,3′-二脱氢-2′,3′-二脱氧嘧啶和嘌呤核苷类似物的不对称合成，并评估了它们的抗HIV和抗HBV活性。关键中间体(1S, 4R)-1-苯甲酰氧基-4-(叔丁氧基甲基)环戊-2-烯(7)通过醇2的苯甲酰化、3的异亚丙基选择性脱保护，然后通过环状原酸酯进行热消除或通过环状硫代碳酸酯进行脱氧反应制备。目标化合物也通过从保护核苷经环状原酸酯进行热消除反应合成。结果发现，L-碳环2′,3′-二脱氢-2′,3′-二脱氧腺苷(34)在体外表现出强效抗HBV活性(EC(50)=0.9微摩尔)和中度抗HIV活性(EC(50)=2.4微摩尔)，在高达100微摩尔时无细胞毒性。