Velázquez S, San-Félix A, Pérez-Pérez M J, Balzarini J, De Clercq E, Camarasa M J
Instituto de Química Médica (C.S.I.C.), Madrid, Spain.
J Med Chem. 1993 Oct 29;36(22):3230-9. doi: 10.1021/jm00074a003.
Several purine and purine-modified analogues of the new lead anti-HIV-1 agent [[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl] thymine]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole 2'',2''-dioxide) (TSAO-T) have been prepared and evaluated as inhibitors of HIV-1-induced cytopathicity. Reaction of O-mesylcyanohydrins of furanos-3'-ulosyladenine with Cs2CO3 afforded beta-D-xylo- and ribofuranosyladenine 3'-spiro nucleosides. Reaction of 1,2-di-O-acetyl-5-O-benzoyl-3-C-cyano-3-O-mesyl-D-ribofuranose with purine bases, followed by treatment with Cs2CO3, stereoselectively afforded beta-D-ribofuranosyl 3'-spiro nucleosides. 2',5'-O-Deacylation and subsequent treatment with tert-butyldimethylsilyl chloride gave the required TSAO derivatives. The 3'-spiro nucleosides with a xylo configuration did not show any anti-HIV activity. However, the purine ribo 3'-spiro nucleosides were potent and selective inhibitors of HIV-1 with a 50% effective concentration in the range of 0.1-1 microM and a selectivity index ranging from 2 to 3 orders of magnitude. Introduction of an alkyl function at N-1 of the purine moiety markedly decreased cytotoxicity without affecting antiviral activity.
新型抗HIV-1先导药物[[2',5'-双-O-(叔丁基二甲基甲硅烷基)-β-D-呋喃核糖基]胸腺嘧啶]-3'-螺-5''-(4''-氨基-1'',2''-氧硫杂环戊烯2'',2''-二氧化物)(TSAO-T)的几种嘌呤及嘌呤修饰类似物已被制备出来，并作为HIV-1诱导细胞病变的抑制剂进行了评估。呋喃糖-3'-酮基腺嘌呤的O-甲磺酰基氰醇与碳酸铯反应，得到β-D-木糖型和呋喃核糖基腺嘌呤3'-螺核苷。1,2-二-O-乙酰基-5-O-苯甲酰基-3-C-氰基-3-O-甲磺酰基-D-呋喃核糖与嘌呤碱反应，然后用碳酸铯处理，立体选择性地得到β-D-呋喃核糖基3'-螺核苷。2',5'-O-脱酰基，随后用叔丁基二甲基甲硅烷基氯处理，得到所需的TSAO衍生物。具有木糖构型的3'-螺核苷未显示出任何抗HIV活性。然而，嘌呤核糖3'-螺核苷是HIV-1的强效和选择性抑制剂，其50%有效浓度在0.1 - 1 microM范围内，选择性指数范围为2至3个数量级。在嘌呤部分的N-1位引入烷基官能团可显著降低细胞毒性，而不影响抗病毒活性。
