A series of 8-substituted 1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrrolo[2,3-d]pyrimidine (methylpyrazolo-fused 7-deazapurine) ribonucleosides have been designed and synthesized. Two synthetic approaches to the key heterocyclic aglycon 7, (i) a six-step classical heterocyclization starting from 5-chloro-1-methyl-4-nitropyrazole and (ii) a three-step cross-coupling and cyclization approach starting from the zincated 4,6-dichloropyrimidine, gave comparable total yields of 18% vs 13%. The glycosylation of 7 was attempted by three different methods but only the Vorbrüggen silyl-base protocol was efficient and stereoselective to give desired β-anomeric nucleoside intermediate 17A. Its nucleophilic substitutions or cross-coupling reactions at position 8 and deprotection of the sugar moiety gave eight derivatives of pyrazolo-fused deazapurine ribonucleosides, some of which were weakly fluorescent. Methyl, amino, and methylsulfanyl derivatives exerted submicromolar cytotoxic effects in vitro against a panel of cancer and leukemia cell lines as well as antiviral effects against hepatitis C virus in the replicon assay.

中文翻译：

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吡唑并融合的7-脱氮嘌呤核苷的合成及生物学分析。

设计并合成了一系列的8-取代的1-甲基-1,4-二氢吡唑并[3'，4'：4,5]吡咯并[2,3- d ]嘧啶（甲基吡唑并稠合的7-脱氮嘌呤）核糖核苷。关键杂环糖苷配基7的两种合成方法，（i）从5-氯-1-甲基-4-硝基吡唑开始的六步经典杂环化，和（ii）从镀锌开始的三步交叉偶联和环化方法4,6-二氯嘧啶的可比总产率为18％对13％。通过三种不同的方法尝试了7的糖基化反应，但只有Vorbrüggen甲硅烷基试剂盒有效且立体选择性，可提供所需的β-异头核苷中间体17A。其在位置8的亲核取代或交叉偶联反应以及糖部分的脱保护得到了吡唑并稠合的脱氮嘌呤核糖核苷的八种衍生物，其中一些具有弱荧光性。甲基，氨基和甲基硫烷基衍生物在体外对一组癌症和白血病细胞系发挥亚微摩尔的细胞毒作用，并在复制子测定中对丙型肝炎病毒产生抗病毒作用。