Sanghvi Y S, Larson S B, Willis R C, Robins R K, Revankar G R
Nucleic Acid Research Institute, Costa Mesa, California 92626.
J Med Chem. 1989 May;32(5):945-51. doi: 10.1021/jm00125a004.
A series of C-4 substituted pyrazolo[3,4-b]pyridine nucleosides have been synthesized and evaluated for their biological activity. Successful synthesis of various C-4 substituted pyrazolo[3,4-b]pyridine nucleosides involves nucleophilic displacement by a suitable nucleophile at the C-4 position of 4-chloro-1H-pyrazolo[3,4-b]pyridine (5), followed by glycosylation of the sodium salt of the C-4 substituted pyrazolo[3,4-b]pyridines with a protected alpha-halopentofuranose. Use of this methodology furnished a simple and direct route to the beta-D-ribofuranosyl, beta-D-arabinofuranosyl, and 2-deoxy-beta-D-erythro-pentofuranosyl nucleosides of C-4 substituted pyrazolo[3,4-b]pyridines, wherein the C-4 substituent was azido, amino, methoxy, chloro, or oxo. The regiospecificity of these glycosylations was determined on the basis of UV data and the anomeric configuration was established by 1H NMR analysis. Conclusive structural assignment was made by a single-crystal X-ray diffraction study of three compounds, 15, 31, and 42, as representatives of ribo-2'-deoxy-, and aranucleosides, respectively. The stereospecific attachment of all three alpha-halogenoses appears to occur by a Walden inversion (SN2 mechanism) at the C-1 carbon of the halogenose by the anionic N-1 of pyrazolo[3,4-b]pyridine. All deprotected nucleosides were tested against various viruses and tumor cells in culture. The effects of these compounds on de novo purine and pyrimidine nucleotide biosynthesis was also evaluated. Among the compounds tested, 4-chloro-1-beta-D-ribofuranosylpyrazolo[3,4-b]pyridine (16) and 1-beta-D-ribofuranosyl-4,7-dihydro-4-oxopyrazolo[3,4-b]pyridine (19) were found to be moderately cytotoxic to L1210 and WI-L2 in culture.
一系列C-4取代的吡唑并[3,4-b]吡啶核苷已被合成并评估其生物活性。成功合成各种C-4取代的吡唑并[3,4-b]吡啶核苷涉及在4-氯-1H-吡唑并[3,4-b]吡啶（5）的C-4位通过合适的亲核试剂进行亲核取代，然后将C-4取代的吡唑并[3,4-b]吡啶的钠盐与受保护的α-卤代戊呋喃糖进行糖基化反应。使用这种方法提供了一条简单直接的路线来合成C-4取代的吡唑并[3,4-b]吡啶的β-D-核糖呋喃糖基、β-D-阿拉伯呋喃糖基和2-脱氧-β-D-赤藓戊呋喃糖基核苷，其中C-4取代基为叠氮基、氨基、甲氧基、氯或氧代。这些糖基化反应的区域特异性是根据紫外数据确定的，异头构型通过1H NMR分析确定。通过对三种化合物15、31和42进行单晶X射线衍射研究分别确定了核糖-2'-脱氧核苷和阿拉伯核苷的结构。所有三种α-卤代糖的立体专一性连接似乎是通过吡唑并[3,4-b]吡啶的阴离子N-1在卤代糖的C-1碳上进行瓦尔登翻转（SN2机制）而发生的。所有脱保护的核苷都在培养物中针对各种病毒和肿瘤细胞进行了测试。还评估了这些化合物对嘌呤和嘧啶核苷酸从头生物合成的影响。在测试的化合物中，发现4-氯-1-β-D-核糖呋喃糖基吡唑并[3,4-b]吡啶（16）和1-β-D-核糖呋喃糖基-4,7-二氢-4-氧代吡唑并[3,4-b]吡啶（19）在培养物中对L1210和WI-L2具有中等细胞毒性。
