Sanghvi Y S, Hanna N B, Larson S B, Fujitaki J M, Willis R C, Smith R A, Robins R K, Revankar G R
Nucleic Acid Research Institute, Costa Mesa, California 92626.
J Med Chem. 1988 Feb;31(2):330-5. doi: 10.1021/jm00397a010.
The 5-amino and certain related derivatives of the powerful purine nucleoside phosphorylase (PNPase) inhibitor 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine (TCNR,3) have been prepared and evaluated for their PNPase activity. Acetylation followed by dehydration of 5-chloro-1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (4a) gave 5-chloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-1,2,4-triazole-3- carbonitrile (5). Ammonolysis of 5 furnished 5-amino-1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine (5-amino-TCNR, 6), the structure of which was assigned by single-crystal X-ray analysis. Acid-catalyzed fusion of methyl 5-chloro-1,2,4-triazole-3-carboxylate (7a) with 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose (8) gave methyl 5-chloro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)- 1,2,4-triazole-3-carboxylate (9a) and the corresponding positional isomer 9b. Transformation of the functional groups in 9a afforded a route to 5'-deoxyribavirin (9i). Compound 9a was converted in four steps to 5-amino-1-(5-deoxy-beta-D-ribofuranosyl)-1,2,4-triazole-3- carboxamidine (5'-deoxy-5-amino-TCNR, 9g). Similar acid-catalyzed fusion of 1,2,4-triazole-3-carbonitrile (7b) with 8 and ammonolysis of the reaction product 9h gave yet another route to 9i. Treatment of 9h with NH3/NH4Cl furnished 1-(5-deoxy-beta-D-ribofuranosyl)- 1,2,4-triazole-3-carboxamidine (5'-deoxy-TCNR, 9k). The C-nucleoside congener of TCNR (3-beta-D-ribofuranosyl- 1,2,4-triazole-5-carboxamidine, 12) was prepared in two steps from 3-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)- 1,2,4-triazole-5-carbonitrile (10) by conventional procedure. 5-Amino-TCNR (6) displayed a more potent, high-affinity inhibition than TCNR, with a Ki of 10 microM. In contrast, 5'-deoxy-5-amino-TCNR (9g) was a significantly less potent inhibitor of PNPase, compared to 5'-deoxy-TCNR (Ki = 80 and 20 microM, respectively). Neither the C-nucleoside congener of TCNR (12) nor that of ribavirin were found to inhibit inosine phosphorolysis.
已制备了强效嘌呤核苷磷酸化酶（PNPase）抑制剂1-β-D-呋喃核糖基-1,2,4-三唑-3-甲脒（TCNR，3）的5-氨基及某些相关衍生物，并对其PNPase活性进行了评估。5-氯-1-β-D-呋喃核糖基-1,2,4-三唑-3-甲酰胺（4a）经乙酰化后脱水得到5-氯-1-(2,3,5-三-O-乙酰基-β-D-呋喃核糖基)-1,2,4-三唑-3-腈（5）。5经氨解得到5-氨基-1-β-D-呋喃核糖基-1,2,4-三唑-3-甲脒（5-氨基-TCNR，6），其结构通过单晶X射线分析确定。5-氯-1,2,4-三唑-3-羧酸甲酯（7a）与5-脱氧-1,2,3-三-O-乙酰基-D-呋喃核糖（8）经酸催化缩合得到5-氯-1-(2,3-二-O-乙酰基-5-脱氧-β-D-呋喃核糖基)-1,2,4-三唑-3-羧酸甲酯（9a）及相应的位置异构体9b。9a中官能团的转化提供了一条合成5'-脱氧利巴韦林（9i）的途径。化合物9a经四步反应转化为5-氨基-1-(5-脱氧-β-D-呋喃核糖基)-1,2,4-三唑-3-甲脒（5'-脱氧-5-氨基-TCNR，9g）。1,2,4-三唑-3-腈（7b）与8进行类似的酸催化缩合以及反应产物9h的氨解反应，得到了另一条合成9i的途径。用NH3/NH4Cl处理9h得到1-(5-脱氧-β-D-呋喃核糖基)-1,2,4-三唑-3-甲脒（5'-脱氧-TCNR，9k）。TCNR的C-核苷类似物（3-β-D-呋喃核糖基-1,2,4-三唑-5-甲脒，12）通过常规方法由3-(2,3,5-三-O-乙酰基-β-D-呋喃核糖基)-1,2,4-三唑-5-腈（10）分两步制备。5-氨基-TCNR（6）对PNPase的抑制作用比TCNR更强且亲和力更高，其Ki为10 microM。相比之下，与5'-脱氧-TCNR（Ki分别为80和2μM）相比，5'-脱氧-5-氨基-TCNR（9g）对PNPase的抑制作用明显较弱。未发现TCNR（12）的C-核苷类似物和利巴韦林的C-核苷类似物对肌苷磷酸解有抑制作用。
