Synthesis and evaluation of 5-amino-1-.beta.-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine and certain related nucleosides as inhibitors of purine nucleoside phosphorylase

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Abstract
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 or 10 .mu.M. 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 .mu.M, respectively). Neither the C-nucleoside congener of TCNR (12) nor that of ribavirin were found to inhibit inosine phosphorolysis.