Synthesis and Evaluation of 5-Amino-1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine and Certain Related Nucleosides as Inhibitors of Purine Nucleoside Phosphorylase

Article abstract of DOI:10.1021/jm00397a010

The 5-amino and certain related derivatives of the powerful purine nucleoside phosphorylase (PNPase) inhibitor 1-β-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-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (4a) gave 5-chloro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-triazole-3-carbonitrile (5).Ammonolysis of 5 furnished 5-amino-1-β-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-catalysed 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-β-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-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamidine (5'-deoxy-5-amino-TCNR, 9g).Similar acid-catalysed 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-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamidine (5'-deoxy-TCNR, 9k).The C-nucleoside congener of TCNR (3-β-D-ribofuranosyl-1,2,4-triazole-5-carboxamidine, 12) was prepared in two steps from 3-(2,3,5-tri-O-acetyl-β-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 K_i of 10 μM.In contrast, 5'-deoxy-5-amino-TCNR (9g) was a significantly less potent inhibitor of PNPase, compared to 5'-deoxy-TCNR (K_i=80 and 20 μM, respectively).Neither the C-nucleoside congener of TCNR (12) nor that of ribavirin were found to inhibit inosine phosphorolysis.