Conformation about the Glycosidic Bond and Susceptibility to 5 '-Nucleotidase of 8-Substituted Analogues of 5'-GMP

Abstract

Susceptibilities to snake [Crotalus adamanteus] venom 5''-nucleotidase were evaluated for several 8-substituted anologs of 5''-GMP with varying populations of sny/anti conformations about the glycosidic bond. Improved syntheses of some of these are described, including direct chlorination of 5''-GMP to give 8-chloro-5''-GMP, a procedure which should be applicable to other purine nucleotides. The conformations of the various analogs were determined by means of 1H NMR spectroscopy, with particular emphasis on the glycosidic bond conformations. All the 8-substituted derivatives of 5''-GMP were relatively poor substrates of 5''-nucleotidase. This resulted largely from steric effects and the nature of the 8-substituent, and was consistent with a requirement for the anti conformation. Although ribose-5-phosphate was not a substrate, it was a weak inhibitor, and its inhibitory properties account in part for the weak inhibitory properties of the 8-substituted 5''-GMP and other analogs. Attention is drawn to the hitherto largely neglected differences in properties of 5''-nucleotidases from different sources and their relevance to the present findings.