A new class of C-nucleoside analogues. 1-(S)-aryl-1,4-dideoxy-1,4-imino-D-ribitols, transition state analogue inhibitors of nucleoside hydrolase

Abstract

The first members of a new class of N-glycohydrolase transition state analogue inhibitors, 1,4-dideoxy-1,4-imino-1-(S)-phenyl-D-ribitol, 1, and 1,4-dideoxy-1,4-imino-1-(S)-(4-imidazolyl)-D-ribitol, 2, have been synthesized. These compounds represent a new type of C-nucleoside analogue in which the endocyclic ribosyl ring oxygen has been replaced with nitrogen. The key synthetic step involves reaction of a protected ribosylimine with a metallated aryl species. The compounds are transition state analogues for enzymes which catalyzed CN glycosidic bond hydrolyses of nucleosides and have transition states with oxocarbenium ion character. Compounds 1 and 2 are potent competitive inhibitors with dissociation constants of 0.03 and 2.5 μM, for nucleoside hydrolase from the trypanosome Crithidia fasciculata. The highly effective inhibition observed demonstrates the importance of including both charge and aglycon mimicry in a glycosylase transition state analogue and differentiates it from simpler analogues.