C-GLYCOSYL BOND CONFORMATION IN OXAZOFURIN - CRYSTALLOGRAPHIC AND COMPUTATIONAL STUDIES OF THE OXAZOLE ANALOG OF TIAZOFURIN

Oxazofurin is the inactive oxazole analogue of the C-glycosyl thiazole antitumor agent tiazofurin. Replacement of the thiazole sulfur in tia zofurin with the oxazole oxygen in oxazofurin produces conformational effects that are examined using crystallographic and computational met hods. The crystal structure of oxazofurin contains six molecules in th e asymmetric unit and has been refined to a standard R value of 6.8% f or all data. The six oxazofurin conformers show an average C-glycosidi c torsion angle of 70(9)degrees. This value is significantly higher th an the average absolute C-glycosidic torsion angle of 24(10)degrees ob tained from previous thiazole nucleoside structures. Previous studies suggest that, in tiazofurin, an electrostatic interaction between a po sitively charged thiazole sulfur and negatively charged furanose oxyge n constrains the C-glycosidic torsion angle to a relatively small valu e. Ab initio molecular orbital studies presented here suggest that the higher C-glycosidic angles observed in the oxazofurin structures resu lt from a repulsive interaction between negatively charged oxazole and furanose oxygens. Thus, it is likely that differences in activity bet ween oxazo- and tiazofurin are either (1) due directly to differences in electronic properties between the thiazole and oxazole rings or (2) due to the variation in C-glycosidic bond conformation resulting from the alteration in the charge distribution of the heterocycle.