STABLE AND NONMETABOLIZABLE C-GLYCOSYLPHOSPHONYL ANALOGS OF 5-PHOSPHORYLRIBOSE 1-ALPHA-DIPHOSPHATE THAT ACT AS INHIBITORS OF OROTATE PHOSPHORIBOSYLTRANSFERASE

Phosphonate analogs of 5-phosphorylribose 1-α-diphosphate (PRPP), in which the anomeric oxygen has been replaced by carbon (C-glycoside analogs), have been prepared in multistep syntheses. The exact "ribosyl" analog could not be elaborated from the 3,4-isopropylidene precursor, 9, owing to attack of the 3-OH onto the phosphonyl phosphorus under conditions for removal of the blocking group. Nevertheless, this isopropylidene derivative is a competitive inhibitor ( Ki Km(PRPP) = 16.4), with respect to PRPP, of yeast orotate phosphoribosyltransferase. This result indicates that the enzyme can accommodate a good deal of bulk at the corresponding 2- and 3-hydroxyl groups of PRPP. The "α-arabinosyl" analog, 15, was successfully synthesized with ultimate stereospecificity that results from the preferential hydrolysis of the "β-anomer" in the same fashion as for the hydrolysis of 9. This α-arabinosyl analog is also a competent competitive inhibitor of yeast orotate phosphoribosyltransferase ( Ki Km(PRPP) = 54). Both compounds are considerably more stable than PRPP both chemically and biochemically. © 1990.