Synthesis and in vitro evaluation of substituted aryl- and hetarylmethyl phosphonate and phosphate — UMP derivatives as potential glucosyltransferase inhibitors

Abstract

The enzyme β (1[Formula: see text]4)-glucosyltransferase (BGT) catalyses the transfer of glucose from uridine diphosphoglucose (UDP-Glc) to 5-hydroxymethylcytosine (5-HMC) bases in double-stranded DNA. Potential inhibitors of BGT were developed by structure-based design and synthesized. The designed inhibitors 1–6 provide conformational mimicry of the transition state in glucosyltransfer reactions. The key synthetic steps involve a Michaelis–Arbuzov reaction followed by coupling with uridine-5'-morpholidophosphate as activated UMP derivative. The compounds were tested for in vitro inhibitory activity against BGT and the inhibition kinetics were examined. Three of the designed molecules were found to be potential inhibitors of BGT having IC50values in the micromolar (µM) range. Useful structure–activity relationships were established which provide guidelines for the design of future generations of inhibitors of BGT.Key words: β-glucosyltransferase, transition state, enzyme inhibitors, structure-based design, synthesis.