Synthesis and inhibitory effect of a trisubstrate transition state analogue for UDP glucuronosyltransferases

Trisubstrate UGT transition state analogue 2 is readily accessible by nucleophilic ring-opening of 1,2-anhydroglucose precursor 5 with diethylmalonate anion followed by reduction of the ethyl ester moieties (6→7). Subsequent C6 oxidation (8→9), NIS/cat. TfOH-mediated introduction of the androsterylmethylene unit (12→15) and phosphitylation with 5′-uridine phosphoramidite 16 furnished, after oxidation and deprotection, target derivative 2, the two individual diastereomers of which (2a and 2b) were separated by HPLC. Trisubstrate analogues 2a,b show a different inhibition pattern for several UGT isoforms, indicating isoenzyme selectivity. Moreover, C7″-epimers 2a and 2b exert a different inhibitory effect on UGT2B15.