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 C 6 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, C 7″ -epimers 2a and 2b exert a different inhibitory effect on UGT2B15.