INHIBITION OF UDP-GLUCURONOSYLTRANSFERASE BY 5'-O-AMINO ACID AND OLIGOPEPTIDE DERIVATIVES OF URIDINE - STRUCTURE-ACTIVITY-RELATIONSHIPS

The inhibitory effect of a series of 5'-O-amino acid and oligopeptide derivatives of uridine on rat liver UDP-glucuronosyltransferase (UGT) activities was investigated using two assay systems. A quantitative st ructure-activity relationship (QSAR) study was performed. The compound s include a lipophilic residue linked to the nucleoside by a variable spacer. Moreover, half of the derivatives have two spacers linked to t he uridine moiety. Compound 1, a serine derivative of isopropylideneur idine, was found to be the most potent inhibitor of both 4-nitrophenol (4-NP) and phenolphthalein (PPh) glucuronidation, with an I-50 Of 0.4 5 mM and 0.22 mM, respectively. Kinetic studies with this substance re vealed a mixed type of inhibition towards 4-NP and UDP-glucuronic acid , with apparent Ki values of 150 mu M and 120 mu M; respectively. The dipeptide derivatives 11-14 exhibited a low activity against 4-NP conj ugation. However, a marked suppression of PPh glucuronidation was foun d with compounds 11 and 13. Generally, compounds with two spacers are more inhibitory against the UGT activities studied. The QSAR analysis outlined the significance of the spacers with a minimum length of 5 at oms and lipophilic residues linked to them for the inhibitory effect o f the compounds. The most significant contribution to this effect is g iven by the six-atom spacer for both, 4-NP and PPh substrates. 4-NP co nverting UGT isoforms seem to respond more specifically to the inhibit ors: a five-atom for the first and a six-atom for the second spacer en hance binding to both 4-NP and PPh conjugating isoenzymes, while a lon g second spacer contributes to inhibitor binding to UGT isoforms only converting PPh.