Monometoxytrityl derivatives of uridine as inhibitors of a human recombinant UDP-glucuronosyltransferase: UGT1*6.
A series of inhibitors of the human liver recombinant UDP-glucuronosyltransferase 1*6 derived from uridine were synthetized as probes of the binding site of the cosubstrate, UDP-glucuronic acid. If triphenylmethanol or uridine alone failed to inhibit the glucuronidation of 4-methylumbelliferone, the trityl derivatives of uridine were found to be very effective inhibitors of the enzyme (Ki 4.4 to 73 microM). The type of inhibition (competitive or mixed) varied with the substitutions on the uracile or on the triphenylmethyl moiety by halogen atoms or methyl groups. Structural features for the binding of the cofactor are postulated.
Cano
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V
Centre du Médicament URA CNRS 597, Nancy, France.
Lorentz
C
C
Magdalou
J
J
Loppinet
V
V
Siest
G
G
Ziegler
J C
JC
D000818:Animals; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D011994:Recombinant Proteins / Q000187:drug effects*; D014529:Uridine / Q000031:analogs & derivatives* / Q000737:chemistry; D014535:Uridine Diphosphate Glucuronic Acid / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D014535:Uridine Diphosphate Glucuronic Acid; D014529:Uridine