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1998 (1)
1Author    ZlatinaG. Naydenova3, KonstantinC. Grancharov3, DimitarK. Alargov3, EvgenyV. Golovinsky3, IvankaM. Stanoevab, LilianaD. Shalamanovab, IlzaK. PajevabRequires cookie*
 Title    Inhibition of UDP-glucuronosyltransferase by 5'-0-am ino Acid and Oligopeptide Derivatives of Uridine: Structure-Activity Relationships  
 Abstract    The inhibitory effect of a series of 5'-0-am ino acid and oligopeptide derivatives of uridine on rat liver UDP-glucuronosyltransferase (U G T) activities was investigated using two assay systems. A quantitative structure-activity relationship (Q SA R) study was performed. The compounds include a lipophilic residue linked to the nucleoside by a variable spacer. More­ over, half of the derivatives have two spacers linked to the uridine moiety. Compound 1, a serine derivative of isopropylideneuridine, was found to be the most potent inhibitor of both 4-nitrophenol (4-NP) and phenolphthalein (PPh) glucuronidation, with an I50 of 0.45 m M and 0.22 m M , respectively. Kinetic studies with this substance revealed a mixed type of inhibition towards 4-NP and UDP-glucuronic acid, with apparent Ki values of 150 ^ m and 120 (.i m , respectively. The dipeptide derivatives 11-14 exhibited a low activity against 4-NP conjuga­ tion. However, a marked suppression of PPh glucuronidation was found with compounds 11 and 13. Generally, compounds with two spacers are more inhibitory against the U G T activi­ ties studied. The Q SA R analysis outlined the significance of the spacers with a minimum length of 5 atoms and lipophilic residues linked to them for the inhibitory effect of the compounds. The most significant contribution to this effect is given by the six-atom spacer for both, 4-NP and PPh substrates. 4-NP converting U G T isoforms seem to respond more specifically to the inhibitors: a five-atom for the first and a six-atom for the second spacer enhance binding to both 4-NP and PPh conjugating isoenzymes, while a long second spacer contributes to inhibitor binding to U G T isoforms only converting PPh. 
  Reference    Z. Naturforsch. 53c, 173—181 (1998); received November 4 1997/January 14. 1998 
  Published    1998 
  Keywords    UDP-glucuronosyltransferase, Microsomes, Uridine Derivatives, Inhibitors, Q SA R 
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 TEI-XML for    default:Reihe_C/53/ZNC-1998-53c-0173.pdf 
 Identifier    ZNC-1998-53c-0173 
 Volume    53