Conception et synthèse d'inhibiteurs pour l'étude du site actif d'une UDP-glucuronosyltransférase recombinante hépatique humaine : l'UGT1*6

Abstract : New UDP-glucuronosyltransferases inhibitors have been designed, synthetized and tested in order to probe the active sites of these proteins which are involved in the metabolism of xenobiotics, such as drugs, and endobiotics such as bilirubin, retinois acids,... The synthetized molecules, whose stucture is analogous to the donor substrate UDP-glucuronic acid, allowed us to characterize more specifically the peptidic domain interacting with this substrate. The maiIÏ results are gathered in three different parts, according to the group of inhibitors considered. 1- Uridine being the mother compound, a chemical series of about fifty molecules has been synthetized by varying the nature of the chemical groups placed successively on the base moiety or on the 2', 3' and 5' positions of the sugar. The inhibitory effect has frrst been estimated in terms of IC50. For the most powerful inhibitors, a detailed kinetic study gave us the inhibition constant and the type of inhibition. 2- These inhibitors have been compared to those previously obtained in the laboratory, such as arylalkyl carboxylic acids (competitive inhibitors) and N-acyl-phenylamino alcohols attached to a uridine molecule by a spacer (transition-state analogs). They have been used to characterize binding site of 4-methylumbelliferone of the UDP-glucuronosyl transferase 1.6 after mutation of amino-acids His54 and Arg52 (mutants H54A, H54Q and R52A). 3- A series of inhibitors derived from triphenylalkyl carboxylic acids containing a primary alcohol group instead of the carboxylic acid group and with various carbon chain length has been tested on rats hepatic microsomes. They show a strong inhibitory effect on bilirubin glucuronidation. The results obtained allowed us to better understand the molecular and electronic basis of substrates interaction with UDP-glucuronosyl transferases.
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Theses
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http://docnum.univ-lorraine.fr/prive/SCD_T_1997_0325_CANO.pdf
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https://hal.univ-lorraine.fr/tel-01747426
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Submitted on : Thursday, March 29, 2018 - 10:59:42 AM
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Virginie Cano. Conception et synthèse d'inhibiteurs pour l'étude du site actif d'une UDP-glucuronosyltransférase recombinante hépatique humaine : l'UGT1*6. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 1997. Français. ⟨NNT : 1997NAN12155⟩. ⟨tel-01747426⟩

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