PMID:10715161
| Citation |
Esteban-Gamboa, A, Balzarini, J, Esnouf, R, De Clercq, E, Camarasa, MJ and Pérez-Pérez, MJ (2000) Design, synthesis, and enzymatic evaluation of multisubstrate analogue inhibitors of Escherichia coli thymidine phosphorylase. J. Med. Chem. 43:971-83 |
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| Abstract |
A series of acyclic phosphonate derivatives of thymine has been synthesized and tested as multisubstrate analogue inhibitors of Escherichia coli thymidine phosphorylase. The compounds synthesized include 1-(phosphonoalkyl)thymines with six to nine methylenes (1-4, respectively); 1-[(Z)-4-phosphonomethoxy-2-butenyl]thymine (5) and its butyl and 2,3-cis-dihydroxybutyl derivatives (6 and 7, respectively); 1-[(Z)-(4-(phosphonomethoxy)methoxy)-2-butenyl]thymine (8) and also its butyl and 2,3-cis-dihydroxybutyl analogues (9 and 10); and 1-[((Z)-4-(phosphonomethoxy)-2-butenoxy)methyl]thymine (11). Evaluation of these compounds against E. coli revealed significant enzymatic inhibition by 2, 3, 4, 6, and 8 at a concentration of 1000 microM, 3 and 4 being the most potent. Replacement of the thymine base in 3 by 6-amino-5-bromouracil and 7-deazaxanthine afforded compounds 12 and 13, which showed a pronounced improvement of TPase inhibition, comparable to 7-deazaxanthine. When inorganic phosphate was used as a variable substrate, compounds 12 and 13 displayed competitive kinetics with respect to phosphate, indicating a direct interaction of these compounds with the phosphate binding site. Also compounds 12 and 13 were found to be competitive inhibitors of TPase against thymidine as a variable substrate. These results are consistent with the compounds being multisubstrate analogue inhibitors of E. coli TPase, and they represent the first example of such TPase inhibitors. |
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| Keywords |
Chromatography, High Pressure Liquid; Drug Design; Enzyme Inhibitors/chemical synthesis; Enzyme Inhibitors/chemistry; Escherichia coli/chemistry; Kinetics; Models, Molecular; Organophosphonates/chemical synthesis; Organophosphonates/chemistry; Pyrimidinones/chemical synthesis; Pyrimidinones/chemistry; Structure-Activity Relationship; Substrate Specificity; Thymidine/chemistry; Thymidine Phosphorylase/antagonists & inhibitors; Thymidine Phosphorylase/chemistry; Uracil/analogs & derivatives; Uracil/chemical synthesis; Uracil/chemistry |
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