Design, synthesis, and enzymatic evaluation of multisubstrate analogue inhibitors of Escherichia coli thymidine phosphorylase.
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-phosphonome...
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| Format: | Journal article |
| Language: | English |
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2000
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| _version_ | 1797076325639389184 |
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| author | Esteban-Gamboa, A Balzarini, J Esnouf, R De Clercq, E Camarasa, M Pérez-Pérez, M |
| author_facet | Esteban-Gamboa, A Balzarini, J Esnouf, R De Clercq, E Camarasa, M Pérez-Pérez, M |
| author_sort | Esteban-Gamboa, A |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T00:02:27Z |
| format | Journal article |
| id | oxford-uuid:766c9443-48d2-4e6f-ac41-d48df272b892 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:02:27Z |
| publishDate | 2000 |
| record_format | dspace |
| spelling | oxford-uuid:766c9443-48d2-4e6f-ac41-d48df272b8922022-03-26T20:16:09ZDesign, synthesis, and enzymatic evaluation of multisubstrate analogue inhibitors of Escherichia coli thymidine phosphorylase.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:766c9443-48d2-4e6f-ac41-d48df272b892EnglishSymplectic Elements at Oxford2000Esteban-Gamboa, ABalzarini, JEsnouf, RDe Clercq, ECamarasa, MPérez-Pérez, MA 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. |
| spellingShingle | Esteban-Gamboa, A Balzarini, J Esnouf, R De Clercq, E Camarasa, M Pérez-Pérez, M Design, synthesis, and enzymatic evaluation of multisubstrate analogue inhibitors of Escherichia coli thymidine phosphorylase. |
| title | Design, synthesis, and enzymatic evaluation of multisubstrate analogue inhibitors of Escherichia coli thymidine phosphorylase. |
| title_full | Design, synthesis, and enzymatic evaluation of multisubstrate analogue inhibitors of Escherichia coli thymidine phosphorylase. |
| title_fullStr | Design, synthesis, and enzymatic evaluation of multisubstrate analogue inhibitors of Escherichia coli thymidine phosphorylase. |
| title_full_unstemmed | Design, synthesis, and enzymatic evaluation of multisubstrate analogue inhibitors of Escherichia coli thymidine phosphorylase. |
| title_short | Design, synthesis, and enzymatic evaluation of multisubstrate analogue inhibitors of Escherichia coli thymidine phosphorylase. |
| title_sort | design synthesis and enzymatic evaluation of multisubstrate analogue inhibitors of escherichia coli thymidine phosphorylase |
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