Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1, 5-a][1,3,5]triazines as thymidine phosphorylase inhibitors
5-Chlorouracil-linked-pyrazolo[1,5-a][1,3,5]triazines were designed as new thymidine phosphorylase inhibitors based on the fragment based drug design approach. Multiple-step convergent synthetic schemes were devised to generate the target compounds. The intermediate 5-chloro-6-chloromethyluracil was...
| Main Authors: | , , , , , |
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| Format: | Journal Article |
| Published: |
Elsevier Masson SAS
2013
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| Online Access: | http://hdl.handle.net/20.500.11937/47444 |
| _version_ | 1848757835090886656 |
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| author | Sun, L. Li, J. Bera, H. Dolzhenko, Anton Chiu, G. Chui, W. |
| author_facet | Sun, L. Li, J. Bera, H. Dolzhenko, Anton Chiu, G. Chui, W. |
| author_sort | Sun, L. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 5-Chlorouracil-linked-pyrazolo[1,5-a][1,3,5]triazines were designed as new thymidine phosphorylase inhibitors based on the fragment based drug design approach. Multiple-step convergent synthetic schemes were devised to generate the target compounds. The intermediate 5-chloro-6-chloromethyluracil was synthesized by a 4-step reaction. A series of the second bicyclic intermediates, namely pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-one, was obtained from various substituted 3-aminopyrazoles. These two intermediates were coupled finally in the presence of sodium ethoxide and methanol to yield the desirable target compounds. The methylthio coupling spacer was found to be suitable in enabling the interaction of the two fragments at the active site and allosteric site of the enzyme. The best coupled compound (9q) inhibited the thymidine phosphorylase with an IC50 value as low as 0.36 ± 0.1 µM. In addition, 9q demonstrated a mixed-type of enzyme inhibition kinetics, thus suggesting that it might indeed potentially bind at two different sites on the enzyme. © Georg Thieme Verlag KG Stuttgart New York ISSN 0935-8943. |
| first_indexed | 2025-11-14T09:34:24Z |
| format | Journal Article |
| id | curtin-20.500.11937-47444 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T09:34:24Z |
| publishDate | 2013 |
| publisher | Elsevier Masson SAS |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-474442017-09-13T14:09:29Z Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1, 5-a][1,3,5]triazines as thymidine phosphorylase inhibitors Sun, L. Li, J. Bera, H. Dolzhenko, Anton Chiu, G. Chui, W. 5-Chlorouracil-linked-pyrazolo[1,5-a][1,3,5]triazines were designed as new thymidine phosphorylase inhibitors based on the fragment based drug design approach. Multiple-step convergent synthetic schemes were devised to generate the target compounds. The intermediate 5-chloro-6-chloromethyluracil was synthesized by a 4-step reaction. A series of the second bicyclic intermediates, namely pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-one, was obtained from various substituted 3-aminopyrazoles. These two intermediates were coupled finally in the presence of sodium ethoxide and methanol to yield the desirable target compounds. The methylthio coupling spacer was found to be suitable in enabling the interaction of the two fragments at the active site and allosteric site of the enzyme. The best coupled compound (9q) inhibited the thymidine phosphorylase with an IC50 value as low as 0.36 ± 0.1 µM. In addition, 9q demonstrated a mixed-type of enzyme inhibition kinetics, thus suggesting that it might indeed potentially bind at two different sites on the enzyme. © Georg Thieme Verlag KG Stuttgart New York ISSN 0935-8943. 2013 Journal Article http://hdl.handle.net/20.500.11937/47444 10.1016/j.ejmech.2013.10.022 Elsevier Masson SAS restricted |
| spellingShingle | Sun, L. Li, J. Bera, H. Dolzhenko, Anton Chiu, G. Chui, W. Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1, 5-a][1,3,5]triazines as thymidine phosphorylase inhibitors |
| title | Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1, 5-a][1,3,5]triazines as thymidine phosphorylase inhibitors |
| title_full | Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1, 5-a][1,3,5]triazines as thymidine phosphorylase inhibitors |
| title_fullStr | Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1, 5-a][1,3,5]triazines as thymidine phosphorylase inhibitors |
| title_full_unstemmed | Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1, 5-a][1,3,5]triazines as thymidine phosphorylase inhibitors |
| title_short | Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1, 5-a][1,3,5]triazines as thymidine phosphorylase inhibitors |
| title_sort | fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1, 5-a][1,3,5]triazines as thymidine phosphorylase inhibitors |
| url | http://hdl.handle.net/20.500.11937/47444 |