title: Synthesis of pyrazolo[1,5-a][1,3,5]triazine derivatives as inhibitors of thymidine phosphorylase.
abstract: Thymidine phosphorylase (TP) is an enzyme that promotes tumor growth and metastasis and therefore is an attractive druggable target. Using a reported TP inhibitor, 7-deazaxanthine (7DX), as the lead compound; this study was set up to evaluate whether pyrazolo[1,5-a][1,3,5]triazin-2,4-diones and pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-ones would exhibit TP inhibitory activity. The pyrazolo[1,5-a][1,3,5]triazine nucleus was constructed using a reaction that annulated the 1,3,5-triazine ring onto a pyrazole scaffold. Among the 52 compounds synthesized and tested, it was found that 1,3-dihydro-pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-ones exhibited various extent of inhibitory activity against TP. The best compound 17p, which bears a para-substituted pentafluorosulfur group, showed an IC50 value of 0.04 μM, which was around 800 times more potent than the 7DX (IC50 = 32 μM) under the same bioassay conditions. The results of the study suggested that a substituent with +σ and +π properties inserted at position 4 of a phenyl ring that is attached to position 8 of the pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-one scaffold would give excellent TP inhibitory action. In addition, 17p was found to be a non-competitive inhibitor thus suggested that it might interact with TP at a position different from the substrate binding site.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. g0801101@nus.edu.sg
authors.forename: Lingyi
authors.initials: L
authors.lastname: Sun
authors.forename: Hriday
authors.initials: H
authors.lastname: Bera
authors.forename: Wai Keung
authors.initials: WK
authors.lastname: Chui
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011719:Pyrazines; D011994:Recombinant Proteins; D014227:Triazines; C586271:pyrazolo(1,5-a)(1,3,5)triazine; D013939:Thymidine Phosphorylase
keywords: Enzyme inhibitor; Pyrazolo[1,5-a][1,3,5]triazines; Thymidine phosphorylase