title: Synthesis and in vitro evaluation of 1,2,4-triazolo[1,5-a][1,3,5]triazine derivatives as thymidine phosphorylase inhibitors.
abstract: In our lead finding program, a series of 1,2,4-triazolo[1,5-a][1,3,5]triazine derivatives were synthesized, and their in vitro thymidine phosphorylase inhibitory potential was explored. Among the different derivatives, compounds having keto group (C = O) at C7 and thioketo group (C = S) at C5 positions showed varying degrees of TP inhibitory activity comparable with positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 μm). Enzyme inhibition kinetics study suggested that compound IVn behaved as a mixed-type inhibitor of the enzyme with respect to thymidine (dThd) as a variable substrate. Compound IVn was also found to inhibit PMA-induced MMP-9 expression in MDA-MB-231 cells at sublethal concentrations. Computational docking study was performed to illustrate the enzyme inhibition kinetics and to explore the ligand-enzyme interactions.
authors.affiliation: Gokaraju Rangaraju College of Pharmacy, Bachupally, Hyderabad, 500090, India; Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Hriday
authors.initials: H
authors.lastname: Bera
authors.forename: Anton V
authors.initials: AV
authors.lastname: Dolzhenko
authors.forename: Lingyi
authors.initials: L
authors.lastname: Sun
authors.forename: Sayan
authors.initials: S
authors.lastname: Dutta Gupta
authors.forename: Wai-Keung
authors.initials: WK
authors.lastname: Chui
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D013816:Thermodynamics; D013936:Thymidine / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
chemical_list: C587498:2-(4-bromo-3-methylphenyl)-5-thioxo-5,6-dihydro-(1,2,4)triazolo(1,5-a)(1,3,5)triazin-7(4H)-one; C115661:7-deazaxanthine; D004791:Enzyme Inhibitors; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D013939:Thymidine Phosphorylase; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine
keywords: 1,2,4-triazolo[1,5-a][1,3,5]triazine; computational docking study; intramolecular heterocyclization; mixed-type inhibition; thymidine phosphorylase inhibitors