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Synthesis and in vitro Evaluation of 1,2,4‐Triazolo[1,5‐ a ][1,3,5]triazine Derivatives as Thymidine Phosphorylase Inhibitors
Author(s) -
Bera Hriday,
Dolzhenko Anton V.,
Sun Lingyi,
Dutta Gupta Sayan,
Chui WaiKeung
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12171
Subject(s) - thymidine phosphorylase , chemistry , triazine , in vitro , enzyme , stereochemistry , docking (animal) , thymidine , enzyme kinetics , kinetics , active site , biochemistry , organic chemistry , medicine , physics , nursing , quantum mechanics
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 ) (IC 50 value = 42.63 μ m ). Enzyme inhibition kinetics study suggested that compound IVn behaved as a mixed‐type inhibitor of the enzyme with respect to thymidine ( dT hd) 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.