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    Discovery of mixed type thymidine phosphorylase inhibitors endowed with antiangiogenic properties: Synthesis, pharmacological evaluation and molecular docking study of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones. Part II

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    Authors
    Bera, H.
    Ojha, P.
    Tan, B.
    Sun, L.
    Dolzhenko, Anton
    Chui, W.
    Chiu, G.
    Date
    2014
    Type
    Journal Article
    
    Metadata
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    Citation
    Bera, H. and Ojha, P. and Tan, B. and Sun, L. and Dolzhenko, A. and Chui, W. and Chiu, G. 2014. Discovery of mixed type thymidine phosphorylase inhibitors endowed with antiangiogenic properties: Synthesis, pharmacological evaluation and molecular docking study of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones. Part II. European Journal of Medicinal Chemistry. 78: pp. 294-303.
    Source Title
    European Journal of Medicinal Chemistry
    DOI
    10.1016/j.ejmech.2014.03.063
    ISSN
    0223-5234
    School
    School of Pharmacy
    URI
    http://hdl.handle.net/20.500.11937/34693
    Collection
    • Curtin Research Publications
    Abstract

    In our drug discovery program, a series of 2-thioxo-pyrazolo[1,5-a][1,3,5] triazin-4-ones were designed, synthesized and evaluated for their TP inhibitory potential. All the synthesized analogues conferred a varying degree of TP inhibitory activity, comparable or better than positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 µM). A systematic approach to the lead optimization identified compounds 3c and 4a as the most promising TP inhibitors, exhibiting mixed mode of enzyme inhibition. Moreover, selected compounds demonstrated the ability to attenuate the expression of the angiogenic markers (viz. MMP-9 and VEGF) in MDA-MB-231 cells at sublethal concentrations. In addition, molecular docking studies revealed the plausible binding orientation of these inhibitors towards TP, which was in accordance with the experimental results. Taken as a whole, these compounds would constitute a new direction for the design of novel TP inhibitors with promising antiangiogenic properties. © 2014 Elsevier Masson SAS. All rights reserved.

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