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    Synthesis and evaluation of modified chalcone based p53 stabilizing agents

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    Type
    Article
    Authors
    Iftikhar, Sunniya
    Khan, Sardraz
    Bilal, Aishah
    Manzoor, Safia
    Abdullah, Muhammad
    Emwas, Abdul-Hamid M.
    Sioud, Salim
    Gao, Xin cc
    Chotana, Ghayoor Abbas
    Faisal, Amir
    Saleem, Rahman Shah Zaib
    KAUST Department
    Computational Bioscience Research Center (CBRC)
    Computer Science Program
    Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
    NMR
    Organics
    Date
    2017-07-15
    Online Publication Date
    2017-07-15
    Print Publication Date
    2017-09
    Permanent link to this record
    http://hdl.handle.net/10754/625233
    
    Metadata
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    Abstract
    Tumor suppressor protein p53 induces cell cycle arrest and apoptotic cell death in response to various cellular stresses thereby preventing cancer development. Activation and stabilization of p53 through small organic molecules is, therefore, an attractive approach for the treatment of cancers retaining wild-type p53. In this context, a series of nineteen chalcones with various substitution patterns of functional groups including chloro, fluoro, methoxy, nitro, benzyloxy, 4-methyl benzyloxy was prepared using Claisen-Schmidt condensation. The compounds were characterized using NMR, HRMS, IR and melting points. Evaluation of synthesized compounds against human colorectal (HCT116) and breast (Cal-51) cancer cell lines revealed potent antiproliferative activities. Nine compounds displayed GI50 values in the low micromolar to submicromolar range; for example (E)-1-phenyl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (SSE14108) showed GI50 of 0.473 ± 0.043 µM against HCT116 cells. Further analysis of these compounds revealed that (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (SSE14105) and (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (SSE14106) caused rapid (4 and 8-hour post-treatment) accumulation of p53 in HCT116 cells similar to its induction by positive control, Nutlin-3. Such activities were absent in 3-(4-methoxyphenyl)propiophenone (SSE14106H2) demonstrating the importance of conjugated ketone for antiproliferative and p53 stabilizing activity of the chalcones. We further evaluated p53 levels in the presence of cycloheximide (CHX) and the results showed that the p53 stabilization was regulated at post-translational level through blockage of its degradation. These chalcones can, therefore, act as fragment leads for further structure optimization to obtain more potent p53 stabilizing agents with enhanced anti-proliferative activities.
    Citation
    Iftikhar S, Khan S, Bilal A, Manzoor S, Abdullah M, et al. (2017) Synthesis and evaluation of modified chalcone based p53 stabilizing agents. Bioorganic & Medicinal Chemistry Letters. Available: http://dx.doi.org/10.1016/j.bmcl.2017.07.042.
    Sponsors
    Authors acknowledge the support by LUMS in the form of faculty initiative fund to enable this research work and extend our acknowledgement to KAUST for NMR and HRMS analysis.
    Publisher
    Elsevier BV
    Journal
    Bioorganic & Medicinal Chemistry Letters
    DOI
    10.1016/j.bmcl.2017.07.042
    PubMed ID
    28743509
    Additional Links
    http://www.sciencedirect.com/science/article/pii/S0960894X17307382
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.bmcl.2017.07.042
    Scopus Count
    Collections
    Articles; Computer Science Program; Computational Bioscience Research Center (CBRC); Computer, Electrical and Mathematical Science and Engineering (CEMSE) Division

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