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Synthesis and biological evaluation of 2-(3 ',4 ',5 '-trimethoxybenzoyl)-3-aryl/arylaminobenzo[b]thiophene derivatives as a novel class of antiproliferative agents

  1. Author:
    Romagnoli, R.
    Baraldi, P. G.
    Cara, C. L.
    Hamel, E.
    Basso, G.
    Bortolozzi, R.
    Viola, G.

  2. Author Address

    [Romagnoli, Romeo; Baraldi, Pier Giovanni; Cara, Carlota Lopez] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Basso, Giuseppe; Bortolozzi, Roberta; Viola, Giampietro] Univ Padua, Dipartimento Pediat, Lab Oncoematol, I-35131 Padua, Italy.;Romagnoli, R, Univ Ferrara, Dipartimento Sci Farmaceut, Via Fossato di Mortara 17-19, I-44100 Ferrara, Italy.;rmr@unife.it giampietro.viola.1@unipd.it
    1. Year: 2010
    2. Date: Dec
  2. Journal: European Journal of Medicinal Chemistry
    1. 45
    2. 12
    3. Pages: 5781-5791
  4. Type of Article: Article
  5. ISSN: 0223-5234
  1. Abstract:

    The biological importance of microtubules in mitosis, as well as in interphase, makes them an interesting target for the development of anticancer agents. Small molecules such as benzo[b]thiophenes are attractive as inhibitors of tubulin polymerization. Thus, a new class of compounds that incorporated the structural motif of the 2-(3',4',5'-trimethoxybenzoyl)-3-aryl/arylamino benzo[b]thiophene molecular skeleton, with electron-donating (Me, OMe, SMe or OEt) or electron-withdrawing (F and Cl) substituents on the B-ring, was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization and cell cycle effects. The most promising compound in this series was 2-(3',4',5'-trimethoxybenzoyl)-3-(4'-ethoxyphenyl)-benzo[b]thiophene (4e), which significantly inhibited cancer cell growth at submicromolar concentrations, especially against HeLa and Jurkat cells, and interacted with tubulin. As determined by flow cytometric analysis, 4e caused G2/M phase arrest and apoptosis in a time and concentration-dependent manner. The block in G2/M was correlated with increased expression of cyclin 131 and phosphorylation of cdc25c. Moreover, 4e perturbed mitochondrial membrane potential and caused activation of caspase-3 and cleavage of poly(ADP-rybose)polymerase (PARP), events that are involved in 4e-induced apoptosis. (C) 2010 Elsevier Masson SAS. All rights reserved.

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External Sources

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  2. DOI: 10.1016/j.ejmech.2010.09.038
  3. View record in Web of Science®
  4. WOS: 000285485000029

Library Notes

  1. Fiscal Year: FY2010-2011
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