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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.

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 B1 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.
AuthorsRomeo Romagnoli, Pier Giovanni Baraldi, Carlota Lopez Cara, Ernest Hamel, Giuseppe Basso, Roberta Bortolozzi, Giampietro Viola
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 45 Issue 12 Pg. 5781-91 (Dec 2010) ISSN: 1768-3254 [Electronic] France
PMID20933308 (Publication Type: Journal Article)
CopyrightCopyright © 2010 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Thiophenes
  • Tubulin
  • Caspase 3
Topics
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Caspase 3 (metabolism)
  • Cell Cycle (drug effects)
  • Cell Death (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • HeLa Cells
  • Humans
  • Jurkat Cells
  • Molecular Structure
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiophenes (chemical synthesis, chemistry, pharmacology)
  • Tubulin (chemistry, metabolism)

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