Synthesis, biological evaluation and molecular docking studies of trans-indole-3-acrylamide derivatives, a new class of tubulin polymerization inhibitors

[Display omitted] In this study, we synthesized a series of trans-indole-3-acrylamide derivatives (3a–k) and investigated their activity for inhibition of cell proliferation against five human cancer cell lines (HeLa, MCF7, MDA-MB-231, Raji and HL-60) by MTT assay. Compound 3e showed significant ant...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2014-06, Vol.22 (12), p.3096-3104
Main Authors: Baytas, Sultan Nacak, Inceler, Nazan, Yılmaz, Akın, Olgac, Abdurrahman, Menevse, Sevda, Banoglu, Erden, Hamel, Ernest, Bortolozzi, Roberta, Viola, Giampietro
Format: Article
Language:English
Subjects:
Acrylamide - chemistry
Acrylamides - chemistry
Acrylamides - pharmacology
Anticancer activity
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Caspase 3 - metabolism
Cell Cycle - drug effects
Cell cycle arrest
Cell Proliferation - drug effects
Colchicine binding
Drug Screening Assays, Antitumor
HeLa Cells
HL-60 Cells
Humans
Indole
Indoles - chemistry
Indoles - pharmacology
Molecular docking
Molecular Docking Simulation
Molecular Structure
Protein Multimerization - drug effects
Structure-Activity Relationship
Synthesis
Tubulin - chemistry
Tubulin - metabolism
Tubulin Modulators - chemical synthesis
Tubulin Modulators - pharmacology
Tubulin polymerization
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Summary:[Display omitted] In this study, we synthesized a series of trans-indole-3-acrylamide derivatives (3a–k) and investigated their activity for inhibition of cell proliferation against five human cancer cell lines (HeLa, MCF7, MDA-MB-231, Raji and HL-60) by MTT assay. Compound 3e showed significant antiproliferative activity against both the Raji and HL-60 cell lines with IC50 values of 9.5 and 5.1μM, respectively. Compound 3e also exhibited moderate inhibitory activity on tubulin polymerization (IC50=17μM). Flow cytometric analysis of cultured cells treated with 3e also demonstrated that the compound caused cell cycle arrest at the G2/M phase in HL-60 and HeLa cells. Moreover, 3e, the most active compound, caused an apoptotic cell death through the activation of caspase-3. Docking simulations suggested that 3e binds to the colchicine site of tubulin.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2014.04.027