Synthesis and biological evaluation of novel pyrano[3,2-c]carbazole derivatives as anti-tumor agents inducing apoptosis via tubulin polymerization inhibition.
Org Biomol Chem
; 13(5): 1404-14, 2015 Feb 07.
Article
em En
| MEDLINE
| ID: mdl-25467166
ABSTRACT
A series of novel pyrano[3,2-c]carbazole derivatives have been synthesized by a simple one-pot, three component reaction of aromatic aldehydes, malononitrile-ethyl cyanoacetate and 4-hydroxycarbazoles catalyzed by triethylamine. The antiproliferative activity of the derivatives on various cancer cell lines such as MDA-MB-231, K562, A549 and HeLa was investigated. Among 9a-p, congeners 9a, 9c, 9g and 9i showed profound antiproliferative activity with IC50 values ranging from 0.43 to 8.05 µM and induced apoptosis significantly by inhibiting tubulin polymerization. Cell-based biological assays demonstrated that treatment of cell lines with compounds 9a, 9c, 9g and 9i results in G2/M phase arrest of the cell cycle. Moreover the derivatives significantly disrupted the microtubule network, produced an elevation of cyclinB1 protein levels and induced apoptosis by increasing the caspase-3 levels. In particular, 9i strongly inhibited tubulin assembly compared to the positive control CA-4. Molecular docking studies demonstrated that all the lead compounds selectively occupy the colchicine binding site of the tubulin polymer.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tubulina (Proteína)
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Carbazóis
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Apoptose
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Multimerização Proteica
Limite:
Humans
Idioma:
En
Revista:
Org Biomol Chem
Ano de publicação:
2015
Tipo de documento:
Article