Synthesis and biological evaluation of novel pyrano[3,2-c]carbazole derivatives as anti-tumor agents inducing apoptosis via tubulin polymerization inhibition

• Published in: Organic & biomolecular chemistry Vol. 13; no. 5; p. 1404
• Main Authors: Padmaja, Pannala, Koteswara Rao, Garikapati, Indrasena, Adisherla, Subba Reddy, Basireddy V, Patel, Nibedita, Shaik, Anver Basha, Reddy, Narayana, Dubey, Pramod K, Bhadra, Manika Pal
• Format: Journal Article
• Language: English
• Published: England 07-02-2015
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Carbazoles - chemical synthesis; Carbazoles - chemistry; Carbazoles - metabolism; Carbazoles - pharmacology; Caspase 3 - metabolism; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; Enzyme Activation - drug effects; Humans; Molecular Docking Simulation; Protein Multimerization - drug effects; Protein Structure, Quaternary; Tubulin - chemistry; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - metabolism; Tubulin Modulators - pharmacology
• ISSN: 1477-0539
• DOI: 10.1039/c4ob02015d

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.