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