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

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.

Indole and 2,4-Thiazolidinedione conjugates as potential anticancer modulators.

BACKGROUND: Thiazolidinediones (TZDs), also called glitazones, are five-membered carbon ring molecules commonly used for the management of insulin resistance and type 2 diabetes. Recently, many prospective studies have also documented the impact of these compounds as anti-proliferative agents, though several negative side effects such as hepatotoxicity, water retention and cardiac issues have been reported. In this work, we synthesized twenty-six new TZD analogues where the thiazolidinone moiety is directly connected to an N-heterocyclic ring in order to lower their toxic effects. METHODS: By adopting a widely applicable synthetic method, twenty-six TZD derivatives were synthesized and tested for their antiproliferative activity in MTT and Wound healing assays with PC3 (prostate cancer) and MCF-7 (breast cancer) cells. RESULTS: Three compounds, out of twenty-six, significantly decreased cellular viability and migration, and these effects were even more pronounced when compared with rosiglitazone, a well-known member of the TZD class of antidiabetic agents. As revealed by Western blot analysis, part of this antiproliferative effect was supported by apoptosis studies evaluating BCL-xL and C-PARP protein expression. CONCLUSION: Our data highlight the promising potential of these TZD derivatives as anti-proliferative agents for the treatment of prostate and breast cancer.