Synthesis and biological evaluation of curcumin inspired indole analogues as tubulin polymerization inhibitors

Abstract

In our endeavour towards the development of potent cytotoxic agents, a series of some new curcumin inspired indole analogues, in which indole and phenyl moieties are linked on either sides of 1,5-diaryl-1,4-pentadien-3-one system have been synthesized and characterized by spectral data. All the newly synthesized analogues were tested for their cytotoxic potential against a panel of eight cancer cell lines namely, lung (A549), breast (MDA-MB-231, BT549 and 4T1), prostate (PC-3, DU145), gastric (HGC-27) and cervical (HeLa). Notably, among all the compounds tested, compounds 11c, 11d and 11f showed potent growth inhibition on PC-3 and BT549 with IC₅₀ values in the range of 3.12-6.34 μM and 4.69-8.72 μM respectively. The most active compound (11c) was also tested on RWPE-1 (normal prostate) cells and was found to be safe compared to the PC-3 cells. In tubulin polymerization assay, compounds 11c and 11f effectively inhibited microtubule assembly with IC₅₀ values of 10.21 ± 0.10 and 8.83 ± 0.06 μM respectively. The results from molecular modelling studies revealed that these compounds bind at the colchicine binding site of the tubulin. Moreover, DAPI and acridine orange/ethidium bromide staining studies indicated that compounds 11c and 11f can induce apoptosis in PC-3 cells. Further flow-cytometry analysis revealed that compound 11c arrests PC-3 cells in G2/M phase of the cell cycle while compound 11f treatment resulted in moderate increase in the G2/M population. Additionally, the treatment by these compounds led to the impairment of mitochondrial membrane potential (DΨm) in PC-3 cells.

Keywords: Apoptosis; Cell cycle; Claisen-Schmidt condensation; Curcumin mimics; Cytotoxic; Indole.