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

• Published in: European journal of medicinal chemistry Vol. 127; pp. 100 - 114
• Main Authors: Sri Ramya, P.V., Angapelly, Srinivas, Guntuku, Lalita, Singh Digwal, Chander, Nagendra Babu, Bathini, Naidu, V.G.M., Kamal, Ahmed
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.02.2017; Elsevier
• Subjects: Apoptosis; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Claisen-Schmidt condensation; Curcumin - chemistry; Curcumin mimics; Cytotoxic; Drug Design; Humans; Indole; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Life Sciences & Biomedicine; Membrane Potential, Mitochondrial - drug effects; Models, Molecular; Pharmacology & Pharmacy; Protein Multimerization - drug effects; Protein Structure, Quaternary; Science & Technology; Structure-Activity Relationship; Tubulin - chemistry; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Claisen-Schmidt condensation; Cytotoxic; Curcumin mimics; Indole; Cell cycle; Apoptosis; DESIGN; POTENT; AGENTS; DERIVATIVES; HYBRIDS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.12.043

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. [Display omitted] •Novel curcumin inspired indole analogues were synthesized.•Anticancer activity was tested on selected eight human cancer cell lines and one normal cell line.•The target compounds 11c and 11f effectively inhibited polymerization of tubulin in a cell-free assay.•11c and 11f induced apoptosis and collapse of DΨm in PC3 cells.•11c arrested PC3 cells in G2/M phase of cell cycle.