期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 127, 期 -, 页码 100-114出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.12.043
关键词
Curcumin mimics; Indole; Cytotoxic; Apoptosis; Cell cycle; Claisen-Schmidt condensation
资金
- DoP, Ministry of Chemicals & Fertilizers, Govt. of India, New Delhi
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 3.12-634 mu M and 4.69-8.72 mu M 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 mu M 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 (D Psi m) in PC-3 cells. (C) 2017 Elsevier Masson SAS. All rights reserved.
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