Add time:08/12/2019 Source:sciencedirect.com
A combinatorial chemical library of fifty-nine novel 3-amino-1′-((1-aryl-1H-1,2,3-triazol-5-yl)methyl)-2′-oxospiro[benzo[a]pyrano[2,3-c]phenazine-1,3′-indoline]-2-carbonitrile, designed as hybrid molecules of phenazine, pyran, indole and 1,2,3-triazole pharmacophores, were constructed in this study. Cytotoxic evaluation indicated that some compounds exhibited moderate cytotoxicity against HCT116, MCF7, HepG2 and A549 cancer cell lines in vitro, in which compound 36 was found to have best antiproliferative activity against the A549 cancer cell line with IC50 value of 5.4 μM. All compounds had low or no effect against L02 and HUVEC non-cancer cell lines. Compound 36 was further confirmed to mainly locate mitochondria in A549 cancer cells via laser-scanning confocal microscopy. Moreover, compound 36 was proved to increase ROS production and induce cell cycle arrest in S phase. Western blot analysis illustrated Bax/Bcl-2 ratio was increased at dose-dependent manner, and both cleaved caspase-3 and cleaved caspase-9 was enhanced by treated with compound 36. All the above evidences in vitro indicated that compound 36 might induce the apoptosis of A549 cancer cells via a mitochondria-dependent pathway.
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