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Synthesis and evaluation of pyridinium‐hydrazone derivatives as potential antitumoral agents
Author(s) -
Parlar Sülünay,
Erzurumlu Yalçın,
Ilhan Recep,
Ballar Kırmızıbayrak Petek,
Alptüzün Vildan,
Erciyas Ercin
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13177
Subject(s) - autophagy , pyridinium , chemistry , cytotoxic t cell , ic50 , bromide , cell culture , stereochemistry , cytotoxicity , biochemistry , in vitro , apoptosis , biology , medicinal chemistry , organic chemistry , genetics
The hydrazones of 4‐hydrazinylpyridinium bearing alkylphenyl groups on pyridinium nitrogen were synthesized and evaluated for their cytotoxic activity against MCF ‐7, PC 3, U2 OS , and HEK 293 cell lines by Wst1 cell proliferation assay. Cytotoxic activity results indicated that d derivatives having butylene chain; 4 and 5 series having naphthalene and anthracene ring systems showed high cytotoxic activity ( IC 50 = 3.27–8.54 μ m ) on cancer cells. 3d (4‐(2‐(4‐hydroxybenzylidene)hydrazinyl)‐1‐(4‐phenylbutyl)pyridinium bromide) was the most cytotoxic compound with IC 50 value of 3.27 μ m against MCF ‐7. The most active derivatives ( 1d , 2d , 3d , 4 , and 5 series) were selected to investigate for the effects on autophagy by analyzing the expression of autophagy marker proteins. The conversion of LC 3‐I to its lipidated form LC 3‐ II is essential for autophagy and related to autophagosomes. According to our results, all tested compounds except for 3d induced lipidated form LC 3‐ II accumulation. Then, the effects of the compounds on p62 protein level were also analyzed by the immunoblotting as the autophagy inhibition results in accumulation of p62. Further molecular mechanistic studies including morphological analysis and live–death assays indicated that all tested compounds ( 1d , 2d , 3d , 4 , and 5 series) are potent antitumoral molecules and all except for 3d have potential to inhibit autophagic flux.