Synthesis and Evaluation of Pyridinium-Hydrazone Derivatives as Potential Antitumoral Agents

Abstract

The hydrazones of 4-hydrazinylpyridinium bearing alkylphenyl groups on pyridinium nitrogen were synthesized and evaluated for their cytotoxic activity against MCF-7, PC3, U2OS and HEK293 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 (IC₅₀= 3.27-8.54 μM) on cancer cells. 3d (4-(2-(4-hydroxybenzylidene)hydrazinyl)-1-(4-phenylbutyl)pyridinium bromide) was the most cytotoxic compound with IC₅₀ value of 3.27 μM 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 LC3-I to its lipidated form LC3-II is essential for autophagy and related to autophagosomes. According to our results, all tested compounds except for 3d, induced lipidated form LC3-II accumulation. Then, the effects of the compounds on p62 protein level were also analyzed by the immunoblotting since 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.

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A series of pyridinium-hydrazones was evaluated for their cytotoxic activity. Among the tested compounds, derivatives with the highest cytotoxicity (1d, 2d, 3d, 4 and 5 series) were found to have potent antitumoral activity and all except for 3d have potential to inhibit autophagic flux.

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