Design, Synthesis and Evaluation of Novel N-Substituted-[Benzoylamino]-5-Ethyl-1,2,3,6-Tetrahydropyridines as Potential Anti-Cancer Agents

Madridge J Pharm Res. 2019;3(1):52-59. doi: 10.18689/mjpr-1000109. Epub 2019 Mar 4.


Background and objective: Inflammation is believed to incite carcinogenesis by causing cell and genome damage. Tetrahydropyridines have gained significant synthetic interest because they constitute biologically active features of pharmaceutical agents. Previous tetrahydropyridines developed by our research group were effective in inhibiting inflammation. Since there is a relationship between inflammation and cancer, the objective of this manuscript is to expand our prior study to determine the anti-cancer activity of novel tetrahydropyridine analogs.

Materials and methods: 3-Ethylpyridine reacted with O-mesitylenesulfonylhydroxylamine to furnish N-amino-3-ethylpyridinium mesitylenesulfonate. The reaction of N-amino-3-ethylpyridinium mesitylenesulfonate with substituted acid chlorides gives the stable crystalline pyridinium ylides. A sodium borohydride reduction of ylides furnishes the target compounds, N-substituted [benzoylamino]-5-ethyl-1,2,3,6-tetrahydropyridines. The evaluation of these analogs cytotoxicity against Ishikawa, MCF-7, and MDA-MB-231 cell lines were determined after 72 hours of drug exposure employing CellTiter-Glo assay. To explore the interaction between the tetrahydropyridine derivatives and estrogen receptor alpha, SYBYL-X 2.1 was used to determine the best bioactive conformations of the tetrahydropyridine derivatives for the active site of the receptor.

Results: Four novel N-substituted [benzoylamino]-5-ethyl-1,2,3,6-tetrahydropyridines were synthesized, purified, and characterized. The four tetrahydropyridine analogs exhibited some anti-cancer activity. Based on the molecular modeling studies, EH3 was expected to have the best antiproliferative activity due to having the highest docking score for ERα. However, EH2 had the best antiproliferative activity. Nevertheless, the biological screening and molecular modeling can provide insight to help with the design of more biologically active compounds as potential anti-cancer agents.

Keywords: Antiproliferative agents; Cancer; Estrogen receptor alpha; Nitrogen ylides; Tetrahydropyridines.