Design, Green Synthesis, and Anticancer Activity of Novel Nicotinonitrile Derivatives

Abstract

Novel pyridine derivatives were successfully synthesized by grinding, microwave-assisted, and conventional techniques. Ethyl 6-amino-5-cyano-2-methyl-4-[(1S,2R,3R,4R)-1,2,3,4,5-pentahydroxypentyl]nicotinate (1) was synthesized and used as a versatile reagent for the synthesis of novel compounds such as nicotinic acid, nicotinohydrazide, 3,5-dioxopyrazolidine, 1,2,4-triazole, cyanoacetamide, urea, 2,5-dioxopyrrolidine, 3-dioxoisoindoline, sulfonamide, Schiff base, and formamide derivatives by its reactions with a series of nucleophilic and electrophilic reagents. The results of the synthesis with the use of the grinding, microwave, and conventional techniques were compared. The structures and compositions of the newly synthesized compounds were confirmed by IR and ¹H and ¹³C NMR spectroscopy, mass spectrometry, and elemental analysis. Some of the synthesized compounds were screened in vitro for the activity against two cancer cell lines. Ethyl 5-cyano-2-methyl-4-[(1S,2R,3R,4R)-1,2,3,4,5-pentahydroxypentyl]-6-(3-phenylureido)nicotinate showed a high cytotoxic activity and selectivity against cancer cells (HePG2: IC₅₀ = 34.31 μM; Caco-2: IC₅₀ = 24.79 μM). Imaging cancer cell lines treated by some synthesized compounds was performed by transmission electron microscopy.