Synthesis of Benzopyrans and Quinolines with Nitrogenated Chain and Their Cytotoxicity Against Human Cancer Cell...

Cancer caused 9.9 million deaths in 2020, and natural products and/or their structural analogs represent the greatest number of approved small-molecules antitumor agents. Benzopyran and quinoline heterocycles have demonstrated cytotoxic activity against different cancer cell lines. Due to its high therapeutic potential, we report the synthesis of 2-propanamide- and 2-propanamine-dihydrobenzopyrans bearing different amine moieties in the side chain, as well as the 7-carbon prenylated derivatives (analogous to natural polyalthidin). Next, we synthesized the 2-substituted and 2,3-disubstituted quinolines as benzopyran analogs. We evaluated the cytotoxic activity of all nitrogenated derivatives against human cancer cell lines, including A549 (lung cancer), A2058 (melanoma), HepG2 (hepatocellular carcinoma), MCF-7 (breast cancer), and Mia PaCa-2 (pancreas cancer) by the MTT assay. Structure-activity relationship analysis revealed: (i) the benzopyran core was twofold more cytotoxic than quinoline analogs and reached ED₅₀ values in the low micromolar range (ED₅₀ < 10 μM) against A2058, HepG2, and MCF-7; (ii) benzopyran amides showed higher cytotoxicity than benzopyran amines against MCF-7, and afforded better results for studied lines except for Mia PaCa-2; and (iii) the amine moiety introduced at 2-position played a key role for activity; (iv) benzyl and p-fluorobenzyl substituents protecting phenol group at 6-position afforded a similar cytotoxicity.