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 ED 50 values in the low micromolar range (ED 50 < 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.
Álvaro et al. (Thu,) studied this question.