Structural simplification of quaternary benzophenanthridine alkaloids generating a candidate for the treatment of non-small cell lung cancer.

Quaternary benzophenanthridine alkaloids (QBAs), such as sanguinarine, chelerythrine, and nitidine, possess diverse pharmacological activities. This study presents a simplified structure for QBAs, yielding twelve three-membered phenanthridine alkaloids. Notably, compound 6f demonstrates enhanced potency in selectively inhibiting thioredoxin reductase (TrxR, TXNRD) and exhibits significant cytotoxicity against non-small cell lung cancer (NSCLC) cells. While TrxR is a selenoenzyme, many of its inhibitors react with biological thiols; however, 6f shows minimal reactivity with thiols such as glutathione (GSH) and cysteine. Mechanistic investigations reveal that 6f stimulates reactive oxygen species production, reduces intracellular thiols, and decreases the GSH/GSSG ratio, leading to cell apoptosis through oxidative stress. Moreover, significant tumor regression has been observed in nude mice with NSCLC following treatment with 6f. The pronounced anticancer activity and possible mechanism of action of 6f suggest its potential as a candidate for further development in NSCLC therapy.