Discovery of hybrids of bisbibenzyl with furoxan as lysosomotropic agents for the treatment of drug-resistant non-small-cell lung cancer.

Twenty-one novel macrocyclic bisbibenzyl-furoxan hybrids were designed and synthesized as lysosomotropic agents, with subsequent evaluation of their anticancer potential against multidrug-resistant (A549/Taxol, MCF-7/ADR) and parental (A549, MDA-MB-231, MCF-7) cancer cell lines. Compound 15a emerged as the most promising candidate, demonstrating potent antiproliferative activity against paclitaxel-resistant A549/Taxol cells (IC = 0.87 μM) with good selectivity over normal cells. Structure-activity relationship studies established a positive correlation between pKa values of the hybrids and their cytotoxic potency against A549/Taxol cells. Mechanistic investigations revealed that the basic nature of 15a facilitated its selective accumulation in acidic lysosomes of drug-resistant cells, where it triggered substantial nitric oxide (NO) release and reactive oxygen species (ROS) generation. This further induced lysosomal membrane permeabilization and subsequent cell apoptosis. Notably, 15a displayed superior in vivo antitumor efficacy in A549/Taxol xenograft models compared to paclitaxel, without observable systemic toxicity. This work establishes that strategic hybridization of basic bisbibenzyl scaffolds with nitric oxide-donating furoxan moieties represents an effective lysosome-targeting approach to overcome multidrug resistance in cancer therapy.