Design, Synthesis, and Biological Evaluation of Marchantin C-NO Donor Hybrids for Overcoming Pgp-Mediated Drug Resistance by Targeting Lysosome

A series of marchantin C-NO donor hybrids were designed, synthesized, and evaluated for their antitumor activity in vitro and in vivo. Notably, MC-furoxan hybrid 14 exhibited the best selective inhibitory activity against MCF-7/ADR (IC₅₀ = 0.024 μM) with 883 times potency compared with MCF-7 cells (IC₅₀ = 21.20 μM), and the cytotoxicity toward A549/Taxol (IC₅₀ = 1.43 μM) increased 17-fold compared with that in A549 cells (IC₅₀ = 23.75 μM). Preliminary pharmacological studies revealed that 14 could "hijack" the lysosomal Pgp and release NO to produce Reactive Oxygen Species (ROS) in lysosomes, resulting in lysosomal membrane permeabilization (LMP) and potentiated cytotoxicity. Additionally, compound 14 achieved stronger antitumor activity and superior biosafety at relatively low doses than paclitaxel in the A549/Taxol xenograft model. In summary, this study provides a promising strategy for the design of such MC-furoxan hybrids like 14 to overcome MDR via the utilization of lysosomal Pgp transport activity.