Design, Synthesis,and Biological Evaluation of MarchantinC‑NO Donor Hybrids for Overcoming Pgp-Mediated Drug Resistanceby Targeting Lysosome

A series of marchantin C-NO donor hybrids were designed, synthesized, and evaluated for their antitumor activity <i>in vitro</i> and <i>in vivo</i>. Notably, MC-furoxan hybrid <b>14</b> 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 <b>14</b> 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 <b>14</b> 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 <b>14</b> to overcome MDR via the utilization of lysosomal Pgp transport activity.