Novel Hybrids of 3-Substituted Coumarin and Phenylsulfonylfuroxan as Potent Antitumor Agents with Collateral Sensitivity against MCF-7/ADR

Twenty-three new coumarin-furoxan hybrids were synthesized, which exhibited nanomole antiproliferation activities in A2780, A2780/CDDP, MCF-7/ADR, and MDA-MB-231. Among them, compound 9 showed the strongest collateral sensitivity to MCF-7/ADR with 499-fold potency compared with MCF-7. Notably, the solubility of compound 9 increased 70-fold compared with the lead 2. And preliminary pharmacological studies displayed that compound 9 obviously increased Rh123 accumulation in MCF-7/ADR and released NO to produce ROS in lysosomes, which were able to damage lysosomal membrane and induce apoptosis. These results reasonably explained that the collateral sensitivity of compound 9 to MCF-7/ADR was closely related to P-gp-mediated lysosome damage and apoptosis. Additionally, compound 9 showed a very weak cytotoxicity both in MCF-10A and hERG potassium channels and had a desirable safety in ion cyclotron resonance (ICR) mice. Hence, compound 9 was merited to further study for developing a desirable candidate against MDR MCF-7/ADR via a potential mechanism of collateral sensitivity in MDR cancer cell lines.