Synthesis and Biological Evaluation of Seco-Coumarin/Furoxan Hybrids as Potent Anti-Tumor Agents to Overcome Multidrug Resistance via Multiple Mechanisms.

In this study, twenty-four new furoxan and seco-coumarin hybrids were synthesized, and their antiproliferative activities against four breast cancer cells (MCF-7/ADR, MCF-7, MDA-MB-231, and MDA-MB-468) were evaluated. Among them, compound 9e exhibited significant toxicity against MCF-7/ADR cells compared to MCF-7 cells, with a 1401-fold increase, indicating its high collateral sensitivity. Meanwhile, 9e exhibited relatively lower toxicity to normal cell lines and improved solubility compared to the previous active compound, 4A93, which features a coumarin integrity core. Preliminary pharmacological studies revealed that 9e might be a potential P-glycoprotein substrate, which enters the lysosomes of MCF-7/ADR to release effective concentrations of nitric oxide, producing reactive oxygen species and inducing apoptosis. Moreover, laser confocal microscopy and Western Blot experiments showed that 9e could induce autophagy in MCF-7/ADR cells. Additionally, the anti-tumor activity of compound 9e could be inhibited by the ferroptosis inhibitor Fer-1. These results suggest that the remarkable antiproliferative potency of these hybrids in MCF-7/ADR may be related to multiple anticancer mechanisms. As a novel nitric oxide donor, compound 9e was used to explore the potential development of an anti-tumor candidate with special pharmacological mechanisms to overcome multidrug resistance in breast cancer.