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 <b>9e</b> exhibited significant toxicity against MCF-7/ADR cells compared to MCF-7 cells, with a 1401-fold increase, indicating its high collateral sensitivity. Meanwhile, <b>9e</b> exhibited relatively lower toxicity to normal cell lines and improved solubility compared to the previous active compound, <b>4A93</b>, which features a coumarin integrity core. Preliminary pharmacological studies revealed that <b>9e</b> 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 <b>9e</b> could induce autophagy in MCF-7/ADR cells. Additionally, the anti-tumor activity of compound <b>9e</b> 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 <b>9e</b> was used to explore the potential development of an anti-tumor candidate with special pharmacological mechanisms to overcome multidrug resistance in breast cancer.