RESUMEN
Cruentarenâ A is a natural product that exhibits potent antiproliferative activity against various cancer cell lines, yet its binding site within ATP synthase remained unknown, thus limiting the development of improved analogues as anticancer agents. Herein, we report the cryogenic electron microscopy (cryoEM) structure of cruentarenâ A bound to ATP synthase, which allowed the design of new inhibitors through semisynthetic modification. Examples of cruentarenâ A derivatives include a trans-alkene isomer, which was found to exhibit similar activity to cruentarenâ A against three cancer cell lines as well as several other analogues that retained potent inhibitory activity. Together, these studies provide a foundation for the generation of cruentarenâ A derivatives as potential therapeutics for the treatment of cancer.