Structure-based design of a novel synthetic spiroketal pyran as a pharmacophore for the marine natural product spongistatin 1

Abstract SPIKET-P, a novel synthetic spiroketal pyran, was rationally designed as a pharmocophore for the tubulin depolymerizing marine natural product Spongistatin 1. SPIKET-P was prepared from the commercially available benzyl ( R )-(−)-glycidyl ether using a versatile 11-step synthetic scheme in a stereocontrolled fashion. At nanomolar concentrations, SPIKET-P caused tubulin depolymerization in cell-free turbidity assays and exhibited potent cytotoxic activity against cancer cells as evidenced by destruction of microtubule organization, and prevention of mitotic spindle formation in human breast cancer cells.