Identification\nof a Privileged Scaffold for Inhibition\nof Sterol Transport Proteins through the Synthesis and Ring Distortion\nof Diverse, Pseudo-Natural Products

Sterol transport proteins mediate intracellular sterol\ntransport,\norganelle contact sites, and lipid metabolism. Despite their importance,\nthe similarities in their sterol-binding domains have made the identification\nof selective modulators difficult. Herein we report a combination\nof different compound library synthesis strategies to prepare a cholic\nacid-inspired compound collection for the identification of potent\nand selective inhibitors of sterol transport proteins. The fusion\nof a primary sterol scaffold with a range of different fragments found\nin natural products followed by various ring distortions allowed the\nsynthesis of diverse sterol-inspired compounds. This led to the identification\nof a complex and three-dimensional spirooxepinoindole as a privileged\nscaffold for sterol transport proteins. With careful optimization\nof the scaffold, the selectivity could be directed toward a single transporter, as showcased by\nthe development of a potent and selective Aster-A inhibitor. We suggest\nthat the combination of different design strategies is generally applicable\nfor the identification of potent and selective bioactive compounds\nwith drug-like properties.