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

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