The First Total Synthesis of Solomonsterol B, a Marine Pregnane X Receptor Agonist

A concise route to the pregnane X receptor (PXR) agonist solomonsterol B, a natural product isolated from the marine sponge Theonella swinhoei, has been developed starting from commercially available hyodeoxycholic acid. The synthesis features a one-carbon side chain degradation and the refunctionalization of the A and B rings to install the desired trans junction and the two hydroxy groups at C2 and C3 in a trans relationship. The protocol proceeded with good yields (10 % over 13 steps), also allowing the preparation of a side chain-modified derivative useful for a preliminary structure-activity relationship on PXR. The pharmacological characterization of solomonsterol B demonstrated that this compound was a PXR agonist in a transactivation assay, and when it was incubated with liver cells, it increased the expression of PXR-regulated genes. These data support the development of sponge steroids as PXR ligands endowed with therapeutic potential.