Vitamin D3 analogues that contain modified A- and seco-B-rings as hedgehog pathway inhibitors

The hedgehog (Hh) signaling pathway is a developmental signaling pathway that has been implicated as a target for anti-cancer drug development in a variety of human malignancies. Several natural and synthetic vitamin D-based seco-steroids have been identified as potent inhibitors of Hh signaling with chemotherapeutic potential. These include the previously characterized analogue 4, which contains the northern CD-ring/side chain region of vitamin D3 (VD3) linked to an aromatic A-ring mimic through an ester bond. To further explore structure-activity relationships for this class of VD3-based Hh pathway inhibitors, we have designed, synthesized and evaluated several series of compounds that modify the length, composition, and stereochemical orientation of the ester linker. These studies have identified compounds 54 and 55, which contain an amine linker and an aromatic A-ring incorporating a para-phenol, as new lead compounds with enhanced potency against the Hh pathway (IC50 values = 0.40 and 0.32 μM, respectively).