Design and synthesis of inhibitors of Hedgehog signaling based on the alkaloid cyclopamine.

The synthesis and biological evaluation of structurally simplified, metabolically stable cyclopamine-like Sonic Hedgehog (SHH) signaling inhibitors, i.e., 5, is described in four chemical steps from commercially available steroidal precursors. Biological evaluation of this cyclopamine analogue in two different systems establishes the high potency of 5 as a SHH signaling inhibitor. This approach provides important new lead structures for the development of new cancer chemotherapeutic agents based on the inhibition on SHH signaling.