C–H-Functionalization logic guides the synthesis of a carbacyclopamine analog

• Sebastian Rabe,
• Johann Moschner,
• Marina Bantzi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2014, 10, 1564–1569, doi:10.3762/bjoc.10.161

• analogs. Keywords: cyclopamine; C–H-functionalization; hedgehog signaling pathway; natural products; steroidal alkaloids; Introduction The isolation of cyclopamine (1, Figure 1) nearly 50 years ago followed by the determination of its biological target and pharmacological profile has drawn considerable

• the adapter protein β-TrCP [20]. The Gli family of transcription factors acts as an effector of the hedgehog signaling pathway and thus, is associated with a wide array of physiological effects, including cell fate determination, proliferation and patterning. The so-formed Gli/β-TrCP complex becomes

Cyclopamine analogs bearing exocyclic methylenes are highly potent and acid-stable inhibitors of hedgehog signaling

• Johann Moschner,
• Anna Chentsova,
• Nicole Eilert,
• Irene Rovardi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2013, 9, 2328–2335, doi:10.3762/bjoc.9.267

• cells. An extension of this study to F-ring-modified structures shows the necessity of a rigidly positioned nitrogen atom for bioactivity as well as the presence of the C21 methyl group for acid stability and bioactivity. Keywords: cyclopamine; hedgehog signaling pathway; natural products; steroidal

• hedgehog signaling pathway to be identified. As a highly selective inhibitor of the transmembrane protein Smoothened (Smo), an integral component of hedgehog signaling, it presents an attractive target for medicinal and pharmaceutical research [29][30]. Unfortunately, its direct development into a drug is