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

• States 10.3762/bjoc.10.161 Abstract The chemical synthesis of carbacyclopamine analog 2, a cyclopamine analog with an all-carbon E-ring, is reported. The use of C–H-functionalization logic and further metal-catalyzed transformations allows for a concise entry to this new class of acid-stable cyclopamine

• 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

• interest from research groups in biology, chemistry and medicine [1][2][3][4]. As the first identified hedgehog signaling inhibitor, cyclopamine exerts its anticancer activity through a novel mechanism of action, which manifests itself in its remarkable activity against several types of human cancer

Physalin H from Solanum nigrum as an Hh signaling inhibitor blocks GLI1–DNA-complex formation

• Midori A. Arai,
• Kyoko Uchida,
• Samir K. Sadhu,
• Firoj Ahmed and
• Masami Ishibashi

Beilstein J. Org. Chem. 2014, 10, 134–140, doi:10.3762/bjoc.10.10

• of tumors such as basal-cell carcinomas and small-cell lung cancer [5][6][7]. To find a drug for the treatment of cancer, Hh inhibitors have been recently developed. SMO inhibitors are a major category of Hh signaling inhibitors (cyclopamine [8][9], Cur-61414 [10] and SANTs [11]). Robotnikinin

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

• 77030, USA 10.3762/bjoc.9.267 Abstract The chemical synthesis and biological evaluation of new cyclopamine analogs bearing exocyclic methylenes in different positions is described. Bis-exo-cyclopamine 6 was identified as a potent inhibitor of the Gli1-dependent luciferase expression in Shh-LIGHTII

• 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

• ], lymphoma [17][18][19], multiple myeloma [17][20], and chronic myeloic leukemia [21][22][23]. More recently, other diseases like diabetes [24][25], neurodegenerative disorders [26], and trisomy [27][28], have been linked with hedgehog signaling. Cyclopamine (1, see Figure 1) was the first inhibitor of the

Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors

• Chao Che,
• Song Li,
• Bo Yang,
• Shengchang Xin,
• Zhixiong Yu,
• Taofeng Shao,
• Chuanye Tao,
• Shuo Lin and
• Zhen Yang

Beilstein J. Org. Chem. 2012, 8, 841–849, doi:10.3762/bjoc.8.94

• human diseases, intense efforts have been invested to identify therapeutic inhibitors acting on the Smo protein. Cyclopamine (Figure 1), a natural alkaloid isolated from Veratrum californicum [12][13], was disclosed as the first small molecule inhibitor of the Hh pathway through direct interaction with

• Smo [14][15]. Cyclopamine can effectively induce a decrease in proliferation and an increase of apoptosis in several murine models [16][17]. However, the clinical development of cyclopamine as a therapeutic in cancer is hampered by its poor aqueous solubility (ca. 5 µg/mL) and acid lability

• . Subsequently, Infinity Pharmaceuticals developed cyclopamine-based Smo inhibitors IPI-926 through structural modification on the A and D rings. IPI-926 exhibited improved pharmaceutical properties as well as a favorable pharmacokinetic profile, and showed complete tumor regression in a Hh-dependent