Semisynthetic Cyclopamine Analogues as Potent and Orally Bioavailable Hedgehog Pathway Antagonists

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• 作者：Martin R. Tremblay ; Marta Nevalainen ; Somarajan J. Nair ; James R. Porter ; Alfredo C. Castro ; Mark L. Behnke ; Lin-Chen Yu ; Margit Hagel ; Kerry White ; Kerrie Faia ; Louis Grenier ; Matthew J. Campbell ; Ji
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：November 13, 2008
• 年：2008
• 卷：51
• 期：21
• 页码：6646-6649
• 全文大小：113K
• 年卷期：v.51,no.21(November 13, 2008)
• ISSN：1520-4804

文摘

Herein is reported the synthesis of a novel class of hedgehog antagonists derived from cyclopamine. The acid sensitive D-ring of cyclopamine was homologated utilizing a sequence of chemoselective cyclopropanation and stereoselective acid-catalyzed rearrangement. Further modification of the A/B-ring homoallylic alcohol to the conjugated ketone led to the discovery of new cyclopamine analogues with improved pharmaceutical properties and in vitro potency (EC₅₀) ranging from 10 to 1000 nM.