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.
Winkler
Jeffrey D
JD
Department of Chemistry, The University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. winkler@sas.upenn.edu
Isaacs
André
A
Holderbaum
Laura
L
Tatard
Valérie
V
Dahmane
Nadia
N
D015195:Drug Design; D004970:Estrone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014704:Veratrum Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D053823:Hedgehog Proteins; D014704:Veratrum Alkaloids; D004970:Estrone; C000541:cyclopamine