Design and synthesis of inhibitors of hedgehog signaling based on the alkaloid cyclopamine

Organic Letters

Volumn 11, Issue 13, 2009, Pages 2824-2827

  Winkler, Jeffrey D ^a   Isaacs, André ^a   Holderbaum, Laura ^b   Tatard, Valérie ^b   Dahmane, Nadia ^b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b WISTAR INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLOPAMINE; DRUG DERIVATIVE; ESTRONE; SONIC HEDGEHOG PROTEIN; VERATRUM ALKALOID;

ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; DRUG DESIGN; DRUG EFFECT; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

DRUG DESIGN; ESTRONE; HEDGEHOG PROTEINS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; SIGNAL TRANSDUCTION; STRUCTURE-ACTIVITY RELATIONSHIP; VERATRUM ALKALOIDS;

EID: 67649476250     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol900974u     Document Type: Article

References (22)

1. Binns, W.; James, L. F.; Keeler, R. F.; Balls, L. D. Effects of teratogenic agents in range plants. Cancer Res. 1968, 28, 2323-2326.
2. Keeler, R. F.; Binns, W. Teratogenic compounds of Veratrum californicum (Durand). II. Production of ovine fetal cyclopia by fractions and alkaloid preparations. Can. J. Biochem. 1966, 44, 829-838.
3. Cooper, M. K.; Porter, J. A.; Young, K. E.; Beachy, P. A. Teratogenmediated inhibition of target tissue response to Shh signaling. Science 1998, 280, 1603-1607.
4. Incardona, J. P.; Gaffield, W.; Kapur, R. P.; Roelink, H. The teratogenic Veratrum, alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 1998, 125, 3553-3562.
5. Hooper, J. E.; Scott, M. P. Communicating with Hedgehogs. Nat. Rev. Mol. Cell Biol, 2005, 6, 306-317.
6. Ingham, P. W.; McMahon, A. P. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001, 15, 3059-3087.
7. Chen, J. K.; Taipale, J.; Cooper, M. K.; Beachy, P. A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 2002, 16, 2743-2748.
8. Janardanannair, S.; Adams, J.; Ripka, A. S.; Hospital, M. R.; Tremblay, M. Methods for preparation cyclopamine analogs and use thereof in treating cancers. 2005-US30406; 2006026430, 20050826, 2006.
9. Tremblay, M. R.; Nevalainen, M.; Nair, S. J.; Porter, J. R.; Castro, A. C.; Behnke, M. L.; Yu, L.-C.; Hagel, M.; White, K.; Faia, K.; Grenier, L.; Campbell, M. J.; Cushing, J.; Woodward, C. N.; Hoyt, J.; Foley, M. A.; Read, M. A.; Sydor, J. R.; Tong, J. K.; Palombella, V. J.; McGovern, K.; Adams, J. Semisynthetic Cyclopamine Analogues as Potent and Orally Bioavailable Hedgehog Pathway Antagonists. J. Med. Chem. 2008, 51, 6646-6649.
10. Berman, D. M.; Karhadkar, S. S.; Hallahan, A. R.; Pritchard, J. I.; Eberhart, C. G.; Watkins, D. N.; Chen, J. K.; Cooper, M. K.; Taipale, J.; Olson, J. M.; Beachy, P. A. Medulloblastoma growth, inhibition by hedgehog pathway blockade. Science 2002, 297, 1559-1561.
11. Dahmane, N.; Sanchez, P.; Gitton, Y.; Palma, V.; Sun, T.; Beyna, M.; Weiner, H.; Ruiz i Altaba, A. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development 2001, 128, 5201-5212.
12. Sanchez, P.; Ruiz i Altaba, A. In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. Mech. Dev. 2005, 122, 223-230.
13. Stecca, B.; Mas, C.; Clement, V.; Zbinden, M.; Correa, R.; Piguet, V.; Beermann, F.; Ruiz, I. A. A. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 5895-5900.
14. Keeler, R. F. Teratogenic compounds in Veratrum, californicum. IX. Structure-activity relation. Teratology 1970, 3, 169-173.
15. Nagata, R.; Izumi, K. Veratramine-induced behavior associated with serotonergic hyperfunction in mice. Jpn. J. Pharmacol. 1991, 55, 129-137.
16. Thron, C. D.; McCann, F. V. Pharmacological tests of the mechanism of the periodic rhythm caused by veratramine in the sinoatrial node of the guinea pig. Gen. Pharmacol. 1998, 32, 81-89.
17. Williams, J. A.; Guicherit, O. M.; Zaharian, B. I.; Xu, Y.; Chai, L.; Wichterle, H.; Kon, C.; Gatchalian, C.; Porter, J. A.; Rubin, L. L.; Wang, F. Y. Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 4616-4621.
18. Hosoya, T.; Arai, M. A.; Koyano, T.; Kowithayakorn, T.; Ishibashi, M.. Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription. ChemBioChem 2008, 9, 1082-1092.
19. Keeler, R. F. Cyclopamine and related steroidal alkaloid teratogens: their occurrence, structural relationship, and biologic effects, Lipids 1978, 13, 708-715.
20. Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. The Selective Reaction of Aryl Halides with KOH: Synthesis of Phenols, Aromatic Ethers, and Benzofurans. J. Am. Chem. Soc. 2006, 128, 10694-10695.
21. Hartwig, J. F. Discovery and understanding of transition-metalcatalyzed aromatic substitution reactions. Synlett 2006, 1283-1294.
22. Taipale, J.; Chen, J. K.; Cooper, M. K.; Wang, B.; Mann, R. K.; Milenkovic, L.; Scott, M. P.; Beachy, P. A. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 2000, 406, 1005-1009.