Hedgehog antagonist cyclopamine isomerizes to less potent forms when acidified

Journal of Pharmaceutical and Biomedical Analysis

Volumn 52, Issue 5, 2010, Pages 707-713

  Wilson, Steven Ray ^a   Strand, Martin Frank ^b   Krapp, Andreas ^a   Rise, Frode ^a   Petersen, Dirk ^a   Krauss, Stefan ^b  

^a UNIVERSITY OF OSLO   (Norway)

^b OSLO UNIVERSITY HOSPITAL   (Norway)

Author keywords

Cyclopamine; Hedgehog; Isomerization; LC MS; NMR

Indexed keywords

CYCLOPAMINE; SONIC HEDGEHOG PROTEIN;

ACIDIFICATION; ANIMAL EXPERIMENT; ARTICLE; DRUG ACTIVITY; DRUG BLOOD LEVEL; DRUG STRUCTURE; ISOMERIZATION; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; MUCOCILIARY TRANSPORT; NONHUMAN; PRIORITY JOURNAL; RAT; STOMACH ACID; STOMACH PH; STRUCTURE ACTIVITY RELATION;

ANIMALS; CHROMATOGRAPHY, LIQUID; FLUORESCENT ANTIBODY TECHNIQUE; HEDGEHOG PROTEINS; ISOMERISM; MAGNETIC RESONANCE SPECTROSCOPY; MALE; MICE; MICE, INBRED C57BL; MICE, INBRED CBA; QUANTUM THEORY; SPECTROMETRY, MASS, ELECTROSPRAY IONIZATION; VERATRUM ALKALOIDS;

EID: 77950858208     PISSN: 07317085     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jpba.2010.02.017     Document Type: Article

References (27)

1. 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. Physiol. 1966, 44:829-838.
2. Cooper M.K., Porter J.A., Young K.E., Beachy P.A. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science (Washington, DC) 1998, 280:1603-1607.
3. Incardona J.P., Gaffield W., Kapur R.P., Roelink H. The teratogenic Veratrum alkaloid cyclopamine inhibits Sonic hedgehog signal transduction. Development (Cambridge, U.K.) 1998, 125:3553-3562.
4. Wang Y., Zhou Z., Walsh C.T., McMahon A.P. Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc. Natl. Acad. Sci. U.S.A. 2009, 106:2623-2628.
5. Wilson C.W., Chen M.H., Chuang P.T. Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium. PLoS One 2009, 4:e5182.
6. Chen J.K., Taipale J., Cooper M.K., Beachy P.A. Inhibition of Hedgehog signalling by direct binding of cyclopamine to Smoothened. Genes Dev. (Cambridge, U.K.) 2002, 16:2743-2748.
7. Scales S.J., de Sauvage F.J. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol. Sci. 2008, 30:303-312.
8. Tremblay M.R., Nevalainen M., Nair S.J., Porter J.R., Castro A.C., Behnke M.L., Yu L., 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.
9. Tremblay M.R., Lescarbeau A., Grogan M.J., Tan E., Lin G., Austad B.C., Yu L.C., Behnke M.L., Nair S.J., Hagel M., White K., Conley J., Manna J.D., Alvarez-Diez T.M., Hoyt J., Woodward C.N., Sydor J.R., Pink M., MacDougall J., Campbell M.J., Jill Cushing, Ferguson J., Curtis M.S., McGovern K., Read M.A., Palombella V.J., Adams J., Castro A.C. Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). J. Med. Chem. 2009, 52:4400-4418.
10. El-Zaatari M., Grabowska A.M., McKenzie A.J., Powe D.G., Scotting P.J., Watson A. Cyclopamine inhibition of the sonic hedgehog pathway in the stomach requires concomitant acid inhibition. Regul. Pept. 2008, 146:131-139.
11. Keeler R.F. Teratogenic compounds of Veratrum californicum (Durand)-VI. The structure of cyclopamine. Phytochemistry 1969, 8:223-255.
12. Badria F.A., McChesney J.D., Halim A.F., Zaghloul A.M., El Sayed K.A. Time course and inhibition of stavaroside K, veratramine and cevine-induced hemolysis by other pregnane glycosides and Veratrum alkaloids. Pharmazie 1995, 50:421-423.
13. Lipinski R.J., Hutson P.R., Hannam P.W., Nydza R.J., Washington I.M., Moore R.W., Girdaukas G.G., Richard E., Peterson R.E., Bushman W. Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the hedgehog signaling antagonist cyclopamine in the mouse. Tox. Sci. 2008, 104:189-197.
14. Becke A.D. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A: Gen. Phys. 1988, 38:3098-3100.
15. Perdew J.P. Density-functional approximation for the correlation energy of the inhomogeneous electron gas. Phys. Rev. B 1986, 33:8822-8824.
16. Eichkorn K., Treutler O., Oehm H., Haeser M., Ahlrichs R. Auxiliary basis sets to approximate Coulomb potentials. Chem. Phys. Lett. 1995, 242:652-660. (Erratum to document cited in CA123:93649).
17. Eichkorn K., Treutler O., Oehm H., Haeser M., Ahlrichs R. Auxiliary basis sets to approximate Coulomb potentials. Chem. Phys. Lett. 1995, 240:283-290.
18. Weigend F., Ahlrichs R. Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: design and assessment of accuracy. Phys. Chem. Chem. Phys. 2005, 7:3297-3305.
19. Weigend F. Accurate Coulomb-fitting basis sets for H to Rn. Phys. Chem. Chem. Phys. 2006, 8:1057-1065.
20. Deglmann P., Furche F., Ahlrichs R. An efficient implementation of second analytical derivatives for density functional methods. Chem. Phys. Lett. 2002, 362:511-518.
21. Kollwitz M., Gauss J. A direct implementation of the GIAO-MBPT (2) method for calculating NMR chemical shifts. Application to the naphthalenium and anthracenium ions. Chem. Phys. Lett. 1996, 260:639-646.
22. Taipale J., Chen J.K., Cooper M.K., Wang B., Mann R.K., Milenkovic L., Scotts M.P., Beachy P.A. Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine. Nature (London) 2000, 406:1005-1009.
23. Corbit K.C., Aanstad P., Singla V., Norman A.R., Stainier D.Y., Reiter J.F. Vertebrate Smoothened functions at the primary cilium. Nature 2005, 437:1018-1021.
24. Masamune T., Mori Y., Takasugi M., Murai A., Ohuchi S., Sato N., Katsui N. C-N or-D-homosteroids and related alkaloids. IV. 11-Deoxojervine, a new alkaloid from Veratrum species. Bull. Chem. Soc. Jpn. 1965, 38:1374-1378.
25. Feldmann G., Dhara S., Fendrich V., Bedja D., Beaty R., Mullendore M., Karikari C., Alvarez H., Iacobuzio-Donahue C., Jimeno A., Gabrielson K.L., Matsui W., Maitra A. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 2007, 67:2187-2196.
26. Athar M., Li C., Tang X., Chi S., Zhang X., Kim A.L., Tyring S.K., Kopelovich L., Hebert J., Epstein E.H., Bickers D.R., Xie J. Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Cancer Res. 2004, 64:7545-7552.
27. Raffa R.B., Stagliano G.W., Spencer S.D. Protonation effect on drug affinity. Eur. J. Pharmacol. 2004, 483:323-324.