Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of β-tubulin

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Issue Date
2009-06-15Author
Hutt, Oliver E.
Inagaki, Jun
Reddy, Bollu S.
Nair, Sajiv K.
Reiff, Emily A.
Henri, John T.
Greiner, Jack F.
VanderVelde, David G.
Chiu, Ting-Lan
Amin, Elizabeth A.
Himes, Richard H.
Georg, Gunda I.
Publisher
Elsevier
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
This article is made available under an Attribution-NonCommercial-NoDerivs 3.0 United States (CC BY-NC-ND 3.0 US) License.
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Show full item recordAbstract
The total synthesis of 22-(3-azidobenzoyloxy)methyl epothilone C is described as a potential photoaffinity probe to elucidate the β-tubulin binding site. A sequential Suzuki-aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C1–C6 fragment. The C22-functionalized analog exhibited good activity in microtubule assembly assays, but cytotoxicity was significantly reduced. Molecular modeling simulations indicated that excessive steric bulk in the C22 position is accommodated by the large hydrophobic pocket of the binding site. Photoaffinity labeling studies were inconclusive suggesting non-specific labeling.
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Citation
Hutt, O. E., Inagaki, J., Reddy, B. S., Nair, S. K., Reiff, E. A., Henri, J. T., … Georg, G. I. (2009). Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of β-tubulin. Bioorganic & Medicinal Chemistry Letters, 19(12), 3293–3296. http://doi.org/10.1016/j.bmcl.2009.04.077
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