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

Oliver E. Hutt; Jun Inagaki; Bollu S. Reddy; Sajiv K. Nair; Emily A. Reiff; John T. Henri; Jack F. Greiner; David G. VanderVelde; Ting Lan Chiu; Elizabeth A. Amin; Richard H. Himes; Gunda I. Georg

doi:10.1016/j.bmcl.2009.04.077

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

Oliver E. Hutt, Jun Inagaki, Bollu S. Reddy, Sajiv K. Nair, Emily A. Reiff, John T. Henri, Jack F. Greiner, David G. VanderVelde, Ting Lan Chiu, Elizabeth A. Amin, Richard H. Himes, Gunda I. Georg

Medicinal Chemistry

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	3293-3296
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	12
DOIs	https://doi.org/10.1016/j.bmcl.2009.04.077
State	Published - Jun 15 2009

Bibliographical note

Funding Information:
This work was supported by the National Institute of Health grants CA79641 and CA105305. E.A.R. and J.F.G. were supported by NIH Training Grant GM 07775. E.A.R. was also supported by DAMD 17-001-0303.

Keywords

Epothilone
Microtubules
Photoaffinity labels

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Hutt, O. E., Inagaki, J., Reddy, B. S., Nair, S. K., Reiff, E. A., Henri, J. T., Greiner, J. F., VanderVelde, D. G., Chiu, T. L., Amin, E. A., Himes, R. H., & Georg, G. I. (2009). Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of β-tubulin. Bioorganic and Medicinal Chemistry Letters, 19(12), 3293-3296. https://doi.org/10.1016/j.bmcl.2009.04.077

Hutt, OE, Inagaki, J, Reddy, BS, Nair, SK, Reiff, EA, Henri, JT, Greiner, JF, VanderVelde, DG, Chiu, TL, Amin, EA, Himes, RH & Georg, GI 2009, 'Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of β-tubulin', Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 12, pp. 3293-3296. https://doi.org/10.1016/j.bmcl.2009.04.077

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abstract = "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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note = "Funding Information: This work was supported by the National Institute of Health grants CA79641 and CA105305. E.A.R. and J.F.G. were supported by NIH Training Grant GM 07775. E.A.R. was also supported by DAMD 17-001-0303.",

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AU - Himes, Richard H.

AU - Georg, Gunda I.

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

Abstract

Bibliographical note

Keywords

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