Total synthesis and evaluation of C25-benzyloxyepothilone C for tubulin assembly and cytotoxicity against MCF-7 breast cancer cells

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

doi:10.1016/j.bmcl.2008.07.024

Total synthesis and evaluation of C25-benzyloxyepothilone C for tubulin assembly and cytotoxicity against MCF-7 breast cancer cells

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

Medicinal Chemistry

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Abstract

The total synthesis of C25-benzyloxy epothilone C is described. A sequential Suzuki-Aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C8-C12 fragment. The C25-benzyloxy analog exhibited significantly reduced biological activity in microtubule assembly and cytotoxicity assays. Molecular modeling simulations indicated that excessive steric bulk in the C25 position may reduce activity by disrupting key hydrogen bonds that are crucial for epothilone binding to β-tubulin.

Original language	English (US)
Pages (from-to)	4904-4906
Number of pages	3
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	17
DOIs	https://doi.org/10.1016/j.bmcl.2008.07.024
State	Published - Sep 1 2008

Bibliographical note

Funding Information:
The authors gratefully acknowledge financial support from the National Institutes of Health: National Cancer Institute CA79641.

Keywords

C-25 epothilone analogue
Cytotoxicity
Epothilones
Total synthesis
Tubulin assembly

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Hutt, O. E., Reddy, B. S., Nair, S. K., Reiff, E. A., Henri, J. T., Greiner, J. F., Chiu, T. L., VanderVelde, D. G., Amin, E. A., Himes, R. H., & Georg, G. I. (2008). Total synthesis and evaluation of C25-benzyloxyepothilone C for tubulin assembly and cytotoxicity against MCF-7 breast cancer cells. Bioorganic and Medicinal Chemistry Letters, 18(17), 4904-4906. https://doi.org/10.1016/j.bmcl.2008.07.024

Hutt, OE, Reddy, BS, Nair, SK, Reiff, EA, Henri, JT, Greiner, JF, Chiu, TL, VanderVelde, DG, Amin, EA, Himes, RH & Georg, GI 2008, 'Total synthesis and evaluation of C25-benzyloxyepothilone C for tubulin assembly and cytotoxicity against MCF-7 breast cancer cells', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 17, pp. 4904-4906. https://doi.org/10.1016/j.bmcl.2008.07.024

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abstract = "The total synthesis of C25-benzyloxy epothilone C is described. A sequential Suzuki-Aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C8-C12 fragment. The C25-benzyloxy analog exhibited significantly reduced biological activity in microtubule assembly and cytotoxicity assays. Molecular modeling simulations indicated that excessive steric bulk in the C25 position may reduce activity by disrupting key hydrogen bonds that are crucial for epothilone binding to β-tubulin.",

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AU - Hutt, Oliver E.

AU - Reddy, Bollu S.

AU - Nair, Sajiv K.

AU - Reiff, Emily A.

AU - Henri, John T.

AU - Greiner, Jack F.

AU - Chiu, Ting Lan

AU - VanderVelde, David G.

AU - Amin, Elizabeth A.

AU - Himes, Richard H.

AU - Georg, Gunda I.

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KW - Cytotoxicity

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KW - Total synthesis

KW - Tubulin assembly

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Total synthesis and evaluation of C25-benzyloxyepothilone C for tubulin assembly and cytotoxicity against MCF-7 breast cancer cells

Abstract

Bibliographical note

Keywords

UN SDGs

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