Single-site chemical modification at C10 of the baccatin III core of paclitaxel and Taxol C reduces P-glycoprotein interactions in bovine brain microvessel endothelial cells

Jared T. Spletstoser; Brandon J. Turunen; Kelly Desino; Antonie Rice; Apurba Datta; Dinah Dutta; Jacquelyn K. Huff; Richard H. Himes; Kenneth L. Audus; Anna Seelig; Gunda I. Georg

doi:10.1016/j.bmcl.2005.10.063

Single-site chemical modification at C10 of the baccatin III core of paclitaxel and Taxol C reduces P-glycoprotein interactions in bovine brain microvessel endothelial cells

Jared T. Spletstoser, Brandon J. Turunen, Kelly Desino, Antonie Rice, Apurba Datta, Dinah Dutta, Jacquelyn K. Huff, Richard H. Himes, Kenneth L. Audus, Anna Seelig, Gunda I. Georg

Medicinal Chemistry

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15 Scopus citations

Abstract

A single-site modification of paclitaxel analogs at the C10 position on the baccatin III core that reduces interaction with P-glycoprotein in bovine brain microvessel endothelial cells is described. Modification and derivatization of the C10 position were carried out using a substrate controlled hydride addition to a key C9 and C10 diketone intermediate. The analogs were tested for tubulin assembly and cytotoxicity, and were shown to retain potency similar to paclitaxel. P-glycoprotein interaction was examined using a rhodamine assay and it was found that simple hydrolysis or epimerization of the C10 acetate of paclitaxel and Taxol C can reduce interaction with the P-glycoprotein transporter that may allow for increased permeation of taxanes into the brain.

Original language	English (US)
Pages (from-to)	495-498
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	16
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2005.10.063
State	Published - Feb 1 2006

Bibliographical note

Funding Information:
This work was supported by a grant from the National Cancer Institute (CA82801). J.T.S. and B.J.T. would like to acknowledge the Department of Defense Breast Cancer Research Program for predoctoral fellowships (DAMD17-99-1-92530 and DAMD17-02-1-0435). Paclitaxel and Taxol C were generously donated by Tapestry Pharmaceuticals, Boulder, CO.

Keywords

10-Deacetylpaclitaxel
10-epi-Paclitaxel
Blood-brain barrier
P-glycoprotein
Paclitaxel

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Spletstoser, J. T., Turunen, B. J., Desino, K., Rice, A., Datta, A., Dutta, D., Huff, J. K., Himes, R. H., Audus, K. L., Seelig, A., & Georg, G. I. (2006). Single-site chemical modification at C10 of the baccatin III core of paclitaxel and Taxol C reduces P-glycoprotein interactions in bovine brain microvessel endothelial cells. Bioorganic and Medicinal Chemistry Letters, 16(3), 495-498. https://doi.org/10.1016/j.bmcl.2005.10.063

Single-site chemical modification at C10 of the baccatin III core of paclitaxel and Taxol C reduces P-glycoprotein interactions in bovine brain microvessel endothelial cells. / Spletstoser, Jared T.; Turunen, Brandon J.; Desino, Kelly et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 16, No. 3, 01.02.2006, p. 495-498.

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

Spletstoser, JT, Turunen, BJ, Desino, K, Rice, A, Datta, A, Dutta, D, Huff, JK, Himes, RH, Audus, KL, Seelig, A & Georg, GI 2006, 'Single-site chemical modification at C10 of the baccatin III core of paclitaxel and Taxol C reduces P-glycoprotein interactions in bovine brain microvessel endothelial cells', Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 3, pp. 495-498. https://doi.org/10.1016/j.bmcl.2005.10.063

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Single-site chemical modification at C10 of the baccatin III core of paclitaxel and Taxol C reduces P-glycoprotein interactions in bovine brain microvessel endothelial cells

Abstract

Bibliographical note

Keywords

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