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

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12 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 languageEnglish (US)
Pages (from-to)495-498
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume16
Issue number3
DOIs
StatePublished - 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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