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.
Bibliographical noteFunding 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.
- Blood-brain barrier