Paclitaxel succinate analogs : anionic and amide introduction as a strategy to impart blood-brain barrier permeability

Turunen, B. J. and Ge, H. and Oyetunji, J. and Desino, K. E. and Vasandani, V. and Guthe, S. and Himes, R. H. and Audus, K. L. and Seelig, A. and Georg, G. I.. (2008) Paclitaxel succinate analogs : anionic and amide introduction as a strategy to impart blood-brain barrier permeability. Bioorganic & medicinal chemistry letters, Vol. 18. pp. 5971-5974.

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Official URL: http://edoc.unibas.ch/dok/A5258454

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A focused library of TX-67 (C10 hemi-succinate) analogs has been prepared, including C7 regioisomers, esters, amides, and one-carbon homologs. These were prepared to investigate whether the lack of TX-67 interaction with P-glycoprotein (Pgp) is due to the presence of the carboxylic acid moiety and whether this phenomenon was restricted to C10 analogs. Tubulin stabilization ability, cytotoxicity, and Pgp interactions were evaluated. All carboxylic acid analogs and several of the amides had no apparent interactions with Pgp at the concentrations used, whereas the ester variants displayed characteristics of Pgp substrates. Furthermore, it was demonstrated that hydrogen-bonding properties were significant with respect to Pgp interactions. Calculations of logD and cross-sectional areas revealed that these analogs are predicted to partition into the membrane and can compete for Pgp binding sites. The anionic and amide introduction strategy may allow for delivery of paclitaxel into the CNS and may be a potential approach for the delivery of other, structurally complex and lipophilic non-CNS permeable drugs.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Biophysical Chemistry (Seelig A)
UniBasel Contributors:Seelig-Löffler, Anna
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
Last Modified:22 Mar 2012 14:20
Deposited On:22 Mar 2012 13:20

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