From taxuspine x to structurally simplified taxanes with remarkable p-glycoprotein inhibitory activity

Daniele Castagnolo; Lorenzo Contemori; Giorgio Maccari; Stanislava I Avramova; Annalisa Neri; Gianpietro Sgaragli; Maurizio Botta

doi:10.1021/ml100118k

From taxuspine x to structurally simplified taxanes with remarkable p-glycoprotein inhibitory activity

ACS Med Chem Lett. 2010 Jul 15;1(8):416-21. doi: 10.1021/ml100118k. eCollection 2010 Nov 11.

Authors

Daniele Castagnolo¹, Lorenzo Contemori¹, Giorgio Maccari¹, Stanislava I Avramova¹, Annalisa Neri², Gianpietro Sgaragli², Maurizio Botta³

Affiliations

¹ Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, 53100 Siena, Italy.
² Dipartimento di Neuroscienze, Università degli Studi di Siena, via A. Moro 2, 53100 Siena, Italy ; Istituto Toscano Tumori, via T. Alderotti 26N, 50139 Firenze, Italy.
³ Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, 53100 Siena, Italy ; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Suite 333, 1900 North 12th Street, Philadelphia, Pennsylvania 19122.

Abstract

Three simplified "non-natural" natural taxanes, related to taxuspine X, were synthetized and assayed as P-glycoprotein (P-gp) inhibitors. One of them (6) proved to be a very efficient P-gp inhibitor with an IC50 = 7.2 × 10(-6) M. In addition, to rationalize biological data, a pharmacophoric model was built through a ligand-based approach. This model represents the first example of a pharmacophore, which describes interactions of taxanes with P-gp.

Keywords: MDR reversing agents; P-glycoprotein; Taxanes; macrolactone; non-natural natural product.