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Synthesis of a Fluorescent Analogue of Paclitaxel That Selectively Binds Microtubules and Sensitively Detects Efflux by P‐Glycoprotein
Author(s) -
Lee Molly M.,
Gao Zhe,
Peterson Blake R.
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201703298
Subject(s) - paclitaxel , p glycoprotein , efflux , flow cytometry , hela , chemistry , cytotoxicity , fluorophore , confocal microscopy , in vitro , tubulin , transporter , fluorescence , microtubule , biophysics , multiple drug resistance , fluorescence microscope , biochemistry , microbiology and biotechnology , biology , cancer , gene , antibiotics , genetics , physics , quantum mechanics
The anticancer drug paclitaxel (Taxol) exhibits paradoxical and poorly understood effects against slow‐growing tumors. To investigate its biological activity, fluorophores such as Oregon Green have been linked to this drug. However, this modification increases its polarity by approximately 1000‐fold and reduces the toxicity of Taxol towards cancer cell lines by over 200‐fold. To construct more drug‐like fluorescent probes suitable for imaging by confocal microscopy and analysis by flow cytometry, we synthesized derivatives of Taxol linked to the drug‐like fluorophore Pacific Blue (PB). We found that PB‐Gly‐Taxol bound the target protein β‐tubulin with both high affinity in vitro and high specificity in living cells, exhibited substantial cytotoxicity towards HeLa cells, and was a highly sensitive substrate of the multidrug resistance transporter P‐glycoprotein (P‐gp).