Synthesis of a Fluorescent Analogue of Paclitaxel that Selectively Binds Microtubules and Sensitively Detects Efflux by P-Glycoprotein

publication · 3 years ago
by Molly M. Lee, Zhe Gao, Blake R. Peterson (The University of Kansas)
MarvinSketch Calculator Plugins (logP logD pKa etc...)

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 ~ 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 beta-tubulin both with high affinity in vitro and with high specificity in living cells, exhibited substantial cytotoxicity towards HeLa cells, and it was a highly sensitive substrate of the multidrug resistance transporter P-glycoprotein (P-gp). This probe provides a new tool for investigation of the proliferation rate paradox associated with Taxol.

Visit publication