Effects of C7 substitutions in a high affinity microtubule-binding taxane on antitumor activity and drug transport

Some C-7 modified analogs of 3, a taxane with high affinity for binding to microtubules, were prepared through multistep transformations. Most of the analogs, bearing less lipophilic C-7 substituents than propionyl in 3, exhibited comparable binding affinities to microtubules but less cytotoxicity against drug-sensitive as well as multidrug-resistant tumor cells overexpressing P-glycoprotein. In addition, these C7 modifications increased P-glycoprotein-mediated drug transport in both directions in a Caco-2 cell assay.

Graphical abstractSome C-7 modified analogs of 3, a taxane with high affinity for binding to microtubules were prepared. Most of the analogs, bearing less lipophilic C-7 substituents than propionyl in 3, exhibited comparable binding affinities to microtubules but less cytotoxicity against drug-sensitive and multidrug-resistant tumor cells overexpressing P-glycoprotein. In addition, these C7 modifications increased P-glycoprotein-mediated drug transport in both directions in a Caco-2 cell assay.Figure optionsDownload full-size imageDownload as PowerPoint slide