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

  • Bioorg Med Chem Lett. 2011 Aug 15;21(16):4852-6. doi: 10.1016/j.bmcl.2011.06.034.
Xi Xiao  1 ,  Ju Wu ,  Chiara Trigili ,  Hui Chen ,  Joseph W K Chu ,  Ying Zhao ,  Peihua Lu ,  Li Sheng ,  Yan Li ,  Frances J Sharom ,  Isabel Barasoain ,  J Fernando Diaz ,  Wei-shuo Fang
Affiliations
  • 1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China.
PMID: 21764308 DOI: 10.1016/j.bmcl.2011.06.034
Abstract

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.