Synthesis and biological evaluation of c-aromataxane derivatives as p-glycoprotein-mediated multi drug resistance reversal agents

Takayuki Doi, Naoko Yamaguchi, Kosuke Ohsawa, Kazuoki Nakai, Masahito Yoshida, Kazuhiro Satake, Yuji Mitani, Hiroshi Nakagawa, Takashi Takahashi, Toshihisa Ishikawa

Research output: Contribution to journalArticlepeer-review

Abstract

Synthesis and evaluation of C-aromataxane derivatives as P-glycoprotein-mediated MDR reversal agents have been demonstrated. Several derivatives possessing N-benzoylphenylisoserine at the C2 or C14 position of the template 2a were readily synthesized and were evaluated their affinity for P-glycoprotein. Most of the synthesized derivatives exhibited much lower cytotoxicity in both KB-3-1 cells and MDR KB-G2-cells than paclitaxel (1), and it should be noted that the compound (14R)-5a exhibited high km and Vmax/Kmvalues, and cytotoxicity of paclitaxel (1) in MDR KB-G2 cells was significantly recovered (98% reduction, IC50 30 nM) in the presence of 5a (5.0 μM). The structural features such as endo-cage conformation and the stereochemistry at the C14 position is crucial to exhibit an excellent affinity for P-glycoprotein.

Original languageEnglish
Pages (from-to)482-501
Number of pages20
JournalHeterocycles
Volume90
Issue number1
DOIs
Publication statusPublished - 2015

ASJC Scopus subject areas

  • Analytical Chemistry
  • Pharmacology
  • Organic Chemistry

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