Synthesis and biological evaluation of taxinine analogues as orally active multidrug resistance reversal agents in cancer

Bioorg Med Chem Lett. 2004 Sep 20;14(18):4767-70. doi: 10.1016/j.bmcl.2004.06.089.

Abstract

Three novel taxinine analogues were prepared and tested for their activity as multidrug resistance (MDR) reversal agents in comparison with verapamil. In vitro testing demonstrated that compounds 8-10 possess MDR-reversal activity in the KB/V cell line. Half-hour after treatment with 5, 10, and 20 micromol/L compound 9, the intracellular rhodamine123 concentration increased 2.3, 2.9, and 3.2-fold, respectively, higher than 1.88-fold of 10 micromol/L verapamil in KB/V cell line. In vivo studies with VCR-resistant KB/V tumor xenografts showed that compound 9 in combination with VCR significantly inhibited tumor growth. Treatment with VCR or 9 alone did not result in growth inhibition. These results reveal that three taxinine analogues are good modifiers of MDR in tumor cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Squamous Cell / drug therapy
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Mice
  • Mice, Nude
  • Taxoids / administration & dosage
  • Taxoids / chemical synthesis
  • Taxoids / pharmacology*
  • Time Factors
  • Vincristine / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Taxoids
  • Vincristine
  • taxinine