Dual-functional abeo-taxane derivatives destabilizing microtubule equilibrium and inhibiting NF-κB activation

J Med Chem. 2013 Jun 13;56(11):4749-57. doi: 10.1021/jm400479p. Epub 2013 May 31.


Taxchinin A, with a 11(15→1)-abeo-taxane skeleton, is a major, but inactive taxoid contained in leaves of Taxus chinensis . In our design of dual-functional antitumor abeo-taxane derivatives, two fragments from antitumor agents with different molecular targets (the N-acyl-3'-phenylisoserine side chain from the antimitotic agent paclitaxel and an α,β-unsaturated carbonyl system from NF-κB inhibitors) were incorporated into the scaffold of taxchinin A. The resulting compounds displayed broad inhibitory effects against proliferation of tumor cell lines, with notable selectivity toward colon cancer, melanoma, and renal cancer, when evaluated in the NCI-60 human tumor cell line screening panel. On the basis of the NCI-60 assay data, structure-activity relationship (SAR) correlations were elucidated. Mechanistic studies indicated that this new compound type can both destabilize microtubules and inhibit NF-κB activation, thereby inducing tumor cell apoptosis. This first report of the dual-functional taxoid-core compounds thus provides new opportunities for future drug development based on natural axoid scaffolds.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Humans
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Paclitaxel / chemistry
  • Polymerization
  • Sesquiterpenes / chemistry
  • Structure-Activity Relationship
  • Taxoids / chemical synthesis*
  • Taxoids / chemistry
  • Taxoids / pharmacology
  • Tubulin / chemistry
  • Tubulin Modulators / chemical synthesis*
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / pharmacology


  • Antineoplastic Agents
  • NF-kappa B
  • Sesquiterpenes
  • Taxoids
  • Tubulin
  • Tubulin Modulators
  • taxchinin A
  • parthenolide
  • Paclitaxel