Design and synthesis of de novo cytotoxic alkaloids by mimicking the bioactive conformation of paclitaxel

Bioorg Med Chem. 2010 Oct 1;18(19):7101-12. doi: 10.1016/j.bmc.2010.07.069. Epub 2010 Aug 6.

Abstract

Novel paclitaxel-mimicking alkaloids were designed and synthesized based on a bioactive conformation of paclitaxel, that is, REDOR-Taxol. The alkaloid 2 bearing a 5-7-6 tricyclic scaffold mimics REDOR-Taxol best among the compounds designed and was found to be the most potent compound against several drug-sensitive and drug-resistant human cancer cell lines. MD simulation study on the paclitaxel mimics 1 and 2 as well as REDOR-Taxol bound to the 1JFF tubulin structure was quite informative to evaluate the level of mimicking. The MD simulation study clearly distinguishes the 5-6-6 and 5-7-6 tricyclic scaffolds, and also shows substantial difference in the conformational stability of the tubulin-bound structures between 2 and REDOR-Taxol. The latter may account for the large difference in potency, and provides critical information for possible improvement in the future design of paclitaxel mimics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Computational Biology
  • Crystallography, X-Ray
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Molecular Dynamics Simulation
  • Molecular Mimicry
  • Paclitaxel / chemical synthesis*
  • Paclitaxel / chemistry
  • Paclitaxel / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Paclitaxel