Total synthesis of natural and non-natural Δ(5,6)Δ(12,13)-jatrophane diterpenes and their evaluation as MDR modulators

J Org Chem. 2011 Jan 21;76(2):512-22. doi: 10.1021/jo1019738. Epub 2010 Dec 30.

Abstract

We report the details of the total synthesis of natural and non-natural jatropha-5,12-dienes. The successful tactic for the assembly of the strained trans-bicyclo[10.3.0]pentadecane scaffold employed a B-alkyl Suzuki-Miyaura cross-coupling for the formation of the C5/C6 double bond and a ring-closing metathesis for the construction of the C12/C13 double bond. The key step of the synthesis of the cyclopentane fragment, an uncatalyzed intramolecular carbonyl-ene reaction, was studied computationally by DFT calculations. The members of the ensemble of synthetic natural and non-natural jatrophanes were subsequently examined as modulators for the ABCB1, ABCG2, and ABCC1 efflux proteins, which are associated with multidrug resistance in cancer chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Biological Products / chemical synthesis*
  • Biological Products / chemistry*
  • Biological Products / pharmacology
  • Cell Line, Tumor
  • Cross-Linking Reagents / chemistry*
  • Crystallography, X-Ray
  • Cyclization
  • Cyclopentanes / chemistry*
  • Diterpenes / chemical synthesis*
  • Diterpenes / chemistry*
  • Diterpenes / pharmacology
  • Drug Resistance, Multiple / drug effects*
  • Euphorbia / chemistry*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Plant Extracts / chemical synthesis*
  • Plant Extracts / chemistry*
  • Plant Extracts / pharmacology
  • Stereoisomerism

Substances

  • Antineoplastic Agents
  • Biological Products
  • Cross-Linking Reagents
  • Cyclopentanes
  • Diterpenes
  • Plant Extracts
  • jatrophane