Total synthesis and biological assessment of (-)-exiguolide and analogues

Chemistry. 2011 Feb 25;17(9):2678-88. doi: 10.1002/chem.201003135. Epub 2011 Jan 24.

Abstract

We describe herein an enantioselective total synthesis of (-)-exiguolide, the natural enantiomer. The methylene bis(tetrahydropyran) substructure was efficiently synthesized by exploiting olefin cross-metathesis for the assembly of readily available acyclic segments and intramolecular oxa-conjugate cyclization and reductive etherification for the formation of the tetrahydropyran rings. The 20-membered macrocyclic framework was constructed in an efficient manner by means of Julia-Kocienski coupling and Yamaguchi macrolactonization. Finally, the (E,Z,E)-triene side chain was introduced stereoselectively via Suzuki-Miyaura coupling to complete the total synthesis. Assessment of the growth inhibitory activity of synthetic (-)-exiguolide against a panel of human cancer cell lines elucidated for the first time that this natural product is an effective antiproliferative agent against the NCI-H460 human lung large cell carcinoma and the A549 human lung adenocarcinoma cell lines. Moreover, we have investigated structure-activity relationships of (-)-exiguolide, which elucidated that the C5-methoxycarbonylmethylidene group and the length of the side chain are important for the potent activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Biological Products / chemical synthesis*
  • Biological Products / chemistry
  • Biological Products / pharmacology
  • Drug Screening Assays, Antitumor
  • Geodia / chemistry
  • Humans
  • Macrolides / chemical synthesis*
  • Macrolides / chemistry
  • Macrolides / pharmacology
  • Molecular Structure
  • Nuclear Magnetic Resonance, Biomolecular
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Biological Products
  • Macrolides
  • exiguolide