Synthesis and structure-activity correlation of natural-product inspired cyclodepsipeptides stabilizing F-actin

J Am Chem Soc. 2010 Mar 10;132(9):3063-77. doi: 10.1021/ja9095126.


The fundamental role played by actin in the regulation of eukaryotic cell maintenance and motility renders it a primary target for small-molecule intervention. In this arena, a class of potent cytotoxic cyclodepsipeptide natural products has emerged over the last quarter-century to stimulate the fields of biology and chemistry with their unique actin-stabilizing properties and complex peptide-polyketide hybrid structures. Despite considerable research effort, a structural basis for the activity of these secondary metabolites remains elusive, not least for the lack of high-resolution structural data and a reliable synthetic route to diverse compound libraries. In response to this, an efficient solid-phase approach has been developed and successfully applied to the total synthesis of jasplakinolide and chondramide C and diverse analogues. The key macrocylization step was realized using ruthenium-catalyzed ring-closing metathesis (RCM) that in the course of a library synthesis produced discernible trends in metathesis reactivity and E/Z-selectivity. After optimization, the RCM step could be operated under mild conditions, a result that promises to facilitate the synthesis of more extensive analogue libraries for structure-function studies. The growth inhibitory effects of the synthesized compounds were quantified and structure-activity correlations established which appear to be in good alignment with relevant biological data from natural products. In this way a number of potent unnatural and simplified analogues have been found. Furthermore, potentially important stereochemical and structural components of a common pharmacophore have been identified and rationalized using molecular modeling. These data will guide in-depth mode-of-action studies, especially into the relationship between the cytotoxicity of these compounds and their actin-perturbing properties, and should inform the future design of simplified and functionalized actin stabilizers as well.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / chemistry*
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Bacterial Proteins / chemical synthesis
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / pharmacology*
  • Biological Factors / chemical synthesis
  • Biological Factors / chemistry
  • Biological Factors / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Depsipeptides / chemical synthesis
  • Depsipeptides / chemistry
  • Depsipeptides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Protein Stability / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship


  • Actins
  • Antineoplastic Agents
  • Bacterial Proteins
  • Biological Factors
  • Depsipeptides
  • chondramide C
  • jasplakinolide