Isosteric replacement of the Z-enone with haloethyl ketone and E-enone in a resorcylic acid lactone series and biological evaluation

Bioorg Med Chem Lett. 2011 Feb 15;21(4):1167-70. doi: 10.1016/j.bmcl.2010.12.100. Epub 2010 Dec 24.

Abstract

The synthesis of a small library of resorcylic acid lactones and evaluation of their biological properties as kinase inhibitors is described. Within the series E-enones were found more active than corresponding Z-enones as inhibitors of a subset of kinases containing a conserved cysteine. Replacement of the enone moiety with a β-haloketone group led to compounds with an interesting kinase selectivity profile and also antiproliferative activity against Jurkat cells. An E-enone derivative also showed activity against capillary tube formation based on a co-culture of primary human umbilical cord endothelial cells (HUVECs) and vascular smooth muscle cells (vSMCs).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / toxicity
  • Cells, Cultured
  • Humans
  • Isomerism
  • Ketones / chemistry*
  • Lactones / chemical synthesis
  • Lactones / chemistry*
  • Lactones / toxicity
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / toxicity
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Ketones
  • Lactones
  • Protein Kinase Inhibitors
  • Protein Kinases