Synthesis and biological activity of anticancer ether lipids that are specifically released by phospholipase A2 in tumor tissue

J Med Chem. 2005 Nov 17;48(23):7305-14. doi: 10.1021/jm049006f.

Abstract

The clinical use of anticancer lipids is severely limited by their ability to cause lysis of red blood cells prohibiting intravenous injection. Novel delivery systems are therefore required in order to develop anticancer ether lipids (AELs) into clinically useful anticancer drugs. In a recent article (J. Med. Chem. 2004, 47, 1694) we showed that it is possible to construct liposome systems composed of masked AELs that are activated by secretory phospholipase A2 in cancerous tissue. We present here the synthesis of six AELs and evaluate the biological activity of these bioactive lipids. The synthesized AEL 1-6 were tested against three different cancer cell lines. It was found that the stereochemistry of the glycerol headgroup in AEL-2 and 3 has a dramatic effect on the cytotoxicity of the lipids. AEL 1-4 were furthermore evaluated for their ability to prevent phosphorylation of the apoptosis regulating kinase Akt, and a correlation was found between their cytotoxic activity and their ability to inhibit Akt phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Ethers / chemical synthesis*
  • Ethers / chemistry
  • Ethers / pharmacology
  • Humans
  • Lipids / chemical synthesis*
  • Lipids / chemistry
  • Lipids / pharmacology
  • Liposomes
  • Phospholipases A / metabolism*
  • Phospholipases A2
  • Phosphorylation
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Prodrugs / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Ethers
  • Lipids
  • Liposomes
  • Prodrugs
  • Proto-Oncogene Proteins c-akt
  • Phospholipases A
  • Phospholipases A2