Synthesis and Biological Activity of Anticancer Ether Lipids That Are Specifically Released by Phospholipase A2 in Tumor Tissue

Thomas L. Andresen, Simon Skøde Jensen, Robert Madsen, Kent Jørgensen

Research output: Contribution to journalJournal articleResearchpeer-review

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 cytoxic activity and their ability to inhibit Akt phosphorylation.
Original languageEnglish
JournalThe Journal of Medicinal Chemistry
Volume48
Issue number23
Pages (from-to)7305-7314
ISSN0022-2623
Publication statusPublished - 2005

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