Chapter 7: Synthetic Glycosylated Ether Glycerolipids as Anticancer Agents
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Published:30 Mar 2015
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Special Collection: 2015 ebook collection , 2011-2015 industrial and pharmaceutical chemistry subject collectionSeries: Drug Discovery Series
G. Arthur, F. Schweizer, and M. Ogunsina, in Carbohydrates in Drug Design and Discovery, ed. J. Jimenez-Barbero, F. J. Canada, and S. Martin-Santamaria, The Royal Society of Chemistry, 2015, ch. 7, pp. 151-179.
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Glycosylated antitumor ether lipids (GAELs) are a class of synthetic antitumor ether lipids (AELs) with a sugar moiety in place of the phosphocholine found in the prototypical AEL, edelfosine. This chapter reviews the development of GAELs as antitumor agents. Studies on structure–activity relationships, mechanism of induction of cell death, metabolism, selectivity against cancer cells, toxicity, hemolysis and thrombogenic effects are discussed. The requirements for significant cytotoxic activity include a glycerol moiety, a cationic sugar other than mannose and an O- or C-glycosidic bond with either α- or β-configuration. Compounds with S- and N-glycosidic linkages are not very active. The most active GAEL to date, 1-O-hexadecyl-2-O-methyl-3-O-(2′-amino-2′-deoxy-α-d-galactopyranosyl)-sn-glycerol, displays greater in vitro activity than edelfosine, the AEL “gold standard”. The unique properties of GAELs as antitumor agents include their apoptotic-independent mechanism of inducing cell death and the ability to kill cancer stem cells. These characteristics of GAELs offer the potential for their development into chemotherapeutic agents to prevent the recurrence of tumors as well as for treatment against drug-resistant cancers.