Clickable Lipids: Azido and Alkynyl Fatty Acids and Triacylglycerols

Authors: Zerkowski, Jonathan; Nunez, Alberto; Strahan, Gary; Solaiman, Daniel

Submitted to: Journal of the American Oil Chemists' Society
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/10/2009
Publication Date: 11/1/2009
Citation: Zerkowski, J.A., Nunez, A., Strahan, G.D., Solaiman, D. 2009. Clickable Lipids: Azido and Alkynyl Fatty Acids and Triacylglycerols. Journal of the American Oil Chemists' Society. 86(11):1115-1121.

Interpretive Summary: Lipids are essential components of biological cells. In recent years, they have also been used --- after being modified with reactive chemical groups --- in a number of innovative technological situations. These include drug delivery materials, biosensors, and nanotechnology. Advances in lipid chemistry would therefore contribute to these fields as well as to studies on the fundamental behavior of biological membranes. Unfortunately, there are two very useful kinds of reactive groups that have to date been very little used in lipid chemistry. One of these is the nitrogen-containing azide group, and the other is the carbon-carbon triple bond. These two groups can react with each other in the presence of a catalyst, and this coupling reaction (which works so well that it has been called a “click” reaction) has been used to construct many new types of polymers and materials. Another benefit of the click reaction is that it can be used to attach a large variety of biomolecules (e.g., proteins or sugars) to the lipid, and hence to a cell. We report here syntheses of lipids that contain these two reactive groups at two different sites within the molecules. These two alternative positions allow the coupling reaction to occur either close to the lipid head-group (which would be near the outside of a cell’s membrane) or at its tail (which would point toward the inside of a cell). Several examples of the coupling reaction are demonstrated, some that tie two lipids together, and some that attach an amino acid building block or a sugar compound to the lipid.

Technical Abstract: Abstract: Hydroxy fatty acids (FA), which were isolated from glycolipids that can be prepared fermentatively from fats and oils, have been synthetically modified to contain azide and alkyne functional groups. These particular functional groups were chosen because they can participate in a copper-catalyzed reaction that combines them into a 1,4-triazole, known as a “click” reaction that has been widely used in a variety of fields but has been underused in lipid chemistry. Depending on the starting hydroxy FA, these groups can be close to the carboxy unit (using 3 hydroxydecanoate) and hence the polar glycerol group, or distant from it (using 17 hydroxyoctadecanoate). These structural alternatives will impart different properties to triacylglycerols that were then prepared from the modified FA. Finally, the click reaction was used to conjugate triacylglycerols to each other as well as to other molecules such as a glycolipid or a protected amine.