Submitted to: Poisonous Plant Global Research and Solutions
Publication Type: Book / Chapter
Publication Acceptance Date: May 31, 2006
Publication Date: June 20, 2007
Citation: Garrossian, M., Lee, S.T., Molyneux, R.J., Gardner, D.R. 2007. N-alkylated derivatives of swainsonine. Poisonous Plant Global Research and Solutions, Chpt. 84, pp. 492 - 497. Interpretive Summary: Locoweeds (Astragalus and Oxytropsis spp.) continue to be a significant rangeland poisonous plant problem. Currently, the prevention of locoweed intoxication is currently best achieved through the application of a number of management programs. The idea of a vaccination program for use against locoweed intoxication would seem attractive; however, protective immunization against plant toxins has been of only limited success. In order to enable many plant toxins, such as that in locoweed, to provoke an immune response they must be connected to a larger carrier molecule such as a protein. The linking of the locoweed toxin to a large carrier molecule (protein) for the purpose of the induction of immunological activity has proven difficult because of the lack of chemical handles on such a small molecule. In this work, we sought an alternate approach by searching for a possible linkage through the nitrogen molecule of the toxin using a 4 carbon allylic system and 4 - 8 carbon alkyl systems. The resulting alkyl-halide toxin derivatives were then linked to several amino acids as a model system for future work with proteins.
Technical Abstract: The linkage of swainsonine to a large carrier molecule (protein) for the purpose of the induction of immunological activity has proven difficult because of the lack of chemical handles on such a small molecule. Swainsonine has been linked via the hydroxyls but no swainsonine specific antibodies were produced. It was assumed that linkage through one of the hydroxyl groups most likely destroys the three dimensional structure that characterizes the swainsonine-specific epitope. We sought an alternate approach by searching for a possible link through the nitrogen. Several N-alkyl derivatives of swainsonine were produced through the reaction of swainsonine acetonide with di-bromo and di-iodo alkyl compounds. In acetonitrile and at high molar excess, 1,4-diiodobutane as found to react to produce N-(1-iodobutane)swainsonine acetonide. This derivative proved to be stable and the acetonide group removed upon the addition of hydroiodoic acid. The N-iodobutaneswainsonine derivative could be further reacted with sulfhydryl (SH) groups as demonstrated with the amino acid cysteine. This derivative was found to react poorly with amine (NH) and hydroxyl (OH) functional group amino acids. Alternatively, swainsonine acetonide was reacted with 1,4-dibromobutene and the acetonide removed upon reaction with hydrobromic acid. The N-bromobuteneswainonine derivative was found to be highly reactive towards OH, SH and NH groups, but these reactions were also highly reversible.