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United States Department of Agriculture

Agricultural Research Service

Title: Separation Of Enantiomeric Mixtures Of Alkaloids And Their Biological Evaluation

Authors
item Lee, Stephen
item Molyneux, Russell
item Panter, Kip

Submitted to: Book Chapter
Publication Type: Book / Chapter
Publication Acceptance Date: January 4, 2007
Publication Date: December 14, 2007
Repository URL: http://pprl.ars.usda.gov
Citation: Lee, S.T., Molyneux, R.J., Panter, K.E. 2007. Separation Of Enantiomeric Mixtures Of Alkaloids And Their Biological Evaluation. In: Bioactive Natural Products: Detection, Isolation, and Structural Determination, Second Edition, ISBN: 9780849372582, ISBN: 0849372585, Chpt. 7, pp. 209-219.

Interpretive Summary: Natural products chemistry involves isolating and characterizing bioactive chemical compounds produced by plants and other organisms. Often, compounds with one or more chiral centers are extracted, isolated and characterized by modern instrumental techniques, but it has become quite commonplace to neglect to determine the optical rotation. Because of the differential toxicity and pharmacological activity of enantiomers it is essential to determine the optical rotation of the enantiomers and the purity with respect to each enantiomer prior to their biological evaluation. Ingestion of Lupinus and Nicotiana species by pregnant livestock at specific gestational periods can result in offspring with cleft palates and deformed front limbs. Ammodendrine and anabasine are teratogens and are found in Lupinus and Nicotiana species, respectively. Both ammodendrine and anabasine are piperidine alkaloids that have chiral centers. Ammodendrine was found to occur as a mixture of enantiomers in several Lupinus species. Anabasine was also found to occur as a mixture of enantiomers in Nicotiana glauca. The N-methyl derivatives of D- and L-ammodendrine were obtained by treatment with iodomethane. Isolation of ammodendrine, N-methylammodendrine and anabasine into the D-(+) and L-(-) forms allowed for optical rotation measurements and toxicological characterization of the enantiomers. The toxicity of the anabasine and ammodendrine enantiomers was evaluated. The rank order toxicity was D-anabasine > L-anabasine and D-ammodendrine > L-ammodendrine. Whenever a new natural product is isolated, it is as important to take measures to establish the optical purity of the compound as to establish its compositional purity. In the absence of such proof, the biological activity data will remain compromised.

Technical Abstract: The fundamental rationale for natural products chemistry involves isolating and characterizing bioactive chemical constituents produced by plants and other organisms. Often, compounds with one or more chiral centers are extracted, isolated and characterized by modern instrumental techniques, but it has become quite commonplace to neglect to determine the optical rotation. Because of the differential toxicity and pharmacological activity of enantiomers it is essential to describe the stereochemical structure of any chiral centers and accurately determine the optical rotation and purity with respect to each enantiomer prior to their biological evaluation. Ingestion of Lupinus and Nicotiana species by pregnant livestock at specific gestational periods can result in offspring with cleft palates and deformed front limbs. Ammodendrine and anabasine are teratogens and are found in Lupinus and Nicotiana species, respectively. Both ammodendrine and anabasine are piperidine alkaloids that have chiral centers. Ammodendrine and anabasine were reacted in a peptide coupling reaction with 9-fluorenylmethoxycarbonyl-L-alanine to give diastereomers which were separated and isolated by HPLC. Ammodendrine was found to occur as a mixture of enantiomers in several Lupinus species. Anabasine was also found to occur as a mixture of enantiomers in Nicotiana glauca. Ammodendrine and anabasine enantiomers were obtained by Edman Degradation of the ammodendrine and anabasine based diastereomers. The N-methyl derivatives of D- and L-ammodendrine were obtained by treatment with iodomethane. Isolation of ammodendrine, N-methylammodendrine and anabasine into the D-(+) and L-(-) forms allowed for optical rotation measurements and toxicological characterization of the enantiomers. The toxicity of the anabasine and ammodendrine enantiomers was evaluated using a mouse lethality (LD50) bioassay. The rank order toxicity in this model was D-anabasine > L-anabasine and D-ammodendrine > L-ammodendrine. Whenever a new natural product is isolated, it is just as important to take measures to establish the optical purity of the compound as to establish its compositional purity. In the absence of such proof, the biological activity data will remain compromised.

Last Modified: 11/20/2014
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