Ammodendrine and N-Methylammodendrine Enantiomers:  Isolation, Optical Rotation, and Toxicity

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2005-05, Vol.68 (5), p.681-685
• Main Authors: Lee, Stephen T, Molyneux, Russell J, Panter, Kip E, Chang, Cheng-Wei Tom, Gardner, Dale R, Pfister, James A, Garrossian, Massoud
• Format: Article
• Language: English
• Subjects: ammodendrine; Animals; Biological and medical sciences; Cattle; Cattle Diseases; chemical reactions; Chromatography, High Pressure Liquid; crooked calf diseases; Dihydropyridines - chemistry; Dihydropyridines - isolation & purification; Dihydropyridines - toxicity; Disease Models, Animal; enantiomers; Lupinus; Lupinus - chemistry; Lupinus - toxicity; Lupinus formosus; Medical sciences; Mice; Molecular Structure; N-acetylhystrine; N-methylammodendrine; phytochemicals; phytotoxins; piperidine alkaloids; Piperidines - chemistry; Piperidines - isolation & purification; Piperidines - toxicity; Plant poisons toxicology; Plants, Edible; Pyridines - chemistry; Pyridines - isolation & purification; Pyridines - toxicity; Stereoisomerism; structure-activity relationships; Toxicology
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np0580199

Ammodendrine (1) was found to occur as a mixture of enantiomers in two different collections of plants identified as Lupinus formosus. The ammodendrine fraction was reacted in a peptide coupling reaction with 9-fluorenylmethoxycarbonyl-l-alanine (Fmoc-l-Ala-OH) to give diastereomers, which were separated by preparative HPLC. The pure d- and l-ammodendrine enantiomers were then obtained by Edman degradation. Optical rotation measurements revealed that the d- and  l-enantiomers had optical rotations of [α]24 D +5.4° and −5.7°, respectively. d- and l-N-methylammodendrine enantiomers were synthesized from the corresponding ammodendrine enantiomers, and their optical rotations established as [α]23 D +62.4° and −59.0°, respectively. A mouse bioassay was used to determine the difference in toxicity between these two pairs of naturally occurring enantiomers. The LD50 of (+)-d-ammodendrine in mice was determined to be 94.1 ± 7 mg/kg and that of (−)-l-ammodendrine as 115.0 ± 7 mg/kg. The LD50 of (+)-d-N-methylammodendrine in mice was estimated to be 56.3 mg/kg, while that of (−)-l-N-methylammodendrine was determined to be 63.4 ± 5 mg/kg. These results establish the rotation values for pure ammodendrine and N-methylammodendrine and indicate that there is little difference in acute murine toxicity between the respective enantiomers.