Stereoselective Potencies and Relative Toxicities of γ-Coniceine and <i>N</i>-Methylconiine Enantiomers

Lee, Stephen T.; Green, Benedict T.; Welch, Kevin D.; Jordan, Glenn T.; Zhang, Qian; Panter, Kip E.; Hughes, David L.; Chang, Cheng‐Wei Tom; Pfister, James A.; Gardner, Dale R.

doi:10.1021/tx400050r

Cited by 13 publications

(9 citation statements)

References 28 publications

(69 reference statements)

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“…[50,60] Lethal doses (LD 50 ) in mice for selected alkaloids are presented in Table 2. [61] The differences in the chemical structures including stereochemistry impart differ-ences in toxicity/potency. For example, (-)-coniine and (-)-Nmethylconiine are more potent than (+)-coniine and (+)-Nmethylconiine, respectively, in a mouse LD 50 toxicity model and in cell-based assays ( Table 2).…”

Section: Conium Alkaloidsmentioning

confidence: 99%

“…In adult animals, poison hemlock alkaloids possess pharmacological actions similar to nicotine although the effects of hemlock alkaloids like coniine are longer lasting ,. Lethal doses (LD 50 ) in mice for selected alkaloids are presented in Table . The differences in the chemical structures including stereochemistry impart differences in toxicity/potency.…”

Section: Conium Alkaloidsmentioning

confidence: 99%

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Bioactive Alkaloids from Plants Poisonous to Livestock in North America

Green

Lee

Gardner

et al. 2019

Israel Journal of Chemistry

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Plants produce a multiplicity of chemical compounds which have a variety of uses including flavors, fragrances, insecticides, dyes, poisons, and pharmaceutical agents. In this review, we focus on plant alkaloids from the genera Delphinium, Lupinus, Conium, Nicotiana, Veratrum, and selected plant endophyte derived alkaloids. Alkaloids discussed include norditerpenoid alkaloids which act as antagonists to block the ligand binding sites of nicotinic acetylcholine receptors and cause acute toxicosis in adult animals which can result in death. The inhibition of fetal movement and resulting fetal defects caused by quinolizidine and piperidine alkaloids, the inhibition of the hedgehog (Hh) signaling pathway by Veratrum alkaloids, and compounds derived from fungal endophytes that form symbioses with plant hosts will be also be discussed. The bioactivity of these alkaloids makes them useful tools for research and in human and veterinary medicine or potentially harmful toxins.

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Section: Conium Alkaloidsmentioning

confidence: 99%

Section: Conium Alkaloidsmentioning

confidence: 99%

Bioactive Alkaloids from Plants Poisonous to Livestock in North America

Green

Lee

Gardner

et al. 2019

Israel Journal of Chemistry

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“…When compared to different alkaloids in nAChR of fetal rat muscle, the efficiency is, from the highest to the lowest: nicotine > coniine > tubocurarine > lobeline [ 118 ]. The toxicities of coniine enantiomers on human tumour cell line TE-671 expressing human foetal nAChR are, in order from the highest to the lowest: γ-coniceine > (−)-coniine > (−)- N -methylconiine > (±)-coniine > (±)- N -methylconiine > (+)-coniine > (+)- N -methylconiine [ 116 , 119 ]. The exact values for different coniine enantiomers are presented in Table 3 .…”

Section: Biological Activity Of Hemlock Alkaloidsmentioning

confidence: 99%

The killer of Socrates: Coniine and Related Alkaloids in the Plant Kingdom

Hotti

Rischer

2017

Molecules

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Coniine, a polyketide-derived alkaloid, is poisonous to humans and animals. It is a nicotinic acetylcholine receptor antagonist, which leads to inhibition of the nervous system, eventually causing death by suffocation in mammals. Coniine’s most famous victim is Socrates who was sentenced to death by poison chalice containing poison hemlock in 399 BC. In chemistry, coniine holds two historical records: It is the first alkaloid the chemical structure of which was established (in 1881), and that was chemically synthesized (in 1886). In plants, coniine and twelve closely related alkaloids are known from poison hemlock (Conium maculatum L.), and several Sarracenia and Aloe species. Recent work confirmed its biosynthetic polyketide origin. Biosynthesis commences by carbon backbone formation from butyryl-CoA and two malonyl-CoA building blocks catalyzed by polyketide synthase. A transamination reaction incorporates nitrogen from l-alanine and non-enzymatic cyclization leads to γ-coniceine, the first hemlock alkaloid in the pathway. Ultimately, reduction of γ-coniceine to coniine is facilitated by NADPH-dependent γ-coniceine reductase. Although coniine is notorious for its toxicity, there is no consensus on its ecological roles, especially in the carnivorous pitcher plants where it occurs. Lately there has been renewed interest in coniine’s medical uses particularly for pain relief without an addictive side effect.

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“…Coniine, γ‐coniceine, and N‐ methyl coniine are the principal alkaloids in Conium , with relative concentration depending on the stage of plant growth. All are toxic and teratogenic, and structural characteristics impart potency (γ‐coniceine > coniine > N‐ methyl coniine) (Leete and Olson, ; Keeler and Balls, ; Lee et al, ; Green et al, ). More detailed research on molecular bioactivity of these toxins is reported in a separate paper by Green et al () in this volume.…”

Section: Lupines Poison‐hemlock and Nicotiana Glaucamentioning

confidence: 99%

Poisonous plants: Effects on embryo and fetal development

Panter

Welch

Gardner

et al. 2013

Birth Defects Research Pt C

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Poisonous plant research in the United States began over 100 years ago as a result of livestock losses from toxic plants as settlers migrated westward with their flocks, herds, and families. Major losses were soon associated with poisonous plants, such as locoweeds, selenium accumulating plants, poison-hemlock, larkspurs, Veratrum, lupines, death camas, water hemlock, and others. Identification of plants associated with poisoning, chemistry of the plants, physiological effects, pathology, diagnosis, and prognosis, why animals eat the plants, and grazing management to mitigate losses became the overarching mission of the current Poisonous Plant Research Laboratory. Additionally, spin-off benefits resulting from the animal research have provided novel compounds, new techniques, and animal models to study human health conditions (biomedical research). The Poisonous Plant Research Laboratory has become an international leader of poisonous plant research as evidenced by the recent completion of the ninth International Symposium on Poisonous Plant Research held July 2013 in Hohhot, Inner Mongolia, China. In this article, we review plants that negatively impact embryo/fetal and neonatal growth and development, with emphasis on those plants that cause birth defects. Although this article focuses on the general aspects of selected groups of plants and their effects on the developing offspring, a companion paper in this volume reviews current understanding of the physiological, biochemical, and molecular mechanisms of toxicoses and teratogenesis.

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Stereoselective Potencies and Relative Toxicities of γ-Coniceine and N-Methylconiine Enantiomers

Cited by 13 publications

References 28 publications

Bioactive Alkaloids from Plants Poisonous to Livestock in North America

Bioactive Alkaloids from Plants Poisonous to Livestock in North America

The killer of Socrates: Coniine and Related Alkaloids in the Plant Kingdom

Poisonous plants: Effects on embryo and fetal development

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