The structure of lasiocarpine: a pyrrolizidine alkaloid

Hay, D. Robert; Mackay, M. F.; Culvenor, C. C. J.

doi:10.1107/s0567740882002271

Cited by 9 publications

(3 citation statements)

References 16 publications

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“…Generally, the bond distances and angles of the pyrrolizidine unit are distorted and this can be explained by the spiro character of the compound and the fused-ring system. In the pyrrolizidine unit, the ring-fusion distance [N1-C5 1.480 (3) Å ] is in good agreement with values in similar structures (Hay et al, 1982;Sussman & Wedak, 1973;Pé rez-Salazar et al, 1978). Bond lengths and angles around the quaternary atom C3 are distorted to some extent from ideal tetrahedral values.…”

Section: Commentsupporting

confidence: 78%

Ethyl 2,2′′-dioxo-2′,3′,5′,6′,7′,7a′-hexahydroacenaphthene-1-spiro-3′-1′H-pyrrolizine-2′spiro-1′′-acenaphthene-1-carboxylate

et al. 2005

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In the title compound, C32H25NO4, the mean plane through the pyrrolizidine system is almost perpendicular [dihedral angle 88.9 (1)°] to that through one of the acenaphthene units, and the dihedral angle between the pyrrolizidine and the second acenaphthene system is 81.6 (1)°. In the pyrrolizidine system, one of the rings is in a half‐chair conformation while the other is in an envelope conformation. The overall conformation is twisted about the fusion bond. The crystal structure is stabilized by a C—H⋯O intermolecular hydrogen bond.

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Section: Commentsupporting

confidence: 78%

Ethyl 2,2′′-dioxo-2′,3′,5′,6′,7′,7a′-hexahydroacenaphthene-1-spiro-3′-1′H-pyrrolizine-2′spiro-1′′-acenaphthene-1-carboxylate

et al. 2005

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“…species. These plants are commonly used as herbal medicines, and they can also contaminate human foods such as wheat. − Exposure to lasiocarpine, as well as other PAs, has been known to cause fatal liver veno-occlusive disease in humans and animals. − For instance, lasiocarpine was detected in the wheat flour that caused a human poisoning outbreak in Afghanistan (2007–2008) . Furthermore, the alkaloid is a carcinogen (Group 2B) capable of inducing hepatocellular tumors and angiosarcomas of the liver as well as malignant tumors of the skin in rats. − On the basis of its LD 50 value, lasiocarpine (77 mg/kg) is the second most potent acutely lethal toxin of the known PAs after retrorsine (34 mg/kg) in rats given a single intraperitoneal dose…”

Section: Introductionmentioning

confidence: 99%

Species-Specific Differences in the in Vitro Metabolism of Lasiocarpine

Fashe

Juvonen

Petsalo

et al. 2015

Chem. Res. Toxicol.

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There are species-related differences in the toxicity of pyrrolizidine alkaloids (PAs) partly attributable to the hepatic metabolism of these alkaloids. In this study, the metabolism of lasiocarpine, a potent hepatotoxic and carcinogenic food contaminant, was examined in vitro with human, pig, rat, mouse, rabbit, and sheep liver microsomes. A total of 12 metabolites (M1-M12) were detected with the human liver microsomes, of which M1, M2, M4, and M6 were unstable in the presence of reduced glutathione (GSH). With the exception of M3 and M8, the formation of all metabolites of lasiocarpine was catalyzed by CYP3A4 in humans. Tandem mass spectra (MS/MS) detected several new metabolites, termed M4-M7; their toxicological significance is unknown. M9 (m/z 398), identified as a demethylation product, was the main metabolite in all species, although the relative dominance of this metabolite was lower in humans. The level of the reactive metabolites, as measured by M1 ((3H-pyrrolizin-7-yl)methanol) and the GSH conjugate, was higher with the liver microsomes of susceptible species (human, pig, rat, and mouse) than with the species (rabbit and sheep) resistant to PA intoxication. In general, in addition to the new metabolites (M4-M7) that could make humans more susceptible to lasiocarpine-induced toxicity, the overall metabolite fingerprint detected with the human liver microsomes differed from that of all other species, yielding high levels of GSH-reactive metabolites.

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“…Pyrrolidine is an important fragment of many natural products [ 1 , 2 , 3 , 4 ] that can be exemplified by complex structures of swainsonin [ 5 ], monocotaline [ 6 ], lasiocarpine [ 7 ], and senecionine [ 8 ]. Pyrrolidine and pyrrolidinone moieties are also present in small biologically active molecules.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Functionalized Diethyl(pyrrolidin-2-yl)phosphonate and Diethyl(5-oxopyrrolidin-2-yl)phosphonate

et al. 2021

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Short and efficient syntheses of functionalized (pyrrolidin-2-yl)phosphonate and (5-oxopyrrolidin-2-yl)phosphonate have been developed. The synthetic strategy involved the diastereospecific 1,3-dipolar cycloaddition of N-benzyl-C-(diethoxyphosphoryl)nitrone to cis-1,4-dihydroxybut-2-ene and dimethyl maleate, respectively. O,O-Diethyl 3-carbamoyl-4-hydroxy(5-oxopyrrolidin-2-yl)phosphonate was obtained from O,O-diethyl 2-benzyl-4,5-dimethoxycarbonyl(isoxazolidin-3-yl)phosphonate by hydrogenation and subsequent treatment with ammonia, whereas transformation of O,O-diethyl 2-benzyl-4,5-dihydroxymethyl(isoxazolidin-3-yl)phosphonate into O,O-diethyl 3-aminomethyl-4-hydroxy(pyrrolidin-2-yl)phosphonate was accomplished by mesylation followed by hydrogenolysis to undergo intramolecular cyclization and the introduction of amino group via ammonolysis. Stereochemistry of the isoxazolidine cycloadducts, as well as the final functionalized (pyrrolidin-2-yl)- and (5-oxopyrrolidin-2-yl)phosphonates were established based on conformational analyses using vicinal H–H, H–P, and C–P couplings and supported by the observed diagnostic NOESY correlation signals.

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The structure of lasiocarpine: a pyrrolizidine alkaloid

Cited by 9 publications

References 16 publications

Ethyl 2,2′′-dioxo-2′,3′,5′,6′,7′,7a′-hexahydroacenaphthene-1-spiro-3′-1′H-pyrrolizine-2′spiro-1′′-acenaphthene-1-carboxylate

Ethyl 2,2′′-dioxo-2′,3′,5′,6′,7′,7a′-hexahydroacenaphthene-1-spiro-3′-1′H-pyrrolizine-2′spiro-1′′-acenaphthene-1-carboxylate

Species-Specific Differences in the in Vitro Metabolism of Lasiocarpine

Synthesis of Functionalized Diethyl(pyrrolidin-2-yl)phosphonate and Diethyl(5-oxopyrrolidin-2-yl)phosphonate

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