Leslie W. Smith

Hepato- and pneumotoxicity of pyrrolizidine alkaloids and derivatives in relation to molecular structure.

62 pyrrolizidine alkaloids and derivatives have been screened for acute and chronic hepato- and pneumotoxicity by the single dose method previously described. This procedure is satisfactory for the compounds of medium to high hepatotoxicity but failed to detect toxicity in certain other compounds of known, low hepatotoxicity. New findings significant in relation to hepatotoxicity are as follows: (i) On a molar basis, diesters of heliotridine and retronecine are about 4 times as toxic as the respective mono-esters and heliotridine esters are 2-4 times as toxic as retronecine esters. (ii) Crotanecine esters are less toxic than retronecine esters, and the 6,9-diester madurensine, 2-4 times less toxic than the 7,9-diester anacrotine (the difference being ascribed to there being only one reactive alkylating centre in the toxic metabolite from madurensine). (iii) Hepatotoxicity was confirmed for 7-angelylheliotridine but not observed for 9-angelyheliotridine and 7- and 9-angelylretronecine. (iv) Other significant compounds failing to induce hepatotoxicity were 9-pivalyl- and 7,9-dipivalyheliotridine, the alpha- and beta-epoxides of monocrotaline, 7-angelyl-1-methylenepyrrolizidine and the methiodides of monocrotaline and senecionine. The following compounds are readily converted by rat liver microsomes in vitro into dehydroheliotridine (or dehydroretronecine): 7- and 9-angelyheliotridine, 7- and 9-angelylretronecine, 7,9-dipivalylheliotridine and otosenine. 7,9-Divalerylheliotridine, the alpha- and beta-epoxides of monocrotaline, and retusamine yield pyrrolic metabolites more slowly. The preparation and characterisation of several alkaloid derivatives are described. Chronic lung lesions were produced by most compounds which gave chronic liver lesions, although a higher dose was required in some instances. This requirement may sometimes mean that chronic lung lesions cannot be induced because of the intervention of acute or peracute deaths. Apart from this factor, structure activity requirements for pneumotoxicity are the same as for hepatotoxicity, consistent with their being both caused by the same toxic metabolites.

Structure and toxicity of the alkaloids of Russian comfrey ( Symphytum x uplandicum Nyman), a medicinal herb and item of human diet

Eight pyrrolizidine alkaloids of hepatotoxic type have been indentified in leaves ofSymphytum × uplandicum The combined alkaloids exhibit chronic hepatotoxicity in rats.

Dihydropyrrolizine derivatives in the ‘hair-pencil’ secretions of danaid butterflies

Von 6 australischen Schmetterlingsarten der Untergruppe Danainae enthielten 4 Dihydropyrrolizine, dazu das bekannte Keton (I) und 2 verwandte Substanzen (II and III).

Grantianine and grantaline, alkaloids of Crotalaria virgulata subsp. Grantiana

Abstract Characterization data are presented for grantianine and grantaline, alkaloids of Crotalaria virgulata subsp. grantiana. The plant growing in Australia also contains 1-hydroxymethyl-1β,2β-epoxy-8αH-pyrrolizidine.

Structure elucidation of phomopsin A, a novel cyclic hexapeptide mycotoxin produced by Phomopsis leptostromiformis

Phomopsin A, the main mycotoxin isolated from cultures of Phomopsis leptostromiformis and the cause of lupinosis disease in animals grazing infected lupins, is a cyclic hexapeptide containing 3-hydroxyisoleucine, 3,4-didehydrovaline, N-methyl-3-(3-chloro-4,5-dihydroxyphenyl)-3-hydroxyalanine, E-2,3-didehydroaspartic acid, E-2,3-didehydroisoleucine, and 3,4-didehydroproline; its 13C n.m.r. spectrum was completely assigned and the amino-acid sequence established unambiguously by extensive heteronuclear 13C-{1H} selective population inversion n.m.r. experiments.

LUPINOSIS: CHEMICAL PROPERTIES OF PHOMOPSIN A, THE MAIN TOXIC METABOLITE OF Phomopsis leptostromiformis

I. ABSTRACT Phomopsin A, the main toxic metabolite of Phomopsis leptostromiformis responsible for lupinosis, has an empirical formula approximately C33H44N5O13Cl. There are 3 acidic centers per molecule which are probably phenolic, β-diketone or ββ-triketone in nature. Ultraviolet, infrared, and nuclear magnetic resonance spectra are described. These and the mild acid hydrolysis of phomopsin A to oxalacetic acid and an amine suggest that the metabolite is related to tenuazonic acid.

Curassavine, an alkaloid from Heliotropium curassavicum Linn. with a C8 necic acid skeleton

Curassavine, the major alkaloid of Heliotropium curassavicum Linn. is shown to be an ester of trachelanthamidine with 3-carboxy-4-methylhexane-2,3-diol (homoviridifloric acid), the first example of a monocarboxylic necic acid with a C8 skeleton; the minor alkaloids, coromandalin and heliovicine are esters of trachelanthamidine with (+)-viridifloric and (–)-trachelanthic acids, respectively, the former providing the first example of natural occurrence of a (+)-viridiflorate.