Claude C. J. Culvenor

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.

Isolation of a lactone, structurally related to the esterifying acids of pyrrolizidine alkaloids, from the costal fringes of male Ithomiinae

Adult male Ithomiinae feed at plants containing pyrrolizidine alkaloids. Certain species secrete on hairs of the “costal fringe,” a specialized organ on their hindwings, a novel γ-lactone structurally related to the unusual branched-chain acids that are unique to these alkaloids.

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).

Dihydropyrrolizine secretions associated with coremata ofUtetheisa moths (family Arctiidae)

Die Duftorgane der männlichen BärenspinnerUtetheisa pulchelloides undU. lotrix (Fam. Arctiidae) scheiden Dihydropyrrolizine aus, die im Typ den Pheromonen von Schmetterlingen der Subfamilie Danainae (Fam. Papilionidae) gleichen. Wahrscheinlich handelt es sich um Derivate von Pyrrolizidin-Alkaloiden, die in den Wirtsplanzen der Raupen in hoher Konzentration vorkommen.

Interaction of phomopsin A and related compounds with purified sheep brain tubulin

Phomopsins comprise a family of peptide mycotoxins containing a 13-membered ring formed by an ether bridge, produced by the fungus Phomopsis leptostromiformis, the causal agent in lupin poisoning (lupinosis). The biochemical actions of two naturally occurring phomopsins, phomopsin A and B, and the chemical derivatives, phomopsinamine A and octahydrophomopsin A, on purified sheep brain tubulin were investigated. All analogues were potent microtubule inhibitors, blocking the polymerization of tubulin at concentrations of less than 1 microM. They inhibited [3H]vinblastine binding to tubulin and, in common with vinblastine and its competitive inhibitor maytansine, enhanced the binding of [3H]colchicine to tubulin. It is postulated that phomopsin A and its analogues exert their action on tubulin by interaction at or near the vinblastine binding site. Two possible mechanisms for the interaction between vinblastine or phomopsins and colchicine binding to tubulin are proposed.

The chemical basis of attraction of ithomiine butterflies to plants containing pyrrolizidine alkaloids

The plantHeliotropium indicum L. (Boraginaceae) contains pyrrolizidine alkaloids. When dried, it is a powerful attractant for male ithomiine and danaine butterflies, which congregate and feed at its dead shoots. The butterflies use alkaloids derived from the plants for the formation of chemicals with pheromone/allomone activity. Baiting with alkaloids and “esterifying acids,” which form a part of the alkaloid molecules, indicates that a volatile product derived from the esterifying acids attracts males to the plants, where intact alkaloids then act as phagostimulants.

Structure elucidation and absolute configuration of phomopsin a, a hexapeptide mycotoxin produced by phomopsis leptostromiformis

Abstract Phomopsin A, C36H45CIN6O12, the main mycotoxin isolated from cultures of Phomopsis leptostromiformis and the cause of lupinosis disease, is a linear hexapeptide containing 3-hydroxy-L-isoleucine, 3,4-didehydrovaline, N-methyl-3-(3-chloro-4,5-dihydroxyphenyl)serine, E-2,3-didehydroaspartic acid, E-2,3-didehydroisoleucine, and 3,4-didehydro-L-proline. The L-configuration of the indicated amino acids was established by a comparison of the N-trifluoroacetyl n-butylester derivatives of the acid hydrolysis products of phomopsin A with samples prepared from authentic amino acids, using capillary gas chromatography on a chiral stationary phase. The E configuration of the two 2,3-didehydro amino acids is based on the products obtained by catalytic hydrogenation and sodium borohydride reduction of phomopsin A followed by acid hydrolysis (for 2,3-didehydroisoleucine) or by analysis of the coupled 13C n.m.r. spectrum of phomopsin A (for 2,3-didehydroaspartic acid). Evidence is presented which shows that the glycine formed during the acid hydrolysis of phomopsin A is derived from the 3,4-didehydrovaline moiety. The sequence of the amino acids was established by heteronuclear 13C{1H} selective population inversion (SPI) experiments and by fast atom bombardment (f.a.b.) mass spectrometry of phomopsin A and its derivatives. An X-ray crystallographic study of phomopsin A confirmed the amino acid sequence and showed that the linear hexapeptide is modified by an ether bridge in place of the 5-hydroxy group of the N-methyl-3-(3-chloro-4,5-dihydroxyphenyl)serine and the hydroxy group of the 3-hydroxyisoleucine units. In addition, the X-ray study specified the absolute configuration of phomopsin A as 22E, 25E, 3R, 4S, 7S, 10S, 11S, 19S.

Corynetoxins causative agents of annual ryegrass toxicity; their identification as tunicamycin group antibiotics

The corynetoxins, formed in galled seeds of Lolium rigidum(annul ryegrass) occupied by Corynebacterium rathayi and responsible for annual ryegrass toxicity, are identified as new members of the tunicamycin group of antibiotics.

The X-ray structure of phomopsin A, a hexapeptide mycotoxin

A crystallographic study of phompsin A, the hexapeptide mycotoxin of Phomopsis leptostromiformis responsible for lupinosis disease in animals, has shown that it is a linear peptide, modified by an ether bridge in place of the hydroxy groups of the N-methyl-3-(3-chloro-4,5-dihydroxyphenyl)-3-hydroxyalanine and 3-hydroxyisoleucine units, and thus containing a 13-membered ring.