Pyrrolizidines radioactive labeling

Pyrrolizidine Alkaloids.—The necic acid component of senecionine (8) derives from two molecules of isoleucine, radioactivity from precursor amino-acid being equally incorporated into both halves of the necic acid fragment, as shown in Scheme 2 (c/. Vol. 9, p. 4). It has now been shown that biotransformation of isoleucine into the necic acid involves loss of half of a tritium label from C-4 in each of the two amino-acid fragments.6 Removal of a proton is, therefore, stereospecific, and oxidation at C-4 does not proceed beyond the two-electron level i.e., a higher intermediate oxidation level, corresponding to a ketone, is excluded. Further results indicate that for each molecule of isoleucine it is the 4-pro-S proton [see (14)] which is lost. 

Toxicity has been demonstrated in analogues of pyrrolizidine alkaloids with a pyrrole or dihydropyrrole ring. The vascular changes in the lungs of rats after intravenous injection of pyrrole carbamates have been reported.60 The distribution of radioactivity in rats given tritium-labelled synthanecine A (16) bis-N-ethyl-carbamate and bis-hydroxymethyl-l-methylpyrrole has been studied.61 Biliary excretion is important for the disposal of pyrrolic metabolites from retrorsine and synthanecine A bis-N-ethylcarbamate, but not for the parent compounds.62... 

Robinson s original suggestion that the natural pyrrolizidine bases are derived in vivo from two molecules of ornithine (149) has been supported by studies using C-labeled compounds. Ornithine has been shown to be a specific precursor for the pyrrolizidine nucleus present in a variety of alkaloids. The feeding experiments carried out to date are listed in Table I. Three groups of workers have obtained labeled alkaloids after feeding C-labeled ornithines.Hydrolysis of the alkaloid to yield the free base, retronecine (127), has established that almost all the radioactivity is in the base portion. It is likely that ornithine is incorporated into retronecine after decarboxylation to putrescine (150) [Eq. (40)] since labeled putrescine is also specifically incorporated into retronecine (Table I). 

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