Other Pyrrolizidine Alkaloids

The Senecio alkaloids discussed above are esters of mono-, di-, and trihydroxy-1-methylpyrrolizidines, and a few of these necine bases or their derivatives have been found free in the plant. The pyrrolizidine structure has more recently been found in a number of other alkaloids. 

The base Festucine, C18H14N2O (diHCl salt, mp 237°-242°, [a]jj 4.6° (water) A-acetyl, mp 202°-203°, [ajj) 4-5.4° JV-nitroso, mp 64°-65.5°) from Festiicia arundinaceae was isolated by Yates and Tookey 251, 252) 

The structures for loline (CLXXXVIa), lolinine (CLXXXVIb), and norloline (CLXXXVIc) follow from reaetions which are shown in Chart 

The ether bridge in loline was established by treating the alkaloid 

The formation of a single product from zinc distillation and only one disulfonic acid by oxidation would follow if cassipourine were a bis-(disulfide) with the two halves symmetrically substituted, and a 1,2-structure was envisaged as the most rational. The X-ray analysis of a 

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Indicine IV-oxide (169) (Scheme 36) is a clinically important pyrrolizidine alkaloid being used in the treatment of neoplasms. The compound is an attractive drug candidate because it does not have the acute toxicity observed in other pyrrolizidine alkaloids. Indicine IV-oxide apparently demonstrates increased biological activity and toxicity after reduction to the tertiary amine. Duffel and Gillespie (90) demonstrated that horseradish peroxidase catalyzes the reduction of indicine IV-oxide to indicine in an anaerobic reaction requiring a reduced pyridine nucleotide (either NADH or NADPH) and a flavin coenzyme (FMN or FAD). Rat liver microsomes and the 100,000 x g supernatant fraction also catalyze the reduction of the IV-oxide, and cofactor requirements and inhibition characteristics with these enzyme systems are similar to those exhibited by horseradish peroxidase. Sodium azide inhibited the TV-oxide reduction reaction, while aminotriazole did not. With rat liver microsomes, IV-octylamine decreased... 

The N-oxide of indicine (49) exhibits anti-tumour activity in experimental tumour systems, without some of the toxic effects associated with other pyrrolizidine alkaloids. The N-oxides of echinatine and europine show similar anti-tumour activity against P 388 lymphocytic leukaemia tumours.23 Indicine N-oxide is metabolized to the free base in rabbits and humans,62 although the N-oxide is the more active anti-tumour agent. It has been suggested that the conversion of indicine N-oxide into indicine is not essential for its anti-tumour activity.63 Indicine N-oxide is the first pyrrolizidine alkaloid to be tested as an anti-tumour agent in humans. The toxicity and pharmacokinetics of this compound have been studied in 29 patients with advanced cancers.64 The major toxic effect was myelosuppression, but acute liver damage was not observed. 

Hyoscyamine, scopolamine, and other tropane alkaloids (AA) acetylheliosupine and some other pyrrolizidine alkaloids arecoline (A) berbamine, berberine, and other isoquinoline alkaloids dicentrine and other aporphine alkaloids strychnine, brucine cryptolepine (AA) sparteine and other quinolizidine alkaloids (A) pilocarpine (A) emetine himbacine and other piperidine alkaloids (A) imperialine (AA) muscarine (A)... 

Rosmarinine (54) was isolated from S. rosmarinifolius Linn (Compositae family) and upon hydrolysis afforded the necine base (-)-rosmarinecine (20) biosynthesis of 20 is well understood. The X-ray crystal structure of rosmarinine has been reported. The necine portion of 54 has been found in other pyrrolizidine alkaloids such as neorosmarinine (55), petitianine (56), angularine (58) and 12-<9-acetylrosmarinine (59)." In... 

Chem. Soc. 74, 5612 (1952). Configuration Adams, Fles, ibid. 81, 5803 (1959) Robin. Crout, J. Chem. Soc. (C) 1969, 1386. Crystal structure H. Stoekli-Evans, Acta Crystallogr. B35, 231 (1979). Toxicology of monocrotaline and other pyrrolizidine alkaloids McLean, Pharmacol Rev. 22, 429-483 (1970) Allen et aL, Toxicol. Appl. Pharmacol. 23, 470 (1972) R. A. Roth ei al ibid. 60, 193 (1981). Review and evaluation of studies of carcinogenic and toxic action in laboratory animals JARC Monographs 10, 291-302, 333-342 (1976). Comprehensive reviews L. Bull et al. The... 

Minor adjustment in oxidation level allows rapid entry to other pyrrolizidine alkaloids (Scheme 124) [187]. Catalytic hydrogenation of 850 gives (-h )-dihydroxyheliotridane (851). Hydrolysis of the dithiane ring of 848 followed by exhaustive reduction of all carbonyls... 

From the hair-pencils of butterflies in Danainae and Ithomiinae (Papilion-oidea Nymphalidae), a wider variety of pyrrolizines (la-d, and 6a-d) have been identified than from Arctiidae moths. These compounds are biosynthesized from pyrrolizidine alkaloids, which are included in host plants fed by the larvae and protect them from the attacks of other herbivores [122]. In addition to novel lactones (7, 8a, and 8b) derived from an acid part of the alkaloids, many volatiles of more than 100 compounds (aromatics, terpenoids, hydrocarbons, and others) constitute scent bouquets of the male butterflies [123]. For example, the hair-pencil of Idea leuconoe (Danainae) which is distributed in South-East Asia contained 16 compounds (6b, 8a, 8b, 9, and others), and a mixture of the major volatiles applied to a butterfly dummy elicited an abdomen-curling acceptance posture in the females as a crude extract of the male hair-pencils did [ 124]. A chiral GC analysis revealed the absolute config-... 

Segall and coworkers described the in vitro mouse hepatic microsomal metabolism of the alkaloid senecionine (159) (Scheme 34). Several pyrrolizidine alkaloid metabolites were isolated from mouse liver microsomal incubation mixtures and identified (222, 223). Preparative-scale incubations with mouse liver microsomes enabled the isolation of metabolites for mass spectral and H-NMR analysis. Senecic acid (161) was identified by GC-MS comparison with authentic 161. A new metabolite, 19-hydroxysenecionine (160), gave a molecular ion consistent with the addition of one oxygen atom to the senecionine structure. The position to which the new oxygen atom had been added was made evident by the H-NMR spectrum. The three-proton doublet for the methyl group at position 19 of senecionine was absent in the NMR spectrum of the metabolite and was replaced by two signals (one proton each) at 3.99 and 3.61 ppm for a new carbinol methylene functional group. All other H-NMR spectral data were consistent for the structure of 160 as the new metabolite (222). 

We knew Utetheisa to feed on poisonous plants as a larva (Figure 1B). The plants, of the genus Crotalaria (family Leguminosae), were known to contain pyrrolizidine alkaloids (henceforth abbreviated as PAs), intensely bitter compounds potently hepatotoxic to mammals (7). Other species of Utetheisa were known to sequester PAs (8). We found this to be true for U. ornatrix as well. Adult Utetheisa raised on Crotalaria spectabilis, one of the principal foodplants available to the moth in the United States, contain on average about 700 p,g of monocrotaline (1), the principal PA in that plant (9, 10). 

Defensive Compounds. The aposematically coloured Chauliognathusfallax which feed on Senecio brasiliensis (Asteraceae) sequester the four pyrrolizidine alkaloids senecionine (100 main compound), integerrimine (101 main compound), retrorsine 102, and usaramine 103 [203] (Scheme 11). Other Chauliognathus-species may contain either precoccinelline 104 and related alkaloids (C. pul-chelus) or Z-dihydromatricaria acid 105 (C. pennsylvanicus). 

Because 1,4-dichlorobenzene is a liver toxin, it probably can interact with other chemicals that are liver toxicants. These toxicants are many, and include ethanol, halogenated hydrocarbons (chloroform, carbon tetrachloride, etc ), benzene, and other haloalkanes and haloalkenes. In addition, 1,4-dichlorobenzene toxicity may also be exacerbated by concurrent exposure with acetaminophen, heavy metals (copper, iron, arsenic), aflatoxins, pyrrolizidine alkaloids (from some types of plants), high levels of vitamin A, and hepatitis viruses. Such interactions could either be additive or S5mergistic effects. 

At overwintering sites of the monarch butterfly [Danaus plexippus) in Mexico, only one of the three local mouse species, Peromyscus melanotis, actually feeds on the butterflies. The monarchs contain cardiac glycosides (CG) and pyrrolizidine alkaloids (PA). All three species of mice have similarly low avoidance thresholds to PA (specifically, monocrotaline). But P. melanotis is less sensitive to CG (specifically, digitoxin) than the other two, Reithrodontomys sumichrasti and Peromyscus aztecus. Laboratory tests indicate that PA is toxic to young mice. 

Monocarboxylic [as in heliotrine (5) and trachelanthamine (6)] and dicarboxylic acids [in senecionine (7) and thesine (8)] are found among the carboxylic acid moieties. All the pyrrolizidine alkaloids afford pyrrolizidine alcohols under conventional conditions of ester hydrolysis. Formerly, these alcohols were used as starting materials for all the studies dealing with pyrrolizidine chemistry synthetic approaches have now been developed. Some pyrrolizidine alcohols, and other derivatives like 1-methylenepyrrolizidine, occur in plants in the free state, forming the special group of the so-called non-ester pyrrolizidine alkaloids. 

The pyrrolizidine alkaloids, found in the genus Senecio and a number of other plant genera, are plant toxins of environmental interest that have been implicated in a number... 

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