Pyrrolizidine alkaloids mechanism

Fu PP, Xia Q, Lin G, and Chou MW (2002) Genotoxic pyrrolizidines alkaloids - mechanisms leading to DNA adduct formation and tumorigenicity. International Journal of Molecular Science 3 948-964. 

Selective ring closure of cyclic secondary alkyl radicals onto the central carbon atom of allenes have been investigated in the course of pyrrolizidine alkaloid syntheses [69]. Thus, reduction of the phenylselenyl-substituted N-(l,2-buten-4-yl)pyrroli-done 42 with Bu3SnH via a radical chain mechanism provides 51% of target compound 44 as a 78 22 mixture of diastereomers (Scheme 11.14). The stereoselectivity... 

Insects have evolved mechanisms to tolerate plant toxins. Such mechanisms enable them to use a plant as a food source that is avoided by other herbivores, and provides the herbivore with its own ecological niche.9 For example, insects may prevent accumulation of detrimental alkaloids in the hemolymph by efficient excretion. Larvae of Spodoptera littoralis (Lepidoptera, Noctuidae) feed freely on plants containing pyrrolizidine alkaloids that are rapidly excreted and only transiently detectable in the hemolymph. Even pyrrolizidine alkaloids directly injected into the hemolymph are efficiently excreted.48 The same has been observed... 

Insects that recruit plant defense for their own protection are promising candidates for understanding the specific mechanisms that insects have evolved to cope with alkaloid-mediated plant defense. Several fascinating examples of alkaloid-recruitment have been described for the pyrrolizidine alkaloid system, some of which are given below. Most likely this is due to the unique feature of these alkaloids to exist in two interchangeable forms, as Y-oxide or as free base (tertiary alkaloid form). 

Whilst the N-oxidation of pyrrolizidine alkaloids is a recognized detoxifying mechanism in mammals [26], it has also been shown that ingested N-oxides are indeed toxic, presumably via in vivo reduction to the parent pyrrolizidine alkaloids... 

Mattocks, A. R. Mechanisms of pyrrolizidine alkaloid toxicity. "Proc. 5th Int. Congr. Pharmacology", vol. 2 S. Karger Basel, 1973 p. 114-123. 

The Monarch butterfly Danaus plexippus) was found to sequester and store pyrrolizidine alkaloids when fed on homogenized leaves of Senecio vulgaris. It is thought that the presence of these alkaloids in the butterfly may contribute towards its defence mechanism, by making it unpalatable to potential predators. Unlike many other danaids, the Monarch is not dependent on pyrrolizidine alkaloids as precursors of its sex pheromones. 

H. Hepatic failure. A variety of dmgs and toxins may cause hepatic injury (Table 1-29). Mechanisms of toxicity include direct hepatocellular damage (eg. Amanita phalloides mushrooms [see p 273]), metabolic creation of a hepato-toxic intermediate (eg, acetaminophen [p 66] or carbon tetrachloride [p 154]), or hepatic vein thrombosis (eg, pyrrolizidine alkaloids see Plants, p 309). 

Insects generally are able to synthesize alkaloids themselves or take them from feed. Alkaloids play an important role in insect metabolism, behavior, protection mechanisms, and species diversification. Many pyrrolizidine alkaloid-adapted insects convert host plant pyrrolizidine alkaloids into insect pyrrolizidine alkaloids. In this operation, the acid component of plant alkaloid is replaced by 2-hydroxy acids of insect origin. This seems to be an effect of physiological adaptation and evolutionary changes in the muton. Insect pyrrolizidine alkaloids can be precursors of insect pheromone hydroxydanaidal in many species. 

As mentioned in an earlier section in this Report, free-radical carbon-carbon bond-forming processes are becoming increasingly important in synthesis, and this year they have proved themselves particularly useful for the synthesis of pyrrolizidine alkaloids. Thus, Hart and his group have now applied their intramolecular tin hydride generated ot-acylamino radical to alkyne cyclization [viz. (97) - (98)] and to the synthesis of (-)-dehydrohastanecine (99), (+)-heliotridene (100), and (+)-hastanecine (101). In addition, free radical in mechanism is the photochemical cyclization of the -acylpyrrolidine (102) to the pyrrolizidene (103), a key intermediate in a synthesis of ( )-isoretronecanol (104). 

Fu PP, Xia Q, Lin G (2004) Pyrrolizidine alkaloids - genotoxicity, metabolism enzymes, metabolic activation, and mechanism. Drug Metab Revs 36 1-55... 

The amino derivatives of rare-earth metals follow a distinct mechanism involving direct insertion of the allene or alkene into the metal-nitrogen bond (Scheme 6.73). With the less-reactive lanthanum complex 6.215, amine 6.214 underwent insertion of only the allene, giving a pyrrolidine product 6.216 as the trans isomer. On the other hand, using the more-reactive samarium complex 6.217, tandem allene and alkene insertion occurred giving, after hydrogenation, the pyrrolizidine alkaloid, xenovenine 6.189, A closely related synthesis of this alkaloid is in Scheme 6.59. Other syntheses may be found in Scheme 6.65, and Scheme 9.46. 

Male Danaus butterflies feed on plants containing pyrrolizidine alkaloids and convert the alkaloids into dihydropyrrolizines such as da-naidone (86), danaidal (87), and hydroxydanaidal (88). These derivatives are used as pheromones 48). Danaid butterflies are also able to store pyrrolizidine alkaloids. This may act as a defence mechanism by rendering... 

---