Pyrrolizidine chemical structure

Some pharmacological properties of pyrrolizidine alkaloids and their relationship to chemical structure. 

There is no uniform classification for the A. In the literature divisions according to origin (examples Aconitum, Amaryllidaceae, Aspidosperma, cactus, Catharanthus, Cephalotaxus, Cinchona, coca, Corydalis, curare, Dendrobates, ergot, Erythrina, Iboga, Lycopodium, Maytenus, opium, Rauvol-fia, Senecio, Strychnos, tobacco, Vinca alkaloids, salamander, Solanum, Veratrum steroid alkaloids) in addition to divisions according to chemical structure (examples aporphine, benzylisoquinoline, bis-benzylisoquinoline, berberine, carboline, diterpene, inudazole, indole, indolizidine, isoquinoline, lupinane, macrocyclic, morphine, peptide, / -phenyl-ethylamine, piperidine, purine, pyridine, pyrrolidine, pyrrolizidine, quinoline, quinolizidine, quinucli-dine, spermine, spermidine, steroid, terpene, tro-pane, tropolone alkaloids) are used. 

Alkaloids can be divided into different t q3es according their pure chemical structures pointing first at the alkaloid base, a basic chemical nucleus. The following are basic types of alkaloids acridones, aromatics, carbo-lines, ephedras, ergots, imidazoles, indoles, bisindoles, indolizidines, manza-mines, oxindoles, quinolines, quinozolines. quinolizidines, phenylisoquinolines, phenylethylamines, piperidines, purines, pyrolidines, pyrrolizidines, pyrro-loindoles, pyrydines, sesquiterpenes, simple tetrahydroisoquinolines, stereoids, tropanes, terpenoids, diterpenes, and triterpenes. 

Pyrrolizidine alkaloids (PAs) are typical constitutively produced plant secondary compounds. PAs exist in a great diversity of some 370 chemical structures [1-3]. They are assiuned to have evolved as chemical defenses under the selection pressure of competing herbivores. This is evidenced by a number of insect herbivores from imrelated taxa which have developed adaptations not only to overcome PA-mediated plant defense, but also to sequester and utilize these alkaloids for their own defense against predators. PAs are an excellent choice to exemplify mechanistic and functional aspects of plant secondary metabolism [4,5]. 

Isolation of a lactone, structurally related to the esterifying acids of pyrrolizidine alkaloids, from the costal fringes of male Ithomiinae. Journal of Chemical Ecology 2 263-270. 

The chemical behavior and reactions of pyrrolizidine derivatives were investigated for the most part during structural analysis of naturally occurring pyrrolizidine alkaloids and in the course of the syntheses of their degradation fragments there are several publications concerned specially with this subject. Pyrrolizidine derivatives are typical tertiary amines, and consequently their chemical behavior is a combination of the properties of tertiary amines and of those of the substituent functions. However, some peculiarities of the class can be explained only in terms of the configuration of the bicyclic system. 

Furthermore, insects are not necessarily passive sequestrators of pyrrolizidine alkaloids, but rather can convert these secondary compounds into novel structures that are utilized adaptively both for defense and chemical communication. 

Many pyrrolizidine alkaloids are metabolized to toxic pyrrole metabolites in the liver by mixed-function oxidases. The structural and chemical features necessary for the formation of these metabolites have been discussed.77 The most important features, in addition to the 3-hydroxymethyl-3-pyrroline system, are steric hindrance to hydrolysis of the ester, lipophilic character (favouring attack by the hepatic microsomal enzymes), and the presence of a conformation that allows preferential oxidation of the pyrroline ring rather than 7V-oxidation. The alkylating activities of a series of these pyrrole derivatives have been examined.78... 

Figure 9.2. Metabolism of pyrrolizidine alkaloids (PAs) in Senecio vernalis. The substrates for alkaloid biosynthesis, putrescine and spermidine, are derived from primary metabolism. Homospermidine, synthesized by homospermidine synthase (HSS), is the first pathway specific intermediate. It is exclusively incorporated into the necine base moiety of senecionine A-oxide, the backbone structure of all PAs found in this Senecio species. During allocation from the roots as site of synthesis to the shoots, it is chemically modified to provide the species specific PA-pattem.

Unfortunately, persistent misconceptions about botanical safety become part of the conventional wisdom about herbs, as the original case reports are repeatedly cited without any acknowledgement of the explicatory letters that follow in subsequent volumes of the journals in which the original reports or letters appeared. In addition to this unfortunate situation, adverse effects of particular herbs have been predicted, in the absence of case reports or even in vitro studies, on the basis of the chemical composition of the herb in question. For instance, Miller (1998) warned about the expected hepatotoxicity of Echinacea spp. based on the occurrence of the pyrrolizidine alkaloids tussilagine and isotussilagine. These compounds are indeed present (at 0.006%) in Echinacea root, but they are nontoxic because they lack the structural features (1,2 unsaturation in the pyrrolizidine ring) mentioned above necessary for hepatic activation into reactive pyrroles. 

Clivorine, the alkaloid of Ligularia clivorum Maxim., was earlier shown to be a pyrrolizidine alkaloid whose basic constituent is otonecine (64). The acid component is a hydroxydicarboxylic acid which readily lactonises, on attempted isolation, to clivonecic acid (65). The structure of this acid has now been firmly established on the basis of chemical and spectroscopic evidence, and its stereochemistry has also been discussed. The present proposal" is that clivonecic acid has the S-configuration at C-2 since the o.r.d. spectrum of tetrahydroclivonecic acid exhibits a positive Cotton effect, in agreement with the modified octant rule. ... 

This nomenclature system, with (8j8) and (8a) referring to the orientation of hydrogen on Cg, and the absolute stereochemical structural assignments will be used in future discussion and depiction of the necines and their chemical relatives wherever possible. Stereochemical formulations which have been used prior to this time (74-76, 98, 152) for all the pyrrolizidine alkaloid products have been necessarily arbitrary. It is now possible to employ the complete stereochemical definitions of the pyrrolizidine products (166). 

A number of closely related naturally occurring pyrrolizidine cyclic ethers have been identified.74 Four of these, loline (=festucine75) (119), norloline (120), lolinine (121), and decorticasine (122), have had their structures and relative configurations established by chemical methods. In addition, the relative stereochemistry of loline has been defined by an X-ray crystal structure determination of its dihydrochloride.76 The absolute configurations for all these alkaloid bases have now been established by the X-ray technique of anomalous dispersion using the same dihydrochloride of loline (119).7 7... 

Chemical degradation of cassipourine gave, among other and intractable products, pyrrolizidine (Raney nickel disulfurization). X-Ray analysis as well as exhaustive spectral data show that this alkaloid has structure XXIX (44). 

As a result of these studies we have isolated bioactive compounds belonging to several chemical classes (sesquiterpenes, diterpenes, lignans, diterpenoid alkaloids, pyrrolizidine alkaloids) with selective modes of action and low toxicity. The structure-activity relationships of these compounds have also been established. 

Pyrrolizidine, quinolizidine, and indolizidine alkaloids are chemically diverse and restricted in distribution. Some similarities in structures and biosynthesis exist, but as the pathways become more clear, these three major groups of alka-... 

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