Pyrrolizidine alkaloid monocrotaline

Figure 6.7 The structure of the pyrrolizidine alkaloid monocrotaline and the microsomal enzyme-mediated metabolic activation of the pyrrolizidine alkaloid nucleus.

The hydroxy part of a hydroxy acid can also be activated for macrolactonization. Vedejs et al. [60] applied such a strategy to the synthesis of the macrocychc pyrrolizidine alkaloid monocrotaline 108). Thus, the seco acid derivative 106 was first mesylated with MsCl/EtjN in dichloromethane, and the crude product was added over 3 h to an excess of tetrabutylammonium fluoride trihydrate in acetonitrile at 34 °C to effect ring carboxy deprotection and ring closure to give 107 in 71% yield (Scheme 36). It has been noted that the active intermediate of this kind of lactonization may be an allylic chloride rather than a mesylate [61a], In addition, an intramolecular nucleophilic displacement process of chloride from an a-chloro ketone moiety by a remote carboxylate has been recently reported as an efficient approach to macrocychc keto lactones [61 bj. 

Pyrrolizidine alkaloids have long been known to be antitumor active and, more recently, have become of interest as anti-cancer agents. They occur naturally in several plant species, but are often difficult to extract and isolate from the plant material without degradation or the use of toxic solvents. The extraction of a model pyrrolizidine alkaloid, monocrotaline, from the seeds of Crotalaria spectabilis was investigated in this work. 

Estep JE, Lame MW,Jones AD, Segall HJ. A-Acetyl cysteine-conjugated pyrrolizidine alkaloids, monocrotaline and senecionine. Toxicol Lett 1990a 54 61-9. 

Wang Y-P, Yan J, Beger RD, Fu PP, Chou MW (2005) Metabolic activation of the tumorigenic pyrrolizidine alkaloid, monocrotaline, leading to DNA adduct formation in vivo. CancCT Lett 226 27-35... 

Nigra L, Huxtable RJ (1992) Hepatic glutathione concentrations and the release of pyrrolic metabolites of the pyrrolizidine alkaloid, monocrotaline, from the isolated perfused liver. Toxicon 30 1195-1202... 

Robertson KA (1982) Alkylation of in deoxyguanosine by dehydroretronecine, a carcinogenic metabolite of the pyrrolizidine alkaloid monocrotaline. Cancer Res 42 8-14... 

Synergistic hepatotoxicity from coexposure to bacterial endotoxin and the pyrrolizidine alkaloid monocrotaline. Toxicol Appl Pharmacol 166 173-185... 

Pyrrolizidine alkaloids (monocrotaline) Medial h qsertrophy of small arterioles pulmonary... 

Robertson, K. A., J. L. Seymour, M.-T. Hsia, and J. R. Allen Covalent Interaction of Dehydroretronecine, a Carcinogenic Metabolite of the Pyrrolizidine Alkaloid, Monocrotaline, with Cysteine and Glutathione. Cancer Res. 37, 3141 (1977). 

Some male arctiid moths produce their courtship pheromone from dietary pyrrolizidine alkaloids acquired during feeding by the larvae [ 126]. Conversion of monocrotaline to hydroxydanaidal by males is accomplished by aromatiza-tion, ester hydrolysis and oxidation of an alcohol to the aldehyde [7]. In the case of Utetheisa ornatirx the stereo-configuration at C7 of the dietary alkaloid is the same as the pheromone released (R). In contrast, another arctiid, Creatono-tos transiens, can convert a dietary precursor alkaloid with the (S) configuration at C7 (heliotrine) to (l )-hydroxydanaidal. The biosynthesis occurs by first oxidation-reduction at C7 to convert the stereochemistry and then proceeds through aromatization, hydrolysis, and oxidation [7]. 

Monocrotaline (170) has been the subject of extensive metabolic study with mammalian and microbiological systems. Pyrrolizidine alkaloids such as monocrotaline require metabolic activation to the corresponding pyrrole derivatives or dehydro alkaloids before they are capable of forming covalent bonds with critical macromolecules within the cell. The X-ray structure of dehydromonocrotaline has recently been determined (226), and the ability of dihydroretronicine derived from monocrotaline to react with deoxyguanosine has been demonstrated in vitro (225). 

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). 

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. 

Bober, M. A., Kurth, M. J., Milco, L. A., Roseman, D. M., Miller, R. B. and Segal, H. J. 1991. A pyrrolizidine alkaloid-enzyme-linked immunosorbent-assay detection strategy. ACS Symposium Series, 451 176-183 and, Bober, M. A., Milco, L. A., Miller, R. B., Mount, M., Wicks, B. and Kurth, M. J. 1989. A competitive enzyme-linked immunosorbent-assay (ELISA) to detect retronecine and monocrotaline in vitro. Toxicon, 27(9) 1059-1064. 

The absolute configuration was also established unequivocally for C-8 of naturally occurring pyrrolizidine bases.88 It was demonstrated in the course of the structural analysis of isoheliotridene (146), obtained by degradation of the alkaloid monocrotaline, that ozonolysis of this compound affords 2-acetylpyrrolidine-l-acetic acid (147).66 The (— )-methyl ester of this acid was condensed with methylmagnesium iodide to give (— )-l-(2-hydroxy-2-methylpropyl)-2-(l-hydroxy-l-methylethyl)pyrrolidine (148). The same glycol (148) was obtained... 

In relation with Crotalaria spp. secondary metabolites, it is well known that these plants produce pyrrolizidine alkaloids and monocrotaline which have high vertebrate toxicity and could potentially be toxic to nematodes but it is possible also that the low C/N ratio of Crotalaria may also contribute to its allelopathic effect against nematodes. Materials with very low C/N or high content of ammonia will either result in plasmolysis of nematodes, or proliferation of nematophagous fungi due to the release of NH4+-N (Rich and Rahi, 1995). 

Further 13C n.m.r. spectral data on pyrrolizidine alkaloids have been reported,58 including a re-assignment for the signals due to C-7 and C-8 in monocrotaline (48) and retronecine (27).59 This re-assignment is supported by 13C n.m.r. spectra that were obtained after biosynthetic enrichment of retronecine with 13C.60... 

The effects of pyrrolizidine alkaloids on the mixed-function oxidase enzyme system in rat liver have been studied.79,80 Dehydroheliotridine and heliotrine (at higher dose rates) have similar effects on pregnant rats and their embryos.81 The development of pulmonary hypertension and obstructive lesions in rats after administration of monocrotaline (48) has been studied.82 Butylated hydroxyanisole protects young mice against the acute toxicity of monocrotaline.83 Reduced levels of pyrrole metabolites were observed. 

Fig. 13.10 The reversed phase HPLC-ESI-MS base ion (mjz 200-500) chromatogram of some authenticated standard pyrrolizidine alkaloids and N-oxides. A Monocrotaline,...

This procedure was developed by Yamaguchi and coworkers [36]. Yamada and coworkers [37] applied it to the synthesis of the macrocyclic pyrrolizidine alkaloids ( — )-integemmine and (—)-monocrotaline. For instance, in the synthesis of (—)-integerrimine 58) [37a], treatment of seco acid 56 with 1.1 equiv of... 

Most of the members of the Crotalaria (rattlebox) species contain pyrrolizidine alkaloids, such as crotaline and monocrotaline, and therefore have hepatotoxic potential (18). These alkaloids are covered in a separate monograph. 

In order to increase the extract purity further, two additional processes were developed. The temperature-solubility cross-over point was utilized to obtain extracts containing as much as 50% monocrotaline. A second novel process incorporating ion exchange resins was also studied and yielded extracts containing 94 to 100% monocrotaline. Because this technique depends only on the basic character common to the pyrrolizidine alkaloids, it is expected to be equally effective in the extraction and isolation of the other members of this class and, in fact, could be extended to the other classes of basic alkaloids. 

The purpose of this study was to develop a general supercritical fluid based process for the separation and purification of pyrrolizidine alkaloids such as monocrotaline (CieHaaNOe, MW=325.3). Monocrotaline was selected as a model because of its role in the development of semisynthetic pyrrolizidine alkaloids (6) and because it occurs in several species of Crotalaria. The seeds of Crotalaria spectabilis served as the source of monocrotaline in this study. 

Host plants play a key role in the production and use of sex pheromones by herbivorous insects through larval or adult sequestration of chemically active compounds and pheromone precursors [210]. One of the best examples of sequestration of plant chemicals by larvae and their subsequent use by adult males in sex attraction or courtship interactions is shown in Utetheisa ornatrix (Arctiidae), whose courtship pheromone derives from pyrrolizidine alkaloids (PAs) ingested at the larval stage from the host plant Crotalaria spectabilis [211]. U. omatrix larvae sequester PAs (e.g. monocrotaline) and retain the alkaloids through metamorphosis into the adult stage to provide egg protection for the next generation. 

Monocrotaline (63) from Crotalaria spectabilis (Legumy is responsible for the activity of Crotalaria extracts against adenocarcinoma-755 in mice. Similar alkaloids have been screened for anti-tumour activity by other researchers in general, however, pyrrolizidine alkaloids have liver toxicity and it is questionable whether they can be used in chemotherapy. Furthermore, cissampareine (64) from Cissampelos pareira (Menisperm.) and coronaridine (65) from Ervata-mia dichotoma (Apocyn.) have been investigated by the Kupchan group. 

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