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1
Choi, Joong-Kwon. "Synthesis of pyrrolizidine alkaloids /." The Ohio State University, 1985. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487259125219504.
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Pereira, Tamara Nishanthi. "Cytotoxic effects of pyrrolizidine alkaloids /." [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18303.pdf.
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Kim, Hea-Young. "Molecular Toxicology of Pyrrolizidine Alkaloids." DigitalCommons@USU, 1994. https://digitalcommons.usu.edu/etd/3910.
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Pyrrolizidine alkaloids are cytotoxic, carcinogenic, and anti-carcinogenic in vivo and in vitro, and they produce many hazardous effects in humans and animals. Pyrrolizidine alkaloids (PAs) also cross-link with DNA and/or protein. However, whether such cross-linking is important to the toxic action of PAs is not known. In addition, the exact mechanism underlying these DNA cross-links or cytotoxicity is also not clear.
In three separate studies, I characterized the nature of PA-induced DNA cross-links and the relationships between PA structures and cross-linking potency. In the first study (Chapter II), I found that cross-linking potency of PA congeners coincided with their abilities to cause cytopathologic effects. Macrocyclic a,p-unsaturated diesters PAs and their pyrrolic metabolites were the most potent inhibitors of colony formation, and inducers of cytopathologic changes and megalocyte formation. The macrocyclic α, β-saturated diester PA and open diesters PAs slightly inhibited colony formation, and slightly changed cell morphology. Retronecine and indicine N-oxide were completely inactive. In the next study (Chapter Ill), I found that pyrrolic macrocyclic metabolites were more potent DNA cross-linkers than their parent compounds as determined by alkaline elution. The pyrroles of the macrocyclic diester PAs were potent DNADNA (inter- and/or intra) cross-linkers in BstEll-digested λ-phage DNA or pBR322 plasmid DNA but dehydroretronecine and indicine N-oxide were not. I also examined which DNA sequences were more susceptible to PA-induced cross-links by using a series of restriction endonucleases to determine sequence specificity. The most favorable cross-linking site for PAs appeared to be 5'd(GG) and 5'-d(GA) although other sites, 5'-d(CC) or 5'-d(CG), might be also preferable cross-linking targets. In the next study (Chapter IV), I characterized the nature of DNA-protein interactions induced by PAs, because I found in previous studies that PA-induced cross-links are largely protein associated. In PA or pyrrolic PA exposed cells, cross-linked proteins with molecular weights 40 - 60 kD were detected. Two-dimensional electrophoretic analysis revealed that these proteins were probably acidic in nature. In an in vitro system utilizing pBR322 or Bst Ell-digested λ-phage DNA. dehydrosenecionine induced DNAprotein cross-links with BSA, indicating that such interactions might be related to amino acid composition of protein.
These results confirmed that PA-induced DNA cross-links (DNA-DNA, DNA-protein cross-links) are influenced by three structural features: the C1 ,2 unsaturation of pyrrolizidine ring, α, β-unsaturation, and size of the macrocyclic diester ring. The ability to form cross-links was closely related to the known toxic potencies of these PAs. From this research, I also conclude that DNA crosslinking is the most critical event leading to PA-related diseases and that crosslinking is due to pyrrolic metabolites of PAs, not via a common metabolite as was once thought.
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Cooper, Roland Arthur 1963. "Pyrrolizidine alkaloids: Chemical basis of toxicity." Diss., The University of Arizona, 1996. http://hdl.handle.net/10150/290581.
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In humans, livestock and experimental animals, pyrrolizidine alkaloids (PAs) are toxic as a consequence of their hepatic metabolism to reactive pyrrolic esters, or dehydroalkaloids (DHAs). Despite their similarity in structures, PAs often vary markedly in their lethality (LD₅₀s) and in the organs in which toxicity is expressed. We have examined whether there are differences in the physicochemical properties of certain DHAs which are associated with differences in patterns of metabolism and toxicity produced by the parent PA. Using a potentiometric method to measure hydrolysis, it was determined that the half-lives of the corresponding DHAs of retrorsine, seneciphylline, monocrotaline and trichodesmine were 1.06, 1.60, 3.39 and 5.36 sec, respectively. These values were supported by similar results from experiments measuring reactivity of DHAs toward 4-(p-nitrobenzyl)pyridine. Studies from the isolated rat liver perfused with PAs show that DHA stability is related to patterns of metabolism and toxicity. Perfusion of the primarily hepatotoxic retrorsine and seneciphylline is associated with a greater proportion of metabolite released as non-toxic 7-glutathionyl-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine (7-GSDHP), a greater proportion alkylating liver macromolecules, and a lower proportion released as DHA into the circulation. Perfusion with monocrotaline and trichodesmine, PAs producing extrahepatic toxicity, produced lower proportions of 7-GSDHP release and liver alkylation, and higher proportions of DHA released into the circulation. Other studies characterizing DHAs included the use of an in vitro enzyme assay in which DHAs were shown to inhibit the phosphotransferase activity of yeast and rat brain hexokinase. Parent PAs, and the hydrolysis product of DHAs, (±)-6,7dihydro-1-hydroxymethyl-5H-pyrrolizine (DHP) did not affect enzyme activity. In vivo studies in rats have established that glutathione and cysteine-conjugated pyrrolic metabolites of PAs likely represent detoxication pathways, providing further support for DHAs as the primary toxic metabolite. We have examined the chemical form of sulfur-bound pyrroles to establish the importance of the 7-ester position in PA toxicity. Additionally, we have developed an efficient technique for the rapid separation and purification of large quantities of PAs using high-speed counter-current chromatography.
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Tang, Minyan. "The asymmetric synthesis of polyhydroxylated pyrrolizidine alkaloids." Department of Chemistry - Faculty of Science, 2004. http://ro.uow.edu.au/theses/233.
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Chapter 1 of this thesis is a review of the literature on the structure, biological activities and synthesis of polyhydroxylated 3-hydroxymethylpyrrolizidine alkaloids. This Chapter also outlines he aims of this project, which were to develop a flexible synthesis of the 1,2,7-trihydroxy-3-hydroxymethylpyrroizidine alkaloid australine, and its epimers. Chapter 2 describes model synthetic chemical studies on the synthesis of the pyrrolizidine core structure. The key synthetic steps, the aminolysis reaction of vinyl expoxides with ally1 amine, the ring-closing metathesis of the resulting diene, syndihydroxylation of the 2,5-dihydropyrrole product and finally ring closure to give the pyrrolizidine nucleus were successfully developed. Chapter 3 describes the application of the chemistry developed in Chapter 2 to the diastereoselective synthesis of the 3-hydroxymethy1-2,3,5,6,7,7 a-hexahydro-1H-pyrrolizine-1,2,7-triol structure, characteristic of several pyrrolizidine natural products. Two unnatural pyrrolizidine alkaloids, (-)-7-espiaustraline and (+)-1,7-diepiaustraline were successfully synthesized. The oxazolidinone group was found to be a useful protecting group in the RCM reaction and, as part of a pyrrolo[1,2-c]oxazol-3-one ring system, functioned as a stereo- and regio-directing group, in a key diastereoselective syn-dihydroxylation reaction and a regioselective nucleophilic ring-opening of a S,S-dioxo-dioxathiole. Chapter 4 describes the asymmetric synthesis of the pyrrolizidine alkaloid, (+)-1-epiaustraline. Attempts to extend this methodology to the synthesis of australine were not successful since the final pyrrolidine ring closure to produce the desired pyrrolizine was not productive.
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Wild, Stacie Lynn. "Pyrrolizidine alkaloids: Hepatic metabolism and extrahepatic toxicity." Diss., The University of Arizona, 1994. http://hdl.handle.net/10150/186599.
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Pyrrolizidine alkaloids are proposed to be metabolized in the liver to reactive pyrrole species, or dehydroalkaloids. These reactive pyrroles are hypothesized to be responsible for pyrrolizidine alkaloid toxicity. This dissertation research has established that dehydroalkaloids are, in fact, metabolites of pyrrolizidine alkaloids. It was first determined that dehydromonocrotaline is produced during hepatic microsomal metabolism of monocrotaline and that it has the ability to bind in vitro with a synthetic thiol-containing resin, Thiopropyl Sepharose 6B. Similarly, synthetic dehydromonocrotaline binds to this resin. Dehydromonocrotaline was identified as a pyrrolizidine alkaloid metabolite based upon its resin cleavage products. When resin-bound pyrrole, synthetic or microsomally generated, was cleaved in a buffered, ethanolic silver nitrate solution, O⁷-ethyl dehydroretronecine was the major product, supporting the suggestion that the pyrrole generated by hepatic microsomes is dehydromonocrotaline. This system was then used to determine the formation of dehydroalkaloids from other pyrrolizidine alkaloids. These other alkaloids--trichodesmine, retrorsine, senecionine and heliotrine--cause toxicity to the liver as well as to extrahepatic organs. Their metabolism in this system reveals that alkaloids which produce extrahepatic toxicity have an increased percentage of reactive metabolites formed by phenobarbital-induced hepatic microsomes. Therefore, this system in vitro can be a good predictor of alkaloids which may produce extrahepatic toxicity in vivo. Trichodesmine is a pyrrolizidine alkaloid that is unique in its neurotoxicity. It is structurally similar to monocrotaline, yet it varies widely in its toxicity. It was determined that trichodesmine is more toxic in the rat than monocrotaline as indexed by LD₅₀ values. The distribution of pyrrolic metabolites reveals that trichodesmine treatment results in brain pyrrole levels 4 times higher than monocrotaline, retrorsine, or control. Histopathologic investigation of trichodesmine-treated animals reveals severe neuronal death in the cerebral cortex. These results suggest that neurotoxicity observed with trichodesmine is a result of pyrrole metabolites reaching the brain, thus providing further evidence for the involvement of pyrrole metabolites in pyrrolizidine alkaloid-induced extrahepatic toxicity.
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Mitchell, Douglas. "Synthetic studies towards pyrrolizidine and indolizidine alkaloids." Thesis, Sheffield Hallam University, 1992. http://shura.shu.ac.uk/20067/.
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This project was concerned with the synthesis of the pyrrolizidine alkaloids supinidine, trachelanthamidine and isoretronecanol and also synthetic studies towards the indolizidine alkaloid 251D. In all cases, the synthesis began from a cheap, readily-available, simple amino acid, in this case glutamic acid, and proceeded to a suitable monocyclic intermediate which could then undergo an intramolecular Horner-Wittig cyclisation reaction to form the required bicyclic core structure. Subsequent modification reactions then led in the pyrrolizidine series to penultimate precursors of the target alkaloids supinidine, trachelanthamidine and isoretronecanol, and in the indolizidine series to a bicyclic intermediate in the synthesis towards the toxin 251D. The intramolecular Horner-Wittig cyclisation reaction was found to proceed with retention of chirality, thus leading to the enantiospecific synthesis of the pyrrolizidine alkaloids. The use of alternative monocyclic intermediates in the intramolecular Horner-Wittig cyclisation reaction, thus leading to other pyrrolizidine alkaloids is also discussed. One of the major problems encountered in this project was the solubility of the unprotected monocyclic amide intermediates, and this was overcome by the use of N-benzyl and N- carbobenzyloxy protecting groups; in the indolizidine synthesis where the unprotected monocyclic amides were necessary, the reaction work-up for these intermediates usually required continuous solvent extraction. Another major problem was the instability of the bicyclic amide intermediates and some of the monocyclic intermediates,As well as covering a comprehensive background of each class of alkaloid, this report also contains an in-depth discussion of the key intramolecular Horner-Wittig cyclisation reaction and suggestions for its use in the possible synthesis of other classes of alkaloids.
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Drew, Gail L. "DNA-Protein Cross-Linking by Pyrrolizidine Alkaloids." DigitalCommons@USU, 1997. https://digitalcommons.usu.edu/etd/3919.
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Pyrrolizidine alkaloids (PAs) are natural plant compounds found in hundreds of plant species worldwide and are reported to have cytotoxic, carcinogenic, antimitotic, and gentotoxic activity. PAs are metabolized by the cytochrome P450 (CYP) sytem to the pyrrole or the N-oxide form. They pyrroles are bifunctional electrophillic alkylators that bind cellular nucleophiles such as DNA and proteins and disrupt normal cell processes, including DNA replication and gene transcription, and can cause megalocytosis. The pyrroles dehyrosenecionine (DHSN) and dehydromoncrotaline (DHMO) are among the most potent PA cross-linkers and inducers of megalocytosis. DHSN and DHMO-induced cross-links in cultured normal (MDBK) and neoplastic (MCF7) cells were nalyzed by SDS-PAGE and Western blot and both were found to contain the protein actin. Actin is crucial to DNA replication and is known to be involved in cross-links induced by cis-dichlorodiammine platinum II (cistplatin), a well known cross-linking drug used for the treatment of cancer. Actin cross-linking may explain the antimitotic, megalocytotic, and anticarcinogenic effects of PAs.
Since protein cross-linking is an important mode of action for PAs, we were interested in what characteristics of the protein might make it a good nucleophilic target. Thus, further research was undertaken based on the hypothesis that cysteine residues, and specifically free sulfhydryl groups, are attractive targets for the bifunctional electrophilic alkylators DHSN and DHMO. Nucleophiles were selected for their abundance in the cell, their cysteine content, and their relationship to the documented side effects of PAs. Actin, glutathione (GSH), metallothionein, topoisomerase II, and cysteine were all found to cross-link with DHSN and DHMO in vitro while methionine, with no free sulfhydryl groups, did not cross-link.
Our results support the hypothesis that cysteine residues are a key characteristic of proteins that are cross-linked by PAs. The cross-links could have negative effects to the cell as in the case of binding actin or topoisomerase II to alter normal DNA processes and replication, or beneficial effects such as binding to electrophillic scavengers like GSH or metallothionine as a detoxifying mechanism. the nucleophiles we tested in vitro and found to form cross-links with DHSN and DHMO may help to explain the antimitotic carcinogenic, and anticarcinogenic effects of PAs.
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Pink, Jennifer Helen. "Synthesis of fused lactams via N-acyliminium ions." Thesis, University of Sheffield, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242373.
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Hagan, Desmond Bernard. "Biosynthesis and synthesis of pyrrolizidine alkaloids and analogues." Thesis, University of Glasgow, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284533.
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Seoane, Gustavo A. "Synthesis of pyrrolizidine diols via azide-diene cycloadditions." Diss., Virginia Polytechnic Institute and State University, 1988. http://hdl.handle.net/10919/81012.
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The generality of the [4+1] annulation methodology in the context of natural product synthesis was demonstrated by extending its applicability to the heteroatom (nitrogen) case thus allowing access to the alkaloid field. This novel methodology involved the intramolecular union of a hypovalent nitrogen atom equivalent and a conjugated diene to afford a pyrroline ring. The flexibility of this strategy was exemplified by the formal synthesis of ring-A oxygenated pyrrolizidine alkaloids platynecine 8, turneforcidine 9, hastanecine 10, and dihydroxyheliotridane 11.
The key features of this technology involved preparation of azidodiene ill, its cyclization, via the intermediate triazoline which was not isolated, to vinylaziridines 234, and the vinylaziridine-pyrroline rearrangement of several derivatives of 234 to pyrrolizidines 239, 241, and 242. A study of the thermal decomposition of oxygenated azidodienes such as 196 and 233 was carried out. Conclusive results regarding the stereochemical control of the C-7 substituent were attained and used for the formal stereospecific syntheses of pyrrolizidinediols 8, 9, 10, and 11.
The possibility of asymmetric induction was also investigated, and was realized in the microbial reduction of only one of the enantiomers of alcohol ill protected as ester 248, providing potential access to either enantiomeric series of pyrrolizidine diols.
[see document for diagram of chemical reaction]Ph. D.
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Rosemann, G. M. (Gertruida Magdalena). "Analysis of pyrrolizidine alkaloids in Crotalaria species by HPLC-MS/MS in order to evaluate related food health risks." Thesis, University of Pretoria, 2007. http://hdl.handle.net/2263/26960.
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Pyrrolizidine alkaloids (PAs) are one of the most significant groups of plant toxins in the world and are an important cause of poisoning in livestock, resulting in significant financial and production losses each year (Kellerman et al. 1996). Pyrrolizidine alkaloids may also enter the human food chain as contaminants of grains, via animal products such as milk, eggs and honey or may be consumed as constituents of herbal medicines (ANZFA 2001). Not all PAs are toxic. Pyrrolizidine alkaloids affecting human health are the esters of 1,2-unsaturated hydroxymethyl dehydropyrrolizidines (DHP). Before it can be converted to DHP, PAs need to have certain essential features, which include an unsaturated 3-pyrrole ring, one or two hydroxyl groups attached to the ring, one or two ester groups and a branched acid moiety (Mattocks 1986). These compounds can be metabolized in the liver to nucleophillic pyrroles which cause damage to hepatocytes (Winter and Segall 1989). Although the involvement of PAs in the development of hepatic veno-occlusive disease is well established (Bras et al. 1961), there is still uncertainty concerning the consequences of long-term, low-dose exposure in humans. Exposure to PAs through the use of herbal remedies may also be a contributing factor to the high rates of liver cancer and cirrhosis seen in Africa (Steenkamp et al. 2000). Crotalaria spp. are known to contain toxic PAs and various incidences of human poisoning through contaminated grains have been recorded in the scientific literature (IPCS 1989). Legislation controlling the allowable levels of toxic seeds in grains in South Africa is generally much stricter than in many other grain producing countries. The Soybean and Sunflower Forum recently commissioned a study (Eloff et al. 2003) to review published and unpublished information on toxic seed that could affect human health in South Africa and to make recommendations accordingly. Crotalaria sphaerocarpa is one of the problem plants discussed in the review and is apparently the only species which regularly contaminate grain in certain areas in South Africa. There is uncertainty at present about the number of these seeds that should be allowed in grains and the threat that this may pose to human health. Based on the review a provisional recommended level of 10 seeds of C. sphaerocarpa per 10 kg of grain was proposed as an approximated safe level in the report. As emphasized by the authors (Eloff et al. 2003), this absolute level is based on assumptions that must still be tested. As a follow-up on the report, a sensitive LC-MS/MS method for the determination of toxic PAs in plants was developed in this study. The characteristic fragments produced by 1,2-unsaturated necine bases under specific MS/MS conditions were used to discriminate between the toxic and non-toxic PAs. The concentration of these PAs were then determined using multi-reaction-mode experiments. Quantitative results were calculated against a retrorsine calibration curve and expressed as µg retrorsine equivalents per gram plant material. Various extraction methods described in the literature were investigated. A final liquid-liquid extraction method was used to extract unsaturated PAs from small amounts (about one gram) of milled plant samples. Recoveries from spiked lucerne samples were 98% for retrorsine and 105% for monocrotaline. To determine the applicability of the LC-MS/MS method the unsaturated PA content of C. laburnifolia and C. dura were investigated. Crotalaria laburnifolia, which is regarded as non-toxic, contained low concentrations (< 20 µg.g-1) of unsaturated PAs. Crotalaria dura, on the other hand, is known to be toxic to livestock and the concentration of unsaturated PAs was significantly higher (585 µg.g-1). The toxic PA content of Senecio inaequidens was also determined after an incident of livestock poisoning. The plant material contained very high concentrations of retrorsine (11.5 mg.g-1) and senecionine (0.5 mg.g-1) which were also present in the rumen content collected post-motally. These results confirmed the suspected toxicity of S. inaequidens. The LC-MS/MS method was also used to follow variations in unsaturated PA content in C. sphaerocarpa plants during the growing season. Pyrrolizidine alkaloids were present in the roots of the growing plants as N-oxides and also found in the mature aerial parts, where it was present mainly as the basic alkaloids. The method was used to determine the concentration of unsaturated PAs, in various C. sphaerocarpa seeds from different locations, in order to calculate the allowable level of C sphaerocarpa seed in maize. Of all the seed samples analyzed, the highest unsaturated PA concentration found was 150 µg.g-1. The allowable level of seed was calculated using this result and was found to be 656 seeds per 10 kg maize, based on the Australian and New Zealand Food Authority level of 0.1 µg.kg-1.day-1. If these results are confirmed with systematic statistical samples of C. sphaerocarpa seed from different grain production areas, the allowable level could be increased substantially. This may have an economic benefit to grain producers.Thesis (PhD (Paraclinical Science))--University of Pretoria, 2006.
Paraclinical Sciences
PhD
unrestricted
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Fortune, Grady Thomas Jr. "Structure-activity relationships in semisynthetic pyrrolizidine alkaloid antitumor agents." Diss., Georgia Institute of Technology, 1989. http://hdl.handle.net/1853/27371.
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Chisholm, Grieg. "Synthesis and biological activity of Pyrrolizidine alkaloids and analogues." Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296045.
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Matheson, Jane Reid. "Biosynthesis of pyrrolizidine alkaloids and bio-transformations of diamines." Thesis, University of Glasgow, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284519.
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Logie, Catherine Gwynedd. "The pyrrolizidine alkaloids of Senecio chrysocoma and Senecio paniculatus." Thesis, Rhodes University, 1996. http://hdl.handle.net/10962/d1005000.
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In order to compare the pyrrolizidine alkaloid content of two closely related species, Senecio chrysocoma and S. paniculatus, nine populations of plants distributed between the two species, were examined. Three novel pyrrolizidine alkaloids, 7ß-angelyl-l-methylene-8∝-pyrrolizidine, 7ß-angelyl-l-methylene-8∝-pyrrolizidine and 7ß-angelyl-l-methyleneSO!-pyrrolizidine-4-oxide, as well as eight known pyrrolizidine alkaloids, 7-angelylhastanecine, 9-angelylhastanecine, 7-angelylplatynecine, 9-angelylplatynecine, 9-angelylplatynecine-4-oxide, sarracine, neosarracine and retrorsine, were isolated and identified by NMR and GC-MS techniques. Traces of five tiglyl isomers, 9-tiglylplatynecine, 9-tigl ylplatynecine-4-oxide, 7ß-tiglyl-l-methylene-8∝-pyrrolizidine, sarranicine and neosarranicine, were also isolated and tentatively identified; however, these compounds could have been artefacts of the extraction and analytical procedures. While both species of plant investigated, S. chrysocoma and S. paniculatus, were found to be morphologically different, their pyrrolizidine alkaloid content was, in fact, very similar. The presence of retrorsine in S. paniculatus plant extracts, but not in those from S. chrysocoma plants, was the only major chemical difference observed. It is perhaps significant that retrorsine was the only macrocyclic pyrrolizidine to be identified. A comprehensive, computerised database of physical data for pyrrolizidine alkaloids has been compiled, which has facilitated the identification of new pyrrolizidines and the examination of trends in proton and carbon-13 NMR data for pyrrolizidine alkaloids. A stereospecific synthesis of 7ß-angelyl-l-methylene-8∝-pyrrolizidine was undertaken toconfirm the absolute stereochemistry of the product isolated from S. chrysocoma and S. paniculatus. An inseparable 5:2 mixture of 7ß-angelyl-l-methylene-8∝-pyrrolizidine and 7ß-angelyl-l,2-didehydro-l-methyl-8∝-pyrrolizidine, together with a small amount of tiglyl isomer, was finally synthesised. The application of various chiral differentiating chromatographic and spectroscopic techniques confirmed that both the natural and synthetic products had the same stereochemistry, permitting the natural alkaloid to be identified as 7ß-angelyl-methylene-8∝-pyrrol izidine
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Kondakal, Vishnu. "The attempted synthesis of indolizidine and pyrrolizidine natural products." Thesis, University of Huddersfield, 2013. http://eprints.hud.ac.uk/id/eprint/19281/.
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Aza-sugars are naturally occurring polyhydroxylated alkaloids in which the ring oxygen is replaced by nitrogen. They are reported to have a wide range of biological properties, most importantly as glycosidase inhibitors; these glycosidases play a key role in various diseases like HIV, cancer and lysosomal storage disorders. This thesis will describe an approach to the synthesis of analogues and precursors of azasugar natural products in the indolizidine (for example castanospermine) and pyrrolizidine (for example hyacinthacine) using cyclopropenones and cyclic imines as key intermediates. This thesis contains work that is an extension of the work pioneered by Eicher and Heimgartner and followed by our group for the reaction of cyclic imines with diphenylcyclopropenone. The methodology was extended towards the synthesis of more complex bicyclic heterocycles like indolizidine and pyrrolizidine aza-sugars and is summarised by the following Scheme. In this thesis, cyclopropenones other than diphenylcyclopropenone were used. This work also extended the range of cyclic imines that can be reacted by using for the first time, the parent aldimines, polyhydroxylated cyclic aldimines synthesised from sugars and other substituted cyclic imines. The reactions gave bicyclic products but always with an extra oxygen at the bridge head postion (X= OH) via aerial oxidation of the initial product (X= H).
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Huizing, Hindrik J. "Phytochemistry, systematics and biogenesis of pyrrolizidine alkaloids of Symphytum taxa /." [S.l. : s.n.], 1985. http://www.gbv.de/dms/bs/toc/011519487.pdf.
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Asibal, Clarita Florendo. "Isolation and structural elucidation of pyrrolizidine alkaloids from four plant sources." Diss., Georgia Institute of Technology, 1987. http://hdl.handle.net/1853/30246.
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Abd, Elhady Mohamed Ibrahim Saleh Mohamed. "Transgenic plants as tool to study the evolution of pyrrolizidine alkaloids." [S.l.] : [s.n.], 2006. http://www.digibib.tu-bs.de/?docid=00009619.
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Fleischmann, Thomas John. "Semisynthetic pyrrolizidine alkaloid antitumor agents and the toxic component of eupatorium rugosum." Diss., Georgia Institute of Technology, 1987. http://hdl.handle.net/1853/30343.
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Bonetti, Sandra J. "Studies on the isolation and biotransformation of pyrrolizidine alkaloids and related bioactive compounds." Diss., Georgia Institute of Technology, 1988. http://hdl.handle.net/1853/30244.
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Nuntawong, Nuchnipa. "Comparative study of pyrrolizidine alkaloids in Heliotropium indicum, H. amplexicaule and H. arborescens." Thesis, Liverpool John Moores University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343131.
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Freire, Kristerson Reinaldo de Luna. "Síntese assimétrica de pirrolizidinonas e pirrolizidinas substituídas a partir da reação de Morita-Baylis-Hillman." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/250256.
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Orientador: Fernando Antônio Santos CoelhoTese (doutorado) - Universidade Estadual de Campinas, Instituto de Química
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Resumo: As glicosidases regulam uma grande variedade de processos biológicos, incluindo a catálise, degradação, e biossíntese de oligossacarídeos e glicoconjugados. Inibidores eficientes dessas enzimas podem ser aplicados para o tratamento de várias doenças ou disfunções metabólicas, tais como doenças do estoque lisossomal, diabetes, cancer, malária e infecções virais, incluindo influenza e HIV. Neste trabalho, descrevemos a primeira síntese total de pirrolizidinonas e pirrolizidinas poli-hidroxiladas, benzillideno- e benzil-pirrolizidinonas e pirrolizidinas a partir de adutos de Morita-Baylis-Hillman (MBH). A estratégia sintética inicia-se com a síntese do aldeído N-Boc-4-hidroxi-D-prolinal, em 3 etapas (82 %), a partir da 4-hidroxi-D-prolina comercial. De posse do aldeído, realizou-se a reação de MBH, produzindo praticamente um único diastereoisômero ( 95% e.e.), que sofreu uma etapa de remoção de um grupo funcional e ciclização, formando uma pirrolizidinona. Esta última foi utilizada em duas sequências distintas: a primeira, envolve uma etapa one pot de ozonólise e redução de carbonila com NaBH4, e outra etapa de redução da carbonila com alana (AlH3), para fornecer a pirrolizidina poli-hidroxilada, com um rendimento global de 24% em 4 etapas; a segunda, envolve a reação de arilação de Mizoroki- Heck, utilizando como catalisador o paladaciclo de Nájera, visando fornecer as benzilideno-pirrolizidinonas. Estas, por sua vez, foram reduzidas com hidrogênio sob paládio, para fornecer as benzil-pirrolizidinonas. Tanto as benzil- quanto as benzilideno-pirrolizidinonas foram reduzidas com AlH3 para fornecer as benzilideno e benzil-pirrolizidinas, em rendimentos globais que variaram de 4 % a 23 %, em 4 ou 5 etapas. Os estudos de cristalografia de raios X permitiram determinar a estereoquímica absoluta e relativa de três pirrolizidinonas. Estudos de 2D-NOESY foram realizados para a confirmação da estereoquímica relativa das pirrolizidinonas e pirrolizidinas
Abstract: Glycosidases regulate a wide variety of biological processes, including catalysis, degradation, and biosynthesis of oligosacharides and glycoconjugates. Efficient inhibitors of these enzymes may therefore be applied to the treatment of several diseases or metabolic dysfunctions, such as lysosomal storage diseases, diabetes, cancers, malaria and viral infections, including influenza and HIV. Here we describe the first approach towards the total synthesis of a polyhydroxylated pyrrolizidinones, pyrrolizidines, benzylidene- and benzyl-pyrrolizidinones and - pyrrolizidines from asymmetric Morita-Baylis-Hillman (MBH) adducts. The synthetic strategy starts with the synthesis of aldehyde N-Boc-4R-Hydroxy-D-prolinal in three steps (82 %), from commercial 4-Hydroxy-D-proline. The MBH reaction between N-Boc-4R-Hydroxy-D-prolinal and methyl acrylate furnished a single isomer ( 95% ee). The MBH adduct was deprotected and cyclized in acid medium to provide the pyrrolizidinone. From this molecule, we evaluated two paths: the first involves a one pot ozonolysis and reduction of the carbonyl group with NaBH4 and reduction of lactam group with alane (AlH3) to provide a poly-hydroxylated pyrrolizidine, in four steps and 24% overall yield; the second involves the Mizoroki-Heck arylation reaction, using the Najera fs palladacycle as catalyst, to provide the benzylidenepyrrolizidinones. These, in turn, were reduced with hydrogen under palladium, providing the benzyl-pyrrolizidinones. Both the benzyl- and benzylidenepyrrolizidinones were reduced with AlH3 to provide the benzylidene and benzylpyrrolizidines, from 4% to 23% overall yields, over 4 or 5 steps. X-ray crystallography studies allowed determining the absolute and relative stereochemistry of three pyrrolizidinones. 2D-NOESY studies were performed to confirm the stereochemistry of pyrrolizidinones and pyrrolizidines
Doutorado
Quimica Organica
Doutor em Ciências
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Affolter, Olena. "Alkaloide aus Alkaloiden enzymatische Funktionalisierung von Tropenonen und deren Anwendung in der Synthese von Pyrrolizidinen." Berlin mbv, 2008. http://d-nb.info/993371027/04.
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Yang, Yicheng. "Quantitative analysis and reaction of pyrrolizidine alkaloids and its metabolites by nuclear magnetic resonance spectroscopy." Thesis, London Metropolitan University, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.542799.
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Langel, Dorothee. "Biosynthesis of the unique necic acid moiety in lycopsamine type pyrrolizidine alkaloids a molecular approach." Göttingen Cuvillier, 2008. http://d-nb.info/989861198/04.
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Frazier, James Owen. "Intramolecular [4+1] pyrroline annulation as a general method for the synthesis of pyrrolizidine alkaloids." Thesis, Virginia Polytechnic Institute and State University, 1986. http://hdl.handle.net/10919/91092.
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A general methodology for the synthesis of pyrrolizidine alkaloids has been developed. The two key steps in the sequence were the synthesis of the dienic azide system 1 and its regioisomer 2 by utilizing the vinylogous Reformatsky reaction, and the intramolecular additions of the azide moiety across the activated dienes with subsequent pyrolyses to provide the pyrrolizidines of type 3. This study broadened the scope of the vinylogous Reformatsky reaction to include the preparation of alkaloid synthons and introduced the heteroatom equivalent of the carbenoid [4+1] annulation as a method or alkaloid synthesis. [See docment for associated image]M.S.
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Dimande, Alberto Francisco Paulo. "The toxicity of Senecio inaequidens DC." Diss., Electronic thesis, 2007. http://upetd.up.ac.za/thesis/available/etd-05122008-080613/.
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Bhardwaj, Minakshi. "FORMATION OF THE ETHER BRIDGE IN THE LOLINE ALKALOID BIOSYNTHETIC PATHWAY." UKnowledge, 2017. http://uknowledge.uky.edu/chemistry_etds/75.
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Lolines are specialized metabolites produced by endophytic fungi, such as Neotyphodium and Epichloë species, that are in symbiotic relationships with cool-season grasses. Lolines are vital for the survival of the grasses because their insecticidal and antifeedant properties protect the plant from insect herbivory. Although lolines have various bioactivities, they do not have any concomitant antimammalian activities.
Lolines have complex structures that are unique among naturally occurring pyrrolizidine alkaloids. Lolines have four contiguous stereocenters, and they contain an ether bridge connecting C(2) and C(7) of the pyrrolizidine ring. An ether bridge connecting bridgehead C atoms is unusual in natural products and leads to interesting questions about the biosynthesis of lolines in fungal endophytes.
Dr. Pan, who was a graduate student in Dr. Schardl Lab at University of Kentucky, isolated a novel metabolite, 1-exo-acetamidopyrrolizidine (AcAP). She observed that AcAP was accumulating in naturally occurring and artificial lolO mutants. I synthesized an authentic sample of (±)-AcAP and compared it spectroscopically with AcAP isolated from a lolO mutant to determine the structure and stereochemistry of the natural product. I was also able to grow crystals of synthetic (±)-AcAP, X-ray analysis of which further supported our structure assignment.
There were two possible explanations for the fact that a missing or nonfunctional LolO led to the accumulation of AcAP: that AcAP was the actual substrate of LolO, or that it was a shunt product derived from the real substrate of LolO, 1-exo-aminopyrrolizidine (AP), and that was produced only when LolO was not available to oxidize AP. To distinguish between the two hypotheses, I synthesized 2´,2´,2´,3-[2H4]-AcAP. Dr. Pan used this material to confirm that AcAP was an intermediate in loline alkaloid biosynthesis, not a shunt product.
To determine the product of LolO acting on AcAP, Dr. Pan expressed LolO in yeast (Saccharomyces cerevisiae). When Dr. Pan fed AcAP (synthesized by me) to the modified organism, it produced NANL, suggesting that LolO catalyzed two C–H activations of AcAP and the formation of both C–O bonds of the ether bridge in NANL, a highly unusual transformation. Dr. Chang then cloned, expressed, and purified LolO and incubated it with (±)-AcAP, 2-oxoglutarate, and O2. He observed the production of NANL, further confirming the function of LolO. Dr. Chang also observed an intermediate, which we tentatively identified as 2-hydroxy-AcAP.
In order to determine whether the initial hydroxylation of AcAP catalyzed by LolO occurred at C(2) or C(7), I prepared (±)-7,7-[2H2]- and (±)-2,2,8-[2H3]-AcAP. When Dr. Pan measured the rate of LolO-catalyzed hydroxylation of these substrates under conditions under which only one C–H activation would occur, she observed a very large kinetic isotope effect when C(2) was deuterated, but not when C(7) was deuterated, establishing that the initial hydroxylation of AcAP occurred at the C(2) position.
In order to determine the stereochemical course of C–H bond oxidation by LolO at C(2) and C(7) of AcAP, I synthesized trans- and cis-3-[2H]-Pro and (2S,3R)-3-[2H]- and (2S,3S)-2,3-[2H2]-Asp. Feeding experiments with these substrates carried out by both Dr. Pan (Pro) and me (Asp) showed that at both the C(2) and C(7) positions of AcAP, LolO abstracted the endo H atoms during ether bridge formation.
In summary, feeding experiments with deuterated (±)-AcAP derivatives and its amino acid precursors have shown that AcAP is an intermediate in loline biosynthesis. We have shown that LolO catalyzes the four-electron oxidation of AcAP at the endo C(2) position first and then the endo C(7) position to give NANL.
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Heinrich, Thomas. "Photo-Elektronen-Transfer-induzierte Reaktionen von Phthalimiden, Succin- und Maleimiden Synthesen von Pyrrolizidinen und cyclischen Peptiden /." [S.l. : s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=964919745.
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Miglioli, Francesca. "Synthesis and biological evaluation of bicyclic iminosugar derivatives as inhibitors of glycosidases." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2018. http://amslaurea.unibo.it/16676/.
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During this work, five pyrrolizidine derivatives and one isoxazolidine derivative have been synthetized in order to evaluate their biological activities towards glycosidases, related to their configurations and type of bridge functionalities between the bicyclic iminosugar moiety and the aromatic part of the molecules. The final pyrrolizidine derivatives have been synthetized through click reactions (urea forming reaction, thiourea forming reaction and CuAAC reaction) performed on a common amino-pyrrolizidine precursor. The final isoxazolidine derivative has been synthetized through a CuAAC reaction. In addition, an indolizidine scaffold was obtained through a ring-closing metathesis on a dialkenyl pyrrolidine. This bicyclic compound could be of interest as intermediate for the synthesis of indolizidine derivatives with potential as glycosidase inhibitors. Biological evaluation towards glycosidases of the final six compounds synthetized in this work revealed that all of these compounds show inhibition towards almonds’ β-glucosidase and/or jack beans’ α-mannosidase.
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Faulkner, Jerome Ralph. "INTERMEDIATE STEPS OF LOLINE ALKALOID BIOSYNTHESIS." UKnowledge, 2011. http://uknowledge.uky.edu/gradschool_diss/209.
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Epichloë species and their anamorphs, Neotyphodium species, are fungal endophytes that inhabit cool-season grasses and often produce bioprotective alkaloids. These alkaloids include lolines, which are insecticidal and insect feeding deterrents. Lolines are exo-1-aminopyrrolizidines with an oxygen bridge between carbons 2 and 7, and are usually methylated and formylated or acetylated on the 1-amine. In previously published studies lolines were shown to be derived from the amino acids L-proline and L-homoserine. In addition the gene cluster involved in loline-alkaloid biosynthesis has also been characterized. In this dissertation a survey of plant-endophyte symbioses revealed a phenotype with only N-acetylnorloline. This phenotype provided insights into loline alkaloid production. This dissertation focuses on determining the steps to loline biosynthesis after the amino acid precursors. The study involves feeding isotopically labeled potential precursors to loline-alkaloid-producing cultures of Neotyphodium uncinatum, as well as RNA interference (RNAi) of N. uncinatum genes for steps in the pathway. Synthesized deuterated compounds were fed to loline-alkaloid-producing cultures of N. uncinatum to test their possible roles as precursors or intermediates in the loline-alkaloid pathway. N-Formylloline was extracted from the cultures and assayed by GCMS for incorporation of the deuterium label. The results indicated that N-(3-amino, 3-carboxy)propylproline and exo-1-aminopyrrolizidine are intermediates in the loline-alkaloid biosynthetic pathway. Plasmids were also designed for expression of double-stranded RNA homologous to loline-alkaloid biosynthesis genes, and introduced by transformation into N. uncinatum. This RNAi strategy resulted in fungal transformants altered in loline-alkaloid profiles. The RNAi results indicated that N-acetyl-1-aminopyrrolizidine is the intermediate before oxygen bridge formation. Based on the results of this study and the likely roles of the loline-alkaloid biosynthesis genes inferred from signature sequences of their predicted protein products, I propose a pathway of bond formation steps in loline-alkaloid biosynthesis.
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Wesseling, Anne-Maria [Verfasser], Dietrich [Akademischer Betreuer] Ober, and Eva [Gutachter] Stukenbrock. "Pyrrolizidine alkaloids and homospermidine synthases in grasses (Poaceae) / Anne-Maria Wesseling ; Gutachter: Eva Stukenbrock ; Betreuer: Dietrich Ober." Kiel : Universitätsbibliothek Kiel, 2017. http://d-nb.info/1236287487/34.
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Letsyo, Emmanuel [Verfasser]. "Quantification and Profiling of Pyrrolizidine Alkaloids in Honey, Herbal Medicines and the Tissues of Lappula squarrosa / Emmanuel Letsyo." Göttingen : Cuvillier Verlag, 2017. http://d-nb.info/1143145852/34.
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Rösemann, G. M. "Analysis of pyrrolizidine alkaloids in Crotalaria species by HPLC-MS/MS in order to evaluate related food health risks." Electronic thesis, 2006. http://upetd.up.ac.za/thesis/available/etd-08032007-170633/.
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Davis, Jonathan C. "Section one : photochemical methodologies towards the pyrrolizidine and indolizidine alkaloid skeleta; section two; synthesis of novel leukotriene photoaffinity labels." Thesis, University of Reading, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360717.
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Kruse, Lars Hendrik [Verfasser], Dietrich [Akademischer Betreuer] Ober, and Axel [Gutachter] Scheidig. "A multifaceted approach to identify unknown enzymes of pyrrolizidine alkaloid biosynthesis / Lars Hendrik Kruse ; Gutachter: Axel Scheidig ; Betreuer: Dietrich Ober." Kiel : Universitätsbibliothek Kiel, 2017. http://d-nb.info/1210925060/34.
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Kruse, Lars Hendrik Verfasser], Dietrich [Akademischer Betreuer] [Ober, and Axel [Gutachter] Scheidig. "A multifaceted approach to identify unknown enzymes of pyrrolizidine alkaloid biosynthesis / Lars Hendrik Kruse ; Gutachter: Axel Scheidig ; Betreuer: Dietrich Ober." Kiel : Universitätsbibliothek Kiel, 2017. http://nbn-resolving.de/urn:nbn:de:gbv:8-diss-211136.
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Becerra, Jimenez Jaime [Verfasser]. "Phytochemical and analytical studies of feed and medicinal plants in relation to the presence of toxic pyrrolizidine alkaloids / Jaime Becerra Jimenez." Bonn : Universitäts- und Landesbibliothek Bonn, 2013. http://d-nb.info/1045276669/34.
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Sandini, Thaísa Meira. "Estudos comportamentais e bioquímicos da exposição perinatal ao Senecio brasiliensis na prole de ratos." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/9/9141/tde-25022013-143518/.
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Senecio brasiliensis, conhecida popularmente como maria-mole, é uma das principais causas de intoxicação em animais de produção, principalmente em eqüinos e bovinos. A toxicidade desta planta ocorre devido à presença dos alcalóides pirrolizidínicos (APs), os quais sofrem biotransformação no fígado gerando como metabólitos tóxicos os pirróis. Além disso, esses compostos tóxicos podem ser transferridos para o homem através de produtos comestíveis de origem animal contaminados ou pelo uso na medicina popular. Até o momento, não há relatos a respeito de seus efeitos tóxicos sobre a prole de animais expostos durante a gestação. Assim, o objetivo deste trabalho foi avaliar os possíveis efeitos tóxicos da exposição pré-natal ao S. brasiliensis. Ratas Wistar fêmeas prenhes receberam por gavagem, do 6° até o 20º dia de gestação, diferentes doses de S. brasiliensis (3, 6 e 9 mg/Kg/dia). Durante o período de gestação foi avaliado o peso materno, consumo de água e de ração; ainda, nas progenitoras se avaliou o comportamento materno e materno agressivo. Na prole avaliaram-se os parâmetros do desenvolvimento físico e reflexológico; quando adultos avaliou-se aspectos comportamentais, hematológicos, bioquímicos, anatomopatológico e níveis de neurotransmissores. Os resultados mostraram diminuição no consumo de ração e no ganho de peso nos diferentes grupos experimentais, de forma dose-dependente. Ratas tratadas com a maior dose de S. brasiliensis apresentaram prejuízo no comportamento materno e materno agressivo. Os filhotes provenientes de ratas que receberam as doses de 6 e 9 mg/Kg apresentaram atraso para o início do desenvolvimento físico e reflexológico. Na prole adulta masculina proveniente da maior dose experimental observou-se aumento da atividade motora no campo aberto, bem como aumento na frequência de entrada e no tempo gasto nos braços abertos do labirinto em cruz elevado. Na natação forçada observou-se aumento no tempo de escalada na prole feminina proveniente da maior dose, enquanto na prole masculina adivinda dos grupos de 6 e 9 mg/Kg notou-se diminuição no tempo de natação. Na avaliação do comportamento estereotipado observou-se aumento deste comportamento em fêmeas advindas do grupo de maior dose experimental. Ainda, na prole adulta, foram osbervadas alterações hematológicas e bioquímicas; a análise histológica revelou aumento de células multinucleadas em animais provenientes dos grupos de 6 e 9 mg/Kg e com relação análise dos neurotransmissores, foram observadas alterações a nível estriatal. Estes resultados indicam que a exposição durante a gestação ao S. brasiliensis causa toxicidade materna acompanhada de prejuízo em ambos comportamento, materno e materno agressivo. Com relação à prole, houve prejuízo no desenvolvimento físico e reflexológico, e na idade adulta foram observadas alterações comportamentais e hematológicas, bem como algumas alterações bioquímicas e anatomapatológicas.Senecio brasiliensis popularly known as \"Maria Mole\" (=lazy Mary), is a principal cause of poisoning in livestock, mainly in horses and cattle. The toxicity of this plant is caused by pyrrolizidine alkaloids (PAs) that are metabolized by hepatic enzymes to very toxic pyrrole metabolites. In addition, these compounds can be transferred to humans through animal products or using this plant as popular medicine. There are no reports about its toxic effects on the offspring. Thus, the aim of this study was evaluate the possible toxic effects of prenatal exposure to S. brasiliensis on rat offspring. Pregnant Wistar rats received different doses of S. brasiliensis (3, 6 and 9 mg/kg, by gavage, from 6th to 20th pregnancy day. During the gestational period were evaluated the maternal weight gain and water and food intakes, as well in dams were evaluated maternal and maternal aggressive behavior. In offspring were evaluated physical and reflexologic development and, when adult, the offspring were evaluated for behavioral aspects, haematological, biochemical, anatomopathological parameters, and neurotransmitters levels. The results showed decreased a dose-dependent decrease in food intake and weight gain of dams. Dams treated with the highest S. brasiliensis dose showed impairment in maternal and maternal aggressive behavior. The offspring exposed to 6 and 9 mg/Kg of S. brasiliensis showed delay at the beginning of the physical and reflexologic development. In adult male offspring the highest dose was observed increased on open field motor activity and the frequency of entries and spent time on open arms of the elevated plus-maze. In forced swimming test was observed increase on climbing time female offspring exposed to highest dose and decrease swimming time in male offspring from 6 mg/kg and 9 mg/kg doses. On stereotypic behavior test, only the female offspring exposed to the highest dose showed increase of this behavior. The adult offspring showed few haematological and biochemical alterations, and the study histophatology demonstrated increased of hepatic multinucleated cells in animals exposed to both 6 and 9 mg/kg groups ;on the neurotransmitters levels alterations only at striatum. These results suggest that the S. brasiliensis exposure during the pregnancy cause maternal toxicity and impairment in both maternal and aggressive maternal behavior. The offspring showed damage in physical and reflexologic development, while in adulthood was observed behavioral and changes and some haematological, biochemical and anatomopathological alterations.
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Carvalho, José Carlos Borges de. "Estudo químico e biológico das espécies vegetais caboverdianas Echium hypertropicum Webb e Echium stenosiphon Webb subsp. Stenosiphon." Niterói, 2017. https://app.uff.br/riuff/handle/1/3281.
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Echium hypertropicum Webb e Echium stenosiphon Webb subsp. stenosiphon são arbustos endêmicos de Cabo Verde, usados na medicina popular para o tratamento de distúrbios gastrintestinais e tosse. As duas espécies tiveram suas frações alcalóidicas obtidas por extração ácido-base. A análise por CG-EM e ESI-EM/EM indicou a presença de alcaloides pirrolizidínicos (APs) e as substâncias purificadas foram analizadas por experimentos de RMN de 1D e 2D. Um total de 10 alcaloides foram isoladas e identificadas, sendo que 8 identificadas através da comparação de suas massas moleculares e padrões de fragmentação de massas, com a base de dados NIST e os dados da litratura para o género. Os diésteres hepatotóxicos equimidana e 7-(2-metilbutiril)-9-equimidinilretronecina foram identificadas em ambas as espécies. Os alcaloides 7-senecioilretronecina, 9-angeloilretronecina, licopsamina, 7-acetil-licopsamina e equihumilina foram identificados nas folhas de E. hypertropicum, enquanto que o N-óxido da 7-(2-metilbutiril)-9-equimidinilretronecina foi identificado nas folhas de E. stenosipnhon. A equimidina foi o componente majoritário na fração em éter dietílico das folhas de E. hypertropicum, enquanto a 7-(2-metilbutiril)-9-equimidinilretronecina foi o componente majoritário na fração em diclorometano das folhas de E. stenosiphon. O alcaloide 7-(2-metilbutiril)-9-equimidinilretronecina N-óxido foi identificado pela primeira vez no gênero Echium. Em adição, 22 componentes de óleo essencial foram identificadas nas flores de Echium hypertropicum, sendo trans-fitol (30,64 %), n-pentacosano (8,28 %) e n-tricosano (6,73) como componentes majoritários. O triterpeno friedelina foi também isolado das folhas de E. hypertropicum. Na avaliação da atividade antibacteriana, os extratos etanólicos das duas espécies vegetais e o alcaloide 7-(2-metilbutiril)-9-equimidinilretronecina foram capazes de inibir o crescimento de Staphylococcus aureus ATCC 29213 com CMI de 250,0 μg/mL e 25,0 μg/mL, respectivamente. A atividade anticolinesterásica foi avaliada e a equimidina foi capaz de inibir a enzima acetilcolinesterase nas concentrações testadas com o valor de P = 0,0011. O alcaloide 7-(2-metilbutiril)-9-equimidinilretronecina retardou o crescimento do fitófago Dysdercus peruvianus na concentração de 1mg/mL. Os extratos etanólicos de E. hypertropicum e E. stenosiphon (3,9 μg/mL) foram avaliados frente ao vírus HSV. O extrato etanólico de E. hypertropicum apresentou uma porcentagem de inibição (PI) de 27,5% contra HSV-1S e 43,8% contra HSV-2S. Apresentaram ainda elevada citotoxidade para as celulas Vero, utilizadas como sistema hospedeiro (CC50 de 140,10 μg/mL e 96,86 μg/mL). A composição química e as atividades biológicas de E. hypertropicum e E. stenosiphon subsp. stenosiphon foram relatadas pela primeira vez. As substâncias identificadas podem ser utilizadas no futuro como marcadores quimiotaxonômicos para o gênero Echium
Echium hypertropicum Webb and Echium stenosiphon Webb subsp. stenosiphon are endemic capeverdian shrubs used in folk medicine for the treatment of gastrointestinal diseases and cough, respectively. The two species had their alkaloidal fractions obtained by acid-base extraction. GC-MS and ESI-MS/MS analysis indicated the presence of pyrrolizidine alkaloids (PAs) and purified substances were also analyzed by 1D and 2D NMR experiments. A total of 10 alkaloids were isolated and identified, which 8 were identified by comparing their molecular masses and mass fragmentation patterns with NIST database and literature data for the genus. The hepatotoxic diesters echimidine and 7-(2-methylbutyryl)-9-echimidinylretronecine were identified in both species. The alkaloids 7-senecioylretronecine, 9-angeloylretronecine, lycopsamine, 7-acetil-lycopsamine and echihumiline were identified in the leaves of E. hypertropicum, whereas the 7-(2-methylbutyryl)-9-equimidinylretronecine N-oxide was identified in the leaves of E. Stenosipnhon. Echimidine was the major component in the diethyl ether fraction from leaves of E. hypertropicum, whereas the 7-(2-methylbutyryl)-9-echimidinylretronecine was the major component in dichloromethane fraction from leaves of E. stenosiphon. The alkaloid 7-(2-methylbutyryl)-9-echimidinylretronecine N-oxide was identified for the first time in Echium genus. In addition, 22 essential oil components were identified in E. hypertropicum flowers, with trans-phytol (30.64%), n-pentacosane (8.28%) and n-tricosane (6.73%) as the major components. The triterpene friedelin was also isolated from E. hypertropicum leaves. The antimicrobial susceptibility tested with the ethanolic extract and the alkaloid 7-(2-methylbutyryl)-9-equimidinilretronecine against Staphylococcus aureus ATCC 29213 showed a MIC of 250.0 μg/mL and 25.0 μg/mL, respectively. The anticholinesterasic activity was evaluated and echimidine was able to inhibit the enzyme at the concentrations tested with p value = 0.0011. The alkaloid 7-(2-methylbutyryl)-9-equimidinilretronecine retarded the growth of phytophagous Dysdercus peruvianus at the concentration of 1mg/mL. For the antiviral activity, the ethanolic extracts from E. hypertropicum and E. stenosiphon (3.9 μg/mL) were analyzed against HSV. The ethanolic extract of E. hypertropicum showed an inhibition percentage (IP) of 27.5% against HSV-1S and 43.8% against HSV-2S. Also showed high cytotoxicity for the Vero cells, used as host for the herpesvirus (CC50 140.10 μg/mL and 96.86 μg/mL). The chemical composition and biological activities of the leaves and flowers of E. hypertropicum and E. stenosiphon subsp. stenosiphon are reported for the first time. The identified pyrrolizidine alkaloids could be used in future as chemotaxonomic markers for Echium genus
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Rossi, Fanny. "Vers une valorisation industrielle d’un remède traditionnel pour le traitement des intoxications ciguatériques." Thesis, Polynésie française, 2014. http://www.theses.fr/2014POLF0002/document.
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Malgré leur existence ancienne et leur incidence dans la zone intertropicale, aucun traitement efficace, autre que symptomatique, n’est disponible à l’heure actuelle pour traiter les intoxications ciguatériques. La médecine traditionnelle à base de plantes vient alors au secours des populations. Dans la région du Pacifique, une des plantes les plus utilisées, et présentant des potentialités dans le traitement de la ciguatéra, est Heliotropium foertherianum Diane & Hilger. Toutefois, cette plante, de la famille des Borraginacées, est connue pour produire des alcaloïdes pyrrolizidiniques, composés hépatotoxiques. Dans ce travail, l’activité biologique sur cellules neuronales et la composition chimique d’H. foertherianum ont été étudiées, en vue d’une valorisation d’un extrait de cette plante. Dans un premier temps, la confirmation de l’activité biologique in vitro de l’extrait aqueux d’H. foertherianum et de ses principes actifs, les acides rosmarinique et caféique, a été apportée. Ensuite, la caractérisation chimique de l’extrait aqueux par CLHP-SM a mené à l’identification potentielle de 25 composés et à la vérification de l’absence des alcaloïdes pyrrolizidiniques. Enfin, l’étude des paramètres de récolte, de conservation et d’extraction des feuilles et extraits a permis de détailler les conditions nécessaires à l’obtention d’un extrait à la teneur maximale en principes actifs dont l’activité biologique serait garantie. Ainsi, la production locale d’un extrait d’H. foertherianum, dosé en principes actifs et dont l’innocuité est vérifiée, en tant que traitement contre les intoxications ciguatériques peut être sérieusement envisagéeDespite its former existence and its impact in the intertropical zone, no effective treatment, other than symptomatic, is available to treat ciguatera fish poisoning yet. People can only rely on traditional herbal medicine. In the Pacific region, one of the most used plants, which is promising for the treatment of ciguatera fish poisoning, is Heliotropium foertherianum Diane & Hilger. However, this plant, from the Boraginaceae family, is known for producing hepatotoxic compounds such as pyrrolizidine alkaloids. In order to valorize this plant extract, its biological activity on neuronal cells and its chemical composition with the means of HPLC-DAD and HPLC-MS have been studied in this work. First, the in vitro biological activity of the aqueous extract of H. foertherianum and its active principles, rosmarinic and caffeic acids, was confirmed. Then the chemical characterization of the aqueous extract led to the possible identification of 25 compounds and the verification of the absence of pyrrolizidine alkaloids. Finally, the study of the harvest, conservation and extraction parameters of leaves and extracts permits to specify the conditions needed for obtaining an extract with high level of active principles and whose biological activity is guaranteed. Therefore, a local production of an extract from H. foertherianum as a treatment against ciguatera fish poisoning, dosed in active principles and whose safety is established, can be seriously considered
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Conegero, Leila de Souza. "Estudos visando a sintese de alcaloides pirrolizidinicos e indolizidinicos : aproveitamento da (+)-retronecina e do acido D-isoascorbico." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/249280.
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Orientador: Ronaldo Aloise PilliTese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica
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Resumo: O trabalho desenvolvido visou a obtenção de alcalóides pirrolizidínicos e indolizidínicos utilizando a (+)-retronecina (1) e o ácido D-isoascórbico (35D) como matérias primas, respectivamente. A retronecina (1) foi isolada da espécie vegetal Senecio brasiliensis. Para a preparação da base necínica (1R,6S,7S,8R)-7- (hidroximetil)-hexaidro-1H-pirrolizina-1,6-diol (37), a retronecina (1) foi submetida à reação de epoxidação com ácido meta-cloroperbenzóico. A a-epóxi-retronecina (44), após proteção das hidroxilas com cloreto de tercbutildimetilsilila, foi submetida à abertura com níquel de Raney, e a posterior desproteção forneceu o triol 37, que foi obtido em 5 etapas e 15 % de rendimento. Os compostos (1R,2R,7R,8S)-1-(hidroximetil)-hexaidro-1H-pirrolizina-1,2,7-triol (39) e a platinecina (72) foram preparados a partir de reações de diidroxilação e hidrogenação estereosseletiva da retronecina (1) em 70 e 86 % de rendimento, respectivamente. A abordagem síntética inicial para obtenção de alcalóides indolizidínicos foi baseada na adição do 2-terc-butildimetilsililoxifurano (94) ao íon N-acilimínio derivado da lactama 90. Em função do moderado rendimento e da modesta diastereosseletividade obtida foi proposta uma segunda abordagem sintética para obtenção de indolizidinas. Os alcalóides indolizidínicos, (1R,2S,8aR)- octaidroindolizina-1,2-diol (100) (ent-epi-lentiginosina) e (1R,2S,6R,7S,8aR)- octaidroindolizina-1,2,6,7-tetrol (101) foram preparados a partir da lactona 77. Os compostos 100 e 101 foram obtidos do intermediário-chave 82, que foi preparado a partir da adição de alilamina à lactona 77, derivada do ácido isoascórbico. Em seguida a hidroxiamida 82 foi oxidada à hidroxilactama correspondente, que foi submetida à reação de acetilação fornecendo o composto 91. Reação de alilação de 91, seguido de metátese de olefinas forneceu a indolizidinona 99. Reação de hidrogenação/hidroxilação de 99, redução da lactama e desproteção do acetal levou ao diol 100 e ao tetrol 101 em rendimentos de 27 e 31 %, respectivamente, a partir da lactona 77
Abstract: The aim of the present work was the synthesis of pyrrolizidine and indolizidine alkaloids using (+)-retronecine (1) and D-isoascorbic acid (35D) as starting materials, respectively. Retronecine (1) was isolated from the vegetal species Senecio brasiliensis. The synthesis of the necine base (1R,6S,7S,7aR)-7-(hydroxymethyl)-hexahydro-1H-pirrolizine-1,6-diol (37) was accomplished by the m-chloroperbenzoic acid epoxidation of retronecine (1). After hydroxyl protection with tert-butyldimethylsilyl chloride, epoxide 44 was subjected to ring opening with nickel Raney and deprotection to yield triol 37, in 5 steps and 15 % yield. Compounds (1R,7S,8R)-7-(hydroxymethyl)-hexahydro-1H-pirrolizin-1-ol (39) and platynecine (72) were prepared after stereoselective dihydroxylation and hydrogenation reactions of retronecine (1) in 70 and 86 % yield, respectively. The first approach to the synthesis of indolizidine alkaloids was based on the 2-tert-butyldimethylsilyloxyfuran addition to lactam 90-derived N-acyliminium ion. Due to moderate yield and diastereoselectivity obtained, a second synthetic approach to the synthesis of indolizidines was suggested. Indolizidine alkaloids 100 and 101 were prepared from lactone 77. Compounds 100 and 101 were obtained from key intermediate 82, which was prepared from allylamine addition to isoascorbic acid-derived lactone 77. Following that, hydroxyamide 82 was oxidized to the corresponding hydroxylactam which was subjected to acetylation, yielding compound 91. Allylation of 91 and subsequent ring closing olefin metathesisyielded indolizidinone 99. Hydrogenation/hydroxylation reaction of 99 followed by lactam reduction and deprotection of acetonide provided diol 100 and tetrol 101, in 27 and 31 % yield, respectively, from lactone 77
Doutorado
Quimica Organica
Doutor em Ciências
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Vevers, William F. "Deoxynivalenol : toxicological profile and potential for reducing cereal grain contamination using bacterial additives in fermented animal feed." Thesis, University of Plymouth, 2015. http://hdl.handle.net/10026.1/4305.
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Deoxynivalenol (DON) contamination of grain destined for animal feeds is a major toxicological risk to monogastrics and is suspected of restricting productivity in ruminants. Whereas bacterial additives have been developed that can detoxify DON in the rumen and lower intestine, there are currently no commercial inoculants able to perform this task in crimped grain (CG) silage, a regionally important method of moist grain preservation based on homo- and heterofermentative lactic acid bacteria or chemical additives. Determining whether this ensiling process alongside the action of detoxifying bacteria has the potential to remove DON in CG prior to ingestion, was explored in mini-silo ensiling experiments. CG was heat treated (100 °C, 60 min) or ensiled fresh in triplicate 50 g silos, spiked with 5 mg/kg DON and inoculated with lactic acid bacteria derived from wild birds, natural epiphytic inoculants and commercially sourced silage additives (21 d). DON recovery was only significantly reduced (31.2 ± 14.4% recovery, p < 0.001, n= 30) by heat treatment, as determined by IAC-RP-HPLC-UV. Bacterial assemblage analysis by 16S rRNA PCR-DGGE-SEQ identified Weissella cibaria, Pantoea agglomerans, Bacillus subtilis, B. licheniformis and Hafnia alvei as candidate detoxification agents, of which W. cibaria and H. alvei decreased DON recovery in vitro (11.3 and 6.2% recovery respectively, p < 0.05, n = 18), which translated to inoculated W. cibaria yielding a decrease in DON recovery (67.2± 14.4%, 28 d) in naturally contaminated crimped wheat (13.5 ± 1.0 mg/kg, 35-40% moisture, p < 0.05, n =15). As W. cibaria is a lactic acid bacteria already associated with fermented CG by default it has promise as a novel DON detoxification agent in CG silage. DON is however just one of many hepatotoxic co-contaminants. Retrorsine, a DNA-crosslinking pyrrolizidine alkaloid derived from Ragwort (Senecio sp.) was investigated for interactive toxicity with DON in an in vitro co-exposure experiment. HepG2 cells were exposed to Log10 multifactorial binary exposures for 48 h followed by a suite of assays to elucidate mechanisms of interactive cytotoxicity, genotoxicity and modulation of the proteome. Retrorsine was tentatively confirmed to form DNA/protein crosslinks in the comet, micronucleus and crosslinking assays, whilst DON was found to potently induce cytotoxicity and apoptosis. Co-exposure yielded a complex toxicity response, with low doses yielding antagonistic effects and high doses trending towards additive effects, although DON dose was generally the principle component. The difficulties associated with undertaking an interactive toxicity study where both toxins have multiple metabolic and cellular targets are highlighted.
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Ryan, Edward Thomas. "The determination of the partition coefficients for a variety of pyrrolizidine alkaloids and the relationship of these values to the anti-tumor activity of the alkaloids." Thesis, Georgia Institute of Technology, 1988. http://hdl.handle.net/1853/27574.
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Pereira, Elaine. "Adição de enolatos de titanio derivados de N-acil-(4S)-4-isopropil-1,3-tiazolidin-2-tiona a ions N-aciliminios ciclicos : sintese assimetrica dos alcaloides (+)-isoretronecanol e (+)-5-epi-tashiromina." [s.n.], 2005. http://repositorio.unicamp.br/jspui/handle/REPOSIP/249250.
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Orientador: Ronaldo Aloise PilliDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica
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Mestrado
Quimica Organica
Mestre em Química
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Elias, Fabiana. "Avaliação imunotóxica e de imunoteratologia de Senecio brasiliensis: estudo em ratos." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/10/10133/tde-26092012-111803/.
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O presente estudo visou avaliar os possiveis efeitos imunotóxicos e imunoteratogênicos da integerrimina N-óxido presente no resíduo butanólico (RB) do ,Senecio brasiliensis, uma planta hepatotóxica que contém alcalóides pirrolizidínicos (APs). Tem sido relatado o uso de APs como fitoterápicos em todo o mundo e também como contaminantes de pastagens e alimentos, sendo assim responsáveis por intoxicações em animais de produção e humanos; porém, até o momento, não há relatos de sua ação sobre o sistema imune. Assim, após a extração da planta, quantificou-se no RB de Senecio brasiliensis, por meio de análise elementar e de espectro (1H e 13C), cerca de 70% de integerrimina N-óxido. O RB foi administrado a ratos Wistar machos adultos, nas doses de 3, 6 e 9 mg/kg, por gavagem, durante 28 dias. Foram avaliados o ganho de peso, o consumo de alimento, os órgãos linfóides e a fenotipagem de sua células, a atividade de fagócitos, as respostas imunes humoral e celular e atividade proliferativa de linfócitos. Já ratas gestantes, receberam as mesmas doses do RB do 6º ao 20º dia de gestação. No final da gestação, parte das fêmeas foi destinada à cesariana e as restantes prosseguiram à termo até o nascimento, para a análise das proles aos 60 dias de idade. Os fetos provenientes da cesariana foram avaliados quanto ao tamanho, peso, viabilidade e malformações externas e também submetidos à análise óssea. As mães tiveram seu desempenho reprodutivo avaliado. Naquelas proles avaliadas até 60 dias de idade, procedeu-se a avaliação dos órgãos linfóides e dos parâmetros hematológicos. O presente estudo revelou que integerrimina N-óxido promoveu diminuição no ganho de peso corporal de ratos machos adultos, redução na atividade proliferativa das células T e interfência na contagem de células sanguíneas destes animais. Por outro lado, esses mesmos animais não apresentaram diferenças na atividade de fagócitos, na fenotipagem de linfócitos e nas respostas imunes estudadas. Em ratas gestantes, o RB causou hepatotoxidade, diminuição do ganho de peso materno, diminuição no tamanho das placentas. A análise fetal revelou menor ossificação. Quando da avaliação da prole aos 60 dias de idade, não foram observados efeitos no ganho de peso atribuídos ao RB, nos órgãos linfóides, e também parâmetros hematológicos e bioquímicos. Concluindo, os estudos aqui realizados permitem sugerir que as doses baixas de integerrimina N-óxido ora empregadas, não promovem efeitos imunotóxicos significantes, bem como não apresentaram potencial teratogênico, seja por meio das avaliações clássicas de teratologia quanto naqueles protocolos de imunoteratogenicidade.The aim of this study was to evaluate the possible immunotoxic and immunoteratogenic effects of integerrimine N-oxide content in the butanolic residue (BR) of Senecio brasiliensis, a hepatotoxic plant that contained pyrrolizidine alkaloids (PAs). PAs have been reported as a pasture and food contaminant and as herbal medicine used worldwide and are related to promote poisoning events in livestock and human beings. After the plant extraction, BR residue from Senecio brasiliensis was submitted to elemental and spectral analyses (1H and 13C ) and was found to contain approximately 70% of integerrimine N-oxide by, which was administered to adult male Wistar rats at doses of 3, 6 and 9 mg/kg for 28 days, by gavage. Body weight gain, food consumption, lymphoid organs and their cell phenotype, phagocyte analysis, humoural and cellular immune responses, and lymphocyte proliferation were evaluated. In addition, pregnant rats received the same doses of BR from the 6th to the 20th gestational day. In late pregnancy, some of the dams were destined for cesarean section and the other females followed the pregnancy until the birth for offspring analysis at 60 days old. Fetuses from cesarean section were evaluated for size, weight, viability and external malformations and also subjected to bone analysis. The reproductive performance of females were performed. The present study showed that integerrimine N-oxide could promote in adult male Wistar rats, body weight gain impairment, interference with blood cell counts and a reducing T cell proliferative; however, no differences in phagocyte activities, lymphocytes phenotyping and immune responses here evaluated were observed. In pregnant rats, BR caused hepatotoxicity, decreased body weight gain and reduced placental size. Fetus analysis showed lower ossification. When 60-days old offspring were it was not observed any toxic effects resulted from BR exposition in body weight gain, lymphoid organs, haematological and biochemical parameters of these rats. It is concluded that low doses of integerrimine N-oxide here employed did not produce marked immunotoxic effects and seems to be a teratogenic signs by both methods, the classical evaluations or by immunoteratological protocols.
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Parizotto, Leíse Herrmann. "Intoxicação experimental por senecio oleosus em frangos de corte." Universidade do Estado de Santa Catarina, 2015. http://tede.udesc.br/handle/handle/931.
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Previous issue date: 2015-02-20Conselho Nacional de Desenvolvimento Científico e Tecnológico
Senecio oleosus is a plant of Astereacea family found in the South and Southeast of Brazil. Species of this genus are recognized to produce liver damage in different animal species, including in human. This study aimed to evaluate the toxicity of S. oleosus in poultry (Gallus gallus domesticus). Green leaves of S. oleosus were collected in the city of Ponte Alta/SC, dried in the shadow, crushed, mixed with feed and fed to four groups of 10 broilers. Group 1 and Group 2 received single doses of 5g/kg and 20g/kg, respectively. Group 3 were given daily doses of 1g/kg for 20 days (amounts corresponding to green plant) and Group 4 (Control) received feed free of S. oleosus. Five broilers from each group were necropsied 30 days after the beginning of the experiment and the five remaining broilers were necropsied 60 days after the start of supply with the plant. Group 1 showed no gross and microscopic changes. In Groups 2 and 3 were observed yellowish color and increase in the volume of the liver, ascites and, microscopically, there was hepatotocyte vacuolation and megalocytosis, fibrosis and biliary epithelium hyperplasia
Senecio oleosus é uma planta da Família Asteraceae encontrada nas regiões Sul e Sudeste do Brasil. Plantas desse gênero são conhecidas por produzirem lesões hepáticas em diferentes espécies de animais, inclusive no homem. Para avaliar a toxicidade do S. oleosus foram conduzidos experimentos em aves (Gallus gallus domesticus). Folhas verdes de S. oleosus foram coletadas no município de Ponte Alta/SC, secadas a sombra, trituradas, misturadas a ração e fornecidas para quatro grupos de 10 frangos de corte. O Grupo 1 e o Grupo 2 receberam doses únicas de 5g/kg e 20g/kg, respectivamente. Ao Grupo 3 foram fornecidas doses diárias de 1g/kg por 20 dias (valores correspondentes a planta verde) e o Grupo Controle recebeu ração livre de S. oleosus. Cincos frangos de cada grupo foram submetidos à necropsia aos 30 dias do início do experimento e os cinco restantes foram submetidos a necropsia aos 60 dias após o início do fornecimento da planta. As aves do Grupo 1 não apresentaram alterações macro e microscópicas. Na necropsia das aves dos Grupos 2 e 3 foi encontrado principalmente aumento de volume e coloração amarela do fígado e ascite. À microscopia foi observado megalocitose, vacuolização de hepatócitos, fibrose e hiperplasia de epitélio biliar
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Kaltner, Florian [Verfasser], Michael [Akademischer Betreuer] Rychlik, Karl-Heinz [Gutachter] Engel, and Michael [Gutachter] Rychlik. "Investigations on Behaviour, Occurrence and Risk Assessment of Toxic Pyrrolizidine Alkaloids in Various Food and Feed Matrices / Florian Kaltner ; Gutachter: Karl-Heinz Engel, Michael Rychlik ; Betreuer: Michael Rychlik." München : Universitätsbibliothek der TU München, 2020. http://d-nb.info/1213447704/34.
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