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Lucienir Pains Duartehttp://lattes.cnpq.br/8518098370099915Rossimiriam Pereira de FreitasClaudia Moraes de RezendeSérgio Scherrer ThomasiDiogo Montes VidalRosemeire Brondi Alveshttp://lattes.cnpq.br/8519753244373407Rafael Cesar Gonçalves Pereira2021-04-30T18:44:30Z2021-04-30T18:44:30Z2021-02-26http://hdl.handle.net/1843/35877https://orcid.org/0000-0003-1600-7621Cheiloclinium cognatum é uma espécie pertencente à família Celastraceae, típica do cerrado brasileiro, e rica em triterpenos pentacíclicos. Folhas e galhos desta planta foram estudados e levaram à identificação de 17 constituintes, dentre eles dois compostos graxos (triacilglicerol e ácido graxo), um esteroide (β-sitosterol), um éster graxo de triterpeno (3β-aciloxiurs-12-eno), nove triterpenos pentacíclicos, sendo eles seis friedelanos (friedelina, friedelinol, canofilol, 29-hidroxifriedelan-3-ona, friedelano-3β,29-diol e acetato de 3-oxofriedelan-29-ila), um glutinano (glutinol), um ursano (α-amirina) e um oleanano (β-amirina), um flavonoide (epigalocatequina), dois ácidos fenólicos (ácido vanílico e ácido siríngico) e uma xantona (mangiferina). Também foi realizada a síntese, em três etapas, de dez derivados glicosiltriazólicos inéditos partindo-se de uma mistura dos triterpenos 29-hidroxifriedelan-3-ona e friedelano-3β,29-diol. A atividade citotóxica para os produtos naturais obtidos de C. cognatum bem como para os produtos de semissíntese foi avaliada frente a duas linhagens de células tumorais de leucemia, THP-1 e K562, sendo a primeira correspondente à leucemia mieloide aguda e a segunda à leucemia mieloide crônica. Foi observado que todos os produtos naturais avaliados apresentaram moderada a elevada atividade citotóxica quando comparados aos controles positivos, com destaque para os triterpenos friedelinol, α-amirina e acetato de 3-oxofriedelan-29-ila, que apresentaram valores de CI50 iguais ou inferiores e índices de seletividade iguais ou superiores aos controles positivos. Para os produtos de semissíntese, dois intermediários, ácido populnônico e N-propargilpopulnonamida, apresentaram CI50 similares ao controle positivo para a linhagem K562, e o derivado glicosiltriazólico, o populnonato de (1-(2,3,4,6-tetra-O-acetil-1-desoxi-α-L-fucopiranosil)1,2,3-triazol-4-il)metila, apresentou uma moderada atividade frente às duas linhagens testadas. Os triterpenos friedelinol e α-amirina foram estudados quanto aos mecanismos de ação, e os resultados sugeriram que houve a ativação da via mitocondrial intrínseca da apoptose, evidenciada pela regulação positiva da expressão do mRNA da BAK. Estudos quimiométricos indicaram que suas atividades podem estar relacionadas ao tamanho e forma molecular, bem como às interações eletrônicas do grupo hidroxila na posição C-3 dos triterpenos com alvos moleculares específicos.Cheiloclinium cognatum is a Celastraceae species, typical of Brazilian Cerrado, and rich in pentacyclic triterpenes. Leaves and branches of this plant were studied and led to the identification of 17 constituents. Among them, two fatty compounds (triacylglycerol and fatty acid), a steroid (β-sitosterol), a triterpene fatty ester (3β acyloxyurs-12-ene), nine pentacyclic triterpenes, six of which are friedelanes (friedelin, friedelinol, canophyllol, 29-hydroxyfriedelan-3-one, friedelane-3β,29-diol and 3-oxofriedelan-29-yl acetate), a glutinane (glutinol), an ursane (α-amyrin) and an oleanane (β-amyrin), a flavonoid (epigallocatechin), two phenolic acids (vanillic and syringic acids) and a xanthone (mangiferin) were obtained. The synthesis, in three stages, of ten new glycosidic triazole triterpenoids was also carried out, starting from a mixture of 29-hydroxyfriedelan-3-one and friedelane-3β,29-diol. The cytotoxic activity for natural products obtained from C. cognatum as well as for synthetic products was evaluated against two leukemia tumor cell lines, THP-1 and K562. The first corresponds to acute myeloid leukemia cells and the second to chronic myeloid leukemia. All assayed natural products exhibited moderate to high cytotoxic activity when compared to positive controls, with emphasis on friedelinol, α-amyrin and 3-oxofriedelan-29-yl acetate, which presented IC50 equal or lower and selectivity indexes equal or greater than controls. In regard of the synthetic products, two intermediates, populnonic acid and N-propargylpopulnonamide, showed IC50 similar to the positive control for the K562 strain. A glycosidic triazole derivative, (1(2,3,4,6-tetra O-acetyl-1-deoxy-α-L-fucopyranosyl)1,2,3-triazole-4-yl)methyl populnonate, showed moderate activity compared to the controls for the two strains tested. The triterpenes friedelinol and α-amyrin had their mechanisms of action evaluated. The results suggested that the apoptosis was due to the activation of intrinsic mitochondrial pathway, evidenced by the positive regulation of BAK mRNA expression. Chemometric studies indicated that their activities may be related to molecular size and shape, as well as to the electronic interactions of the hydroxyl group at the C-3 position and specific molecular targets.CNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoporUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em QuímicaUFMGBrasilICX - DEPARTAMENTO DE QUÍMICAhttp://creativecommons.org/licenses/by-nc-nd/3.0/pt/info:eu-repo/semantics/openAccessQuímica orgânicaCelastraceaeProdutos naturaisTerpeniosAgentes antineoplásicosLeucemiaCelastraceaeCheiloclinium cognatumTriterpeno pentacíclicoGlicosiltriazolLeucemiaPentacyclic triterpeneGlycosyltriazoleLeukemiaEstudo fitoquímico de folhas e galhos de Cheiloclinium cognatum (Celastraceae) e síntese de derivados glicosiltriazólicos de triterpenos pentacíclicos com potencial citotóxicoPhytochemical study of leaves and branches of Cheiloclinium cognatum (Celastraceae) and synthesis glycosyltriazole derivatives of pentacyclic triterpenes with cytotoxic potentialinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALTese - Rafael Pereira - Final.pdfTese - Rafael Pereira - Final.pdfapplication/pdf11688888https://repositorio.ufmg.br/bitstream/1843/35877/1/Tese%20-%20Rafael%20Pereira%20-%20Final.pdfb0eb4366b627223d8a8d13863fcd39ebMD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8811https://repositorio.ufmg.br/bitstream/1843/35877/2/license_rdfcfd6801dba008cb6adbd9838b81582abMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82119https://repositorio.ufmg.br/bitstream/1843/35877/3/license.txt34badce4be7e31e3adb4575ae96af679MD531843/358772021-04-30 15:44:31.017oai:repositorio.ufmg.br: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Repositório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2021-04-30T18:44:31Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
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