Glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreator
Main Author: | |
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Publication Date: | 2019 |
Format: | Master thesis |
Language: | por |
Source: | Repositório Institucional da UFG |
Download full: | http://repositorio.bc.ufg.br/tede/handle/tede/10888 |
Summary: | Introduction: Hesperetina is a flavonoid, belongs to flavanones class, with several pharmacological activities, the most cited being the antioxidant potential. However, it presents low solubility and consequently low bioavailability, making it difficult to apply it in a systemic pharmaceutical formulation. Glycosylation of hesperetin effectively modifies its pharmacokinetic properties, increasing its antidiabetic, antitilipidemic activity and efficacy against helicobacter pylori. Filamentous fungi are used in biotechnological processes to increase the activity of molecules, being able to glycosylate, regio and stereoselective derivatives, with less cytotoxicity. Cunninghamella belongs to the class of filamentous fungi capable of catalyzing glycosylation reactions. With the demand of scale-up the production of bioactive compounds, bioreactors are a promising strategy, providing a controlled environment. Aim: The objective of this work was to scale-up the regioselective glycosylation of hesperetin catalyzed by Cunninghamella echinulata 9244 in a bioreactor, with pharmacological activities improved. Methods: Hesperetin was incubated with the microorganism in PDSM medium on two scales, semi-preparative (100 mL) and preparative (2 L). HPLC-MS was used to monitoring and the caracterization of the product formed was confirmed by 1H13C NMR. Tests of anticancer and cytotoxicity were realized. Results and Discussion: The glycosylation yield in the semi-preparative scale was 0.8%, while in the preparative scale the result was 22.9%. The increase in yield can be explained by the automated control of the main parameters such as pH and oxygenation. The ideal time for biosynthesis of the glycosylated derivative in bioreactor was 72 hours. The purified product glycosylated was identified by NMR in hesperetin 7-O-β-D-glucopyranoside, not exhibiting anticancer activity, but with reduction of cytotoxicity, with IC 50 9.5 times lower than the starting compound. Conclusions: Regioselective glycosylation of hespertin was performed in a single step in bioreactor, significantly increasing the yield. The chromatographic procedure proposed by the HPLC-MS allowed a fast and efficient identification and characterization of the derivative. |
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Oliveira, Valéria dehttp://lattes.cnpq.br/6300240031300604Oliveira, Valéria deArruda, Evilanna LimaBara, Maria Teresa FreitasSantiago, Mariângela Fonteshttp://lattes.cnpq.br/5538102689548279Carvalho, Pedro Henrique de Oliveira2020-10-26T13:20:46Z2020-10-26T13:20:46Z2019-03-19CARVALHO, P. H. O. Glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreator. 2019. 81 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal de Goiás, Goiânia, 2019.http://repositorio.bc.ufg.br/tede/handle/tede/10888Introduction: Hesperetina is a flavonoid, belongs to flavanones class, with several pharmacological activities, the most cited being the antioxidant potential. However, it presents low solubility and consequently low bioavailability, making it difficult to apply it in a systemic pharmaceutical formulation. Glycosylation of hesperetin effectively modifies its pharmacokinetic properties, increasing its antidiabetic, antitilipidemic activity and efficacy against helicobacter pylori. Filamentous fungi are used in biotechnological processes to increase the activity of molecules, being able to glycosylate, regio and stereoselective derivatives, with less cytotoxicity. Cunninghamella belongs to the class of filamentous fungi capable of catalyzing glycosylation reactions. With the demand of scale-up the production of bioactive compounds, bioreactors are a promising strategy, providing a controlled environment. Aim: The objective of this work was to scale-up the regioselective glycosylation of hesperetin catalyzed by Cunninghamella echinulata 9244 in a bioreactor, with pharmacological activities improved. Methods: Hesperetin was incubated with the microorganism in PDSM medium on two scales, semi-preparative (100 mL) and preparative (2 L). HPLC-MS was used to monitoring and the caracterization of the product formed was confirmed by 1H13C NMR. Tests of anticancer and cytotoxicity were realized. Results and Discussion: The glycosylation yield in the semi-preparative scale was 0.8%, while in the preparative scale the result was 22.9%. The increase in yield can be explained by the automated control of the main parameters such as pH and oxygenation. The ideal time for biosynthesis of the glycosylated derivative in bioreactor was 72 hours. The purified product glycosylated was identified by NMR in hesperetin 7-O-β-D-glucopyranoside, not exhibiting anticancer activity, but with reduction of cytotoxicity, with IC 50 9.5 times lower than the starting compound. Conclusions: Regioselective glycosylation of hespertin was performed in a single step in bioreactor, significantly increasing the yield. The chromatographic procedure proposed by the HPLC-MS allowed a fast and efficient identification and characterization of the derivative.Introdução: A Hesperetina é um flavonoide da classe das flavanonas, apresenta diversas atividades farmacológicas, sendo a mais citada o potencial antioxidante. Porém, apresenta baixa solubilidade e consequentemente baixa biodisponibilidade, dificultando sua aplicação em formulação farmacêutica sistêmica. A glicosilação da hesperetina modifica efetivamente suas propriedades farmacocinéticas, aumentando sua atividade antidiabética, antilipidêmica e eficácia contra Helicobacter pylori. Fungos filamentosos são usados em processos biotecnológicos para alterar propriedades de moléculas pouco ativas, como exemplo a produção de derivados glicosilados de forma régio e estereosseletivo e com menor citotoxicidade. Cunninghamella pertence à classe dos fungos filamentosos capazes de catalisar reações de glicosilação. Com a necessidade de escalonamento na produção de compostos bioativos, os biorreatores são uma estratégia promissora. Objetivo: O objetivo do trabalho foi realizar a glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata 9244, em biorreator, tendo em vista suas melhores atividades farmacológicas. Metodologia: A hesperetina foi incubada com o microrganismo em meio PDSM em duas escalas, semi-preparativa (100 mL) e preparativa (2 L). O monitoramento da reação foi realizado por CLAE-EMAR e a caracterização do composto obtido por RMN 1H13C. Foram realizados testes de potencial atividade antitumoral e citotoxicidade. Resultados e discussão: O rendimento da glicosilação na escala semi-preparativa foi de 0,8% enquanto que na escala preparativa o rendimento foi de 22,9%. O aumento do rendimento pode ser explicado pelo controle automatizado dos principais parâmetros como pH e oxigenação do meio reacional. O tempo ideal de biossíntese do derivado glicosilado no biorreator foi de 72 horas. O composto glicosilado purificado foi identificado por RMN em hesperetina 7-O-β-D-glicopiranosídeo com acentuada redução de citotoxicidade, apresentando IC50 9,5 vezes menor que o composto de partida. Conclusões: Foi possível realizar a glicosilação regiosseletiva da hespertina em uma única etapa em biorreator, aumentando o rendimento. O ensaio cromatográfico proposto por CLAE-EMAR permitiu a rápida e eficiente identificação e caracterização dos derivados.Submitted by Franciele Moreira (francielemoreyra@gmail.com) on 2020-10-26T13:11:05Z No. of bitstreams: 2 license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5) Dissertação - Pedro Henrique de Oliveira Carvalho - 2020.pdf: 2500506 bytes, checksum: e89f228b6af2c5e127ff75666e430a28 (MD5)Rejected by Franciele Moreira (francielemoreyra@gmail.com), reason: on 2020-10-26T13:12:19Z (GMT)Submitted by Franciele Moreira (francielemoreyra@gmail.com) on 2020-10-26T13:13:48Z No. of bitstreams: 2 license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5) Dissertação - Pedro Henrique de Oliveira Carvalho - 2019.pdf: 2500506 bytes, checksum: e89f228b6af2c5e127ff75666e430a28 (MD5)Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2020-10-26T13:20:46Z (GMT) No. of bitstreams: 2 license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5) Dissertação - Pedro Henrique de Oliveira Carvalho - 2019.pdf: 2500506 bytes, checksum: e89f228b6af2c5e127ff75666e430a28 (MD5)Made available in DSpace on 2020-10-26T13:20:46Z (GMT). No. of bitstreams: 2 license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5) Dissertação - Pedro Henrique de Oliveira Carvalho - 2019.pdf: 2500506 bytes, checksum: e89f228b6af2c5e127ff75666e430a28 (MD5) Previous issue date: 2019-03-19Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de GoiásPrograma de Pós-graduação em Ciências Farmacêuticas (FF)UFGBrasilFaculdade de Farmácia - FF (RG)Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessBiotransformaçãoHesperetina 7-O-β-D- glicopiranosídeoCitotoxicidadeCunninghamellaBiotransformationHesperetinGlycosylationBioreactorCIENCIAS DA SAUDE::FARMACIA::ANALISE E CONTROLE E MEDICAMENTOSGlicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreatorRegiosselective glycosilation of hesperetin catalelized by Cunninghamella echinulata ATCC 9244, in bioreactorinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesis26500500500500225121reponame:Repositório Institucional da UFGinstname:Universidade Federal de Goiás (UFG)instacron:UFGLICENSElicense.txtlicense.txttext/plain; charset=utf-81748http://repositorio.bc.ufg.br/tede/bitstreams/d99f6f1f-66d0-446b-ae0d-dcf305f8eefc/download8a4605be74aa9ea9d79846c1fba20a33MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8805http://repositorio.bc.ufg.br/tede/bitstreams/8fff752e-5e51-4916-b4e9-023fcbadb137/download4460e5956bc1d1639be9ae6146a50347MD52ORIGINALDissertação - Pedro Henrique de Oliveira Carvalho - 2019.pdfDissertação - Pedro Henrique de Oliveira Carvalho - 2019.pdfapplication/pdf2500506http://repositorio.bc.ufg.br/tede/bitstreams/95c70bc1-9ee2-4b9e-a1dd-4646f4014e42/downloade89f228b6af2c5e127ff75666e430a28MD53tede/108882020-10-26 10:22:01.996http://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 Internationalopen.accessoai:repositorio.bc.ufg.br:tede/10888http://repositorio.bc.ufg.br/tedeRepositório InstitucionalPUBhttp://repositorio.bc.ufg.br/oai/requesttasesdissertacoes.bc@ufg.bropendoar:2020-10-26T13:22:01Repositório Institucional da UFG - Universidade Federal de Goiás (UFG)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 |
dc.title.pt_BR.fl_str_mv |
Glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreator |
dc.title.alternative.eng.fl_str_mv |
Regiosselective glycosilation of hesperetin catalelized by Cunninghamella echinulata ATCC 9244, in bioreactor |
title |
Glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreator |
spellingShingle |
Glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreator Carvalho, Pedro Henrique de Oliveira Biotransformação Hesperetina 7-O-β-D- glicopiranosídeo Citotoxicidade Cunninghamella Biotransformation Hesperetin Glycosylation Bioreactor CIENCIAS DA SAUDE::FARMACIA::ANALISE E CONTROLE E MEDICAMENTOS |
title_short |
Glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreator |
title_full |
Glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreator |
title_fullStr |
Glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreator |
title_full_unstemmed |
Glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreator |
title_sort |
Glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreator |
author |
Carvalho, Pedro Henrique de Oliveira |
author_facet |
Carvalho, Pedro Henrique de Oliveira |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Oliveira, Valéria de |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/6300240031300604 |
dc.contributor.referee1.fl_str_mv |
Oliveira, Valéria de |
dc.contributor.referee2.fl_str_mv |
Arruda, Evilanna Lima |
dc.contributor.referee3.fl_str_mv |
Bara, Maria Teresa Freitas |
dc.contributor.referee4.fl_str_mv |
Santiago, Mariângela Fontes |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/5538102689548279 |
dc.contributor.author.fl_str_mv |
Carvalho, Pedro Henrique de Oliveira |
contributor_str_mv |
Oliveira, Valéria de Oliveira, Valéria de Arruda, Evilanna Lima Bara, Maria Teresa Freitas Santiago, Mariângela Fontes |
dc.subject.por.fl_str_mv |
Biotransformação Hesperetina 7-O-β-D- glicopiranosídeo Citotoxicidade Cunninghamella |
topic |
Biotransformação Hesperetina 7-O-β-D- glicopiranosídeo Citotoxicidade Cunninghamella Biotransformation Hesperetin Glycosylation Bioreactor CIENCIAS DA SAUDE::FARMACIA::ANALISE E CONTROLE E MEDICAMENTOS |
dc.subject.eng.fl_str_mv |
Biotransformation Hesperetin Glycosylation Bioreactor |
dc.subject.cnpq.fl_str_mv |
CIENCIAS DA SAUDE::FARMACIA::ANALISE E CONTROLE E MEDICAMENTOS |
description |
Introduction: Hesperetina is a flavonoid, belongs to flavanones class, with several pharmacological activities, the most cited being the antioxidant potential. However, it presents low solubility and consequently low bioavailability, making it difficult to apply it in a systemic pharmaceutical formulation. Glycosylation of hesperetin effectively modifies its pharmacokinetic properties, increasing its antidiabetic, antitilipidemic activity and efficacy against helicobacter pylori. Filamentous fungi are used in biotechnological processes to increase the activity of molecules, being able to glycosylate, regio and stereoselective derivatives, with less cytotoxicity. Cunninghamella belongs to the class of filamentous fungi capable of catalyzing glycosylation reactions. With the demand of scale-up the production of bioactive compounds, bioreactors are a promising strategy, providing a controlled environment. Aim: The objective of this work was to scale-up the regioselective glycosylation of hesperetin catalyzed by Cunninghamella echinulata 9244 in a bioreactor, with pharmacological activities improved. Methods: Hesperetin was incubated with the microorganism in PDSM medium on two scales, semi-preparative (100 mL) and preparative (2 L). HPLC-MS was used to monitoring and the caracterization of the product formed was confirmed by 1H13C NMR. Tests of anticancer and cytotoxicity were realized. Results and Discussion: The glycosylation yield in the semi-preparative scale was 0.8%, while in the preparative scale the result was 22.9%. The increase in yield can be explained by the automated control of the main parameters such as pH and oxygenation. The ideal time for biosynthesis of the glycosylated derivative in bioreactor was 72 hours. The purified product glycosylated was identified by NMR in hesperetin 7-O-β-D-glucopyranoside, not exhibiting anticancer activity, but with reduction of cytotoxicity, with IC 50 9.5 times lower than the starting compound. Conclusions: Regioselective glycosylation of hespertin was performed in a single step in bioreactor, significantly increasing the yield. The chromatographic procedure proposed by the HPLC-MS allowed a fast and efficient identification and characterization of the derivative. |
publishDate |
2019 |
dc.date.issued.fl_str_mv |
2019-03-19 |
dc.date.accessioned.fl_str_mv |
2020-10-26T13:20:46Z |
dc.date.available.fl_str_mv |
2020-10-26T13:20:46Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
CARVALHO, P. H. O. Glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreator. 2019. 81 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal de Goiás, Goiânia, 2019. |
dc.identifier.uri.fl_str_mv |
http://repositorio.bc.ufg.br/tede/handle/tede/10888 |
identifier_str_mv |
CARVALHO, P. H. O. Glicosilação regiosseletiva da hesperetina catalisada por Cunninghamella echinulata ATCC 9244, em biorreator. 2019. 81 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal de Goiás, Goiânia, 2019. |
url |
http://repositorio.bc.ufg.br/tede/handle/tede/10888 |
dc.language.iso.fl_str_mv |
por |
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por |
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26 |
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500 500 500 500 |
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22 |
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512 |
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1 |
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Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Goiás |
dc.publisher.program.fl_str_mv |
Programa de Pós-graduação em Ciências Farmacêuticas (FF) |
dc.publisher.initials.fl_str_mv |
UFG |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Faculdade de Farmácia - FF (RG) |
publisher.none.fl_str_mv |
Universidade Federal de Goiás |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFG instname:Universidade Federal de Goiás (UFG) instacron:UFG |
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