Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-Lapachona

Detalhes bibliográficos
Autor(a) principal: Souza, Antonio Albuquerque de
Data de Publicação: 2011
Tipo de documento: Tese
Idioma: por
Título da fonte: Repositório Institucional da Universidade Federal de Alagoas (UFAL)
Texto Completo: http://www.repositorio.ufal.br/handle/riufal/2305
Resumo: Quinones have been the subject of much interest due to their various biological activities, mainly as antitumor and as trypanocidal agents. Quinones are cytotoxic by two main mechanisms: the generation of ROS resulting in oxidative stress and alkylation of cellular nucleophiles, such as DNA and some enzymes such as topoisomerases. Their activity depends on bioreduction, similarly to what happens to nitroaromatic compounds. They also catalyze electron transfer reactions in biological processes and, after reduction generate radical anions (semiquinone radical anion and nitro), which depending on stability, can furnish their free electrons to acceptor molecules. In the present study, compounds with mixed functionalities derived from nor-β-lapachone, including a nitroaniline group were electrochemically studied in protic (acetate buffer) and aprotic (DMF+TBABF4, DMSO+TBAP and Acetonitrile+TBABF4) media, using glassy carbon and mercury as working electrodes. The compounds showed a complex redox behavior and the mechanism was elucidated using electron spin resonance. The electroreduced products of nor-β-lapachone and of the nitroquinones reacted with oxygen, indicative of the generation of reactive oxygen species, reactivity in the order of 2 > nor-β-lapachone > 3 > 1. We investigated their interaction with DNA, which was shown to be positive for nitroquinones and negative for the precursor nor-β-lapachone, in agreement with biological assays which had also shown that the nitroquinones cause DNA damage. The stability of the nitrosemiquinones, their half-life times were measured using mercury electrode, and the reaction rates for the electrochemical process-following-up-isproportionation reaction were measured. From these studies, a lower stability for the meta-substituted nitrophenylaniline (k2 = 5.188 x 103 L mol-1 s-1 and t1/2 = 0.06 s) was evidenced. Upon spectroelectrochemical reduction studies of the nitroquinones, the generation of radicalar intermediates (semiquinone radical anion and nitro radical anion) was observed, with differences between o- and m-derived compounds and the p-substituted one. To increase the solubility of the nitroquinones, in order to allow in vivo studies, the formation of inclusion complexes with β-cyclodextrin were evaluated. Positive results were obtained, leading to a viable formulation alternative for further biological studies with the compounds.
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spelling Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-LapachonaBioelectrochemistry studies of nitroquinones derivatives of Nor-β-LapachoneBioeletroquímicaSensores de DNANor-β-lapachonaNitroquinonasFarmacoeletroquímicaβ-ciclodextrinaBioelectrochemistryDNA SensorsNor-β-lapachoneNitroquinonesPharmacoelectrochemistryβ-CyclodextrinCNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICAQuinones have been the subject of much interest due to their various biological activities, mainly as antitumor and as trypanocidal agents. Quinones are cytotoxic by two main mechanisms: the generation of ROS resulting in oxidative stress and alkylation of cellular nucleophiles, such as DNA and some enzymes such as topoisomerases. Their activity depends on bioreduction, similarly to what happens to nitroaromatic compounds. They also catalyze electron transfer reactions in biological processes and, after reduction generate radical anions (semiquinone radical anion and nitro), which depending on stability, can furnish their free electrons to acceptor molecules. In the present study, compounds with mixed functionalities derived from nor-β-lapachone, including a nitroaniline group were electrochemically studied in protic (acetate buffer) and aprotic (DMF+TBABF4, DMSO+TBAP and Acetonitrile+TBABF4) media, using glassy carbon and mercury as working electrodes. The compounds showed a complex redox behavior and the mechanism was elucidated using electron spin resonance. The electroreduced products of nor-β-lapachone and of the nitroquinones reacted with oxygen, indicative of the generation of reactive oxygen species, reactivity in the order of 2 > nor-β-lapachone > 3 > 1. We investigated their interaction with DNA, which was shown to be positive for nitroquinones and negative for the precursor nor-β-lapachone, in agreement with biological assays which had also shown that the nitroquinones cause DNA damage. The stability of the nitrosemiquinones, their half-life times were measured using mercury electrode, and the reaction rates for the electrochemical process-following-up-isproportionation reaction were measured. From these studies, a lower stability for the meta-substituted nitrophenylaniline (k2 = 5.188 x 103 L mol-1 s-1 and t1/2 = 0.06 s) was evidenced. Upon spectroelectrochemical reduction studies of the nitroquinones, the generation of radicalar intermediates (semiquinone radical anion and nitro radical anion) was observed, with differences between o- and m-derived compounds and the p-substituted one. To increase the solubility of the nitroquinones, in order to allow in vivo studies, the formation of inclusion complexes with β-cyclodextrin were evaluated. Positive results were obtained, leading to a viable formulation alternative for further biological studies with the compounds.Conselho Nacional de Desenvolvimento Científico e TecnológicoQuinonas despertam muito interesse devido às suas diversas atividades biológicas, principalmente como agentes antitumoral e tripanossomicida. A citotoxicidade de quinonas decorre de dois mecanismos principais: geração de EROs resultando no estresse oxidativo e alquilação de nucleófilos celulares, como o DNA e algumas enzimas, como as topoisomerases. Sua atividade depende de biorredução, similarmente ao que acontece com compostos nitroaromáticos. Eles também catalisam reações de transferência de elétrons biológicas e, após a redução geram ânions radicais (ânions radicais semiquinona e nitro), que dependendo da estabilidade, podem transferir seus elétrons livres a moléculas aceptoras. Neste trabalho, compostos de funcionalidade mista derivados da nor-β-lapachona, com um grupo nitroanilina, foram estudados eletroquimicamente nos meios prótico (tampão acetato) e aprótico (DMF + TBABF4, DMSO + TBAP e acetonitrila + TBABF4), utilizando carbono vítreo e mercúrio como eletrodos de trabalho. Os compostos apresentaram um comportamento redox complexo e o mecanismo elucidado por espectroeletroquímica. Os produtos da eletro-redução da nor-β-lapachona e nitroquinonas reagiram com oxigênio, indicativo da geração de EROs, na ordem de reatividade 2 > nor-β-lapachona > 3 > 1. Foi investigada a interação com DNA, que se mostrou positiva para as nitroquinonas e negativa para o precursor nor-β-lapachona, concordantes com ensaios biológicos que também evidenciou que as nitroquinonas causam dano ao DNA. A estabilidade do nitrosemiquinona, tempos de meia-vida e as taxas reacionais referentes à reação química de desproporcionamento acoplada ao processo eletroquímico para cada derivado foram determinadas usando eletrodo de mercúrio. A partir desses estudos, foi evidenciada a menor estabilidade para o nitrofenilamina meta-substituída (k2 = 15,188 x 103 L mol-1 s-1 and t1/2 = 0,06 s). Nos estudos por espectroeletroquímica das nitroquinonas, observou-se a geração de intermediários radicalares (ânions radicais semiquinona e nitro), com diferenças entre os nitroderivados o- e m-, assim como para o p- derivado. Com objetivo de aumentar a solubilidade das nitroquinonas, para posteriores estudos in vivo, foi avaliada a formação de complexos de inclusão com β-ciclodextrina. Foram obtidos resultados positivos, refletindo em alternativa viável para formulações posteriores com estes compostos e ensaios biológicos.Universidade Federal de AlagoasBrasilPrograma de Pós-Graduação em Química e BiotecnologiaUFALGoulart, Marília Oliveira Fonsecahttp://lattes.cnpq.br/5271094336884473Donnici, Claudio Luishttp://lattes.cnpq.br/7301980773116724Santos, Josué Carinhanha Caldashttp://lattes.cnpq.br/3735618604163061Galdino, Fabiane Caxico de Abreuhttp://lattes.cnpq.br/4203326795155880Meneghetti, Simoni Margareti Plentzhttp://lattes.cnpq.br/0280121582234738Souza, Antonio Albuquerque de2018-01-17T15:56:12Z2018-01-172018-01-17T15:56:12Z2011-08-26info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfSOUSA, Antonio Albuquerque de. Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-Lapachona. 167 f. Tese (Doutorado em Química e Biotecnologia) - Instituto de Química e Biotecnologia, Programa de Pós-Graduação em Química e Biotecnologia, Universidade Federal de Alagoas, Maceió, 2011.http://www.repositorio.ufal.br/handle/riufal/2305porinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da Universidade Federal de Alagoas (UFAL)instname:Universidade Federal de Alagoas (UFAL)instacron:UFAL2018-10-24T20:14:51Zoai:www.repositorio.ufal.br:riufal/2305Repositório InstitucionalPUBhttp://www.repositorio.ufal.br/oai/requestri@sibi.ufal.bropendoar:2018-10-24T20:14:51Repositório Institucional da Universidade Federal de Alagoas (UFAL) - Universidade Federal de Alagoas (UFAL)false
dc.title.none.fl_str_mv Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-Lapachona
Bioelectrochemistry studies of nitroquinones derivatives of Nor-β-Lapachone
title Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-Lapachona
spellingShingle Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-Lapachona
Souza, Antonio Albuquerque de
Bioeletroquímica
Sensores de DNA
Nor-β-lapachona
Nitroquinonas
Farmacoeletroquímica
β-ciclodextrina
Bioelectrochemistry
DNA Sensors
Nor-β-lapachone
Nitroquinones
Pharmacoelectrochemistry
β-Cyclodextrin
CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA
title_short Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-Lapachona
title_full Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-Lapachona
title_fullStr Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-Lapachona
title_full_unstemmed Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-Lapachona
title_sort Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-Lapachona
author Souza, Antonio Albuquerque de
author_facet Souza, Antonio Albuquerque de
author_role author
dc.contributor.none.fl_str_mv Goulart, Marília Oliveira Fonseca
http://lattes.cnpq.br/5271094336884473
Donnici, Claudio Luis
http://lattes.cnpq.br/7301980773116724
Santos, Josué Carinhanha Caldas
http://lattes.cnpq.br/3735618604163061
Galdino, Fabiane Caxico de Abreu
http://lattes.cnpq.br/4203326795155880
Meneghetti, Simoni Margareti Plentz
http://lattes.cnpq.br/0280121582234738
dc.contributor.author.fl_str_mv Souza, Antonio Albuquerque de
dc.subject.por.fl_str_mv Bioeletroquímica
Sensores de DNA
Nor-β-lapachona
Nitroquinonas
Farmacoeletroquímica
β-ciclodextrina
Bioelectrochemistry
DNA Sensors
Nor-β-lapachone
Nitroquinones
Pharmacoelectrochemistry
β-Cyclodextrin
CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA
topic Bioeletroquímica
Sensores de DNA
Nor-β-lapachona
Nitroquinonas
Farmacoeletroquímica
β-ciclodextrina
Bioelectrochemistry
DNA Sensors
Nor-β-lapachone
Nitroquinones
Pharmacoelectrochemistry
β-Cyclodextrin
CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA
description Quinones have been the subject of much interest due to their various biological activities, mainly as antitumor and as trypanocidal agents. Quinones are cytotoxic by two main mechanisms: the generation of ROS resulting in oxidative stress and alkylation of cellular nucleophiles, such as DNA and some enzymes such as topoisomerases. Their activity depends on bioreduction, similarly to what happens to nitroaromatic compounds. They also catalyze electron transfer reactions in biological processes and, after reduction generate radical anions (semiquinone radical anion and nitro), which depending on stability, can furnish their free electrons to acceptor molecules. In the present study, compounds with mixed functionalities derived from nor-β-lapachone, including a nitroaniline group were electrochemically studied in protic (acetate buffer) and aprotic (DMF+TBABF4, DMSO+TBAP and Acetonitrile+TBABF4) media, using glassy carbon and mercury as working electrodes. The compounds showed a complex redox behavior and the mechanism was elucidated using electron spin resonance. The electroreduced products of nor-β-lapachone and of the nitroquinones reacted with oxygen, indicative of the generation of reactive oxygen species, reactivity in the order of 2 > nor-β-lapachone > 3 > 1. We investigated their interaction with DNA, which was shown to be positive for nitroquinones and negative for the precursor nor-β-lapachone, in agreement with biological assays which had also shown that the nitroquinones cause DNA damage. The stability of the nitrosemiquinones, their half-life times were measured using mercury electrode, and the reaction rates for the electrochemical process-following-up-isproportionation reaction were measured. From these studies, a lower stability for the meta-substituted nitrophenylaniline (k2 = 5.188 x 103 L mol-1 s-1 and t1/2 = 0.06 s) was evidenced. Upon spectroelectrochemical reduction studies of the nitroquinones, the generation of radicalar intermediates (semiquinone radical anion and nitro radical anion) was observed, with differences between o- and m-derived compounds and the p-substituted one. To increase the solubility of the nitroquinones, in order to allow in vivo studies, the formation of inclusion complexes with β-cyclodextrin were evaluated. Positive results were obtained, leading to a viable formulation alternative for further biological studies with the compounds.
publishDate 2011
dc.date.none.fl_str_mv 2011-08-26
2018-01-17T15:56:12Z
2018-01-17
2018-01-17T15:56:12Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv SOUSA, Antonio Albuquerque de. Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-Lapachona. 167 f. Tese (Doutorado em Química e Biotecnologia) - Instituto de Química e Biotecnologia, Programa de Pós-Graduação em Química e Biotecnologia, Universidade Federal de Alagoas, Maceió, 2011.
http://www.repositorio.ufal.br/handle/riufal/2305
identifier_str_mv SOUSA, Antonio Albuquerque de. Estudos bioeletroquímicos de nitroquinonas derivadas da Nor-β-Lapachona. 167 f. Tese (Doutorado em Química e Biotecnologia) - Instituto de Química e Biotecnologia, Programa de Pós-Graduação em Química e Biotecnologia, Universidade Federal de Alagoas, Maceió, 2011.
url http://www.repositorio.ufal.br/handle/riufal/2305
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language por
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universidade Federal de Alagoas
Brasil
Programa de Pós-Graduação em Química e Biotecnologia
UFAL
publisher.none.fl_str_mv Universidade Federal de Alagoas
Brasil
Programa de Pós-Graduação em Química e Biotecnologia
UFAL
dc.source.none.fl_str_mv reponame:Repositório Institucional da Universidade Federal de Alagoas (UFAL)
instname:Universidade Federal de Alagoas (UFAL)
instacron:UFAL
instname_str Universidade Federal de Alagoas (UFAL)
instacron_str UFAL
institution UFAL
reponame_str Repositório Institucional da Universidade Federal de Alagoas (UFAL)
collection Repositório Institucional da Universidade Federal de Alagoas (UFAL)
repository.name.fl_str_mv Repositório Institucional da Universidade Federal de Alagoas (UFAL) - Universidade Federal de Alagoas (UFAL)
repository.mail.fl_str_mv ri@sibi.ufal.br
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