Toxicidade e atividade antitumoral do derivado acridínico (E)-1’-{(4-flúorbenzilideno)-amino}-5’oxo-1,5’diidro-10H-espiro[acridina9,2’-pirrol]-4’carbonitrila (AMTAC-07)
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFPB |
Texto Completo: | https://repositorio.ufpb.br/jspui/handle/123456789/19371 |
Resumo: | Cancer is one of the leading causes of death in the world. It is now considered a human tragedy and its prevalence is steadily increasing. By 2018, cancer statistics in the United States predicted more than 1.7 million new cancers and more than 600,000 disease-related deathsAcridine derivatives are DNA intercalators and topoisomerase inhibitors, and thus the synthesis of novel acridine derivatives has been of interest in medicinal chemistry. The compound (E)-1'-{(4- fluorobenzylidene) amino}-5'oxo-1,5'-dihydro-10H-spiro [acridine-9,2'-pyrrole]- 4'carbonitrile (AMTAC-07) is an acridine derivative capable of inhibiting a topoisomerase II. However, despite data related to this mechanism of action, there are no reports in the literature describing the antitumor potential and toxicity profile of AMTAC-07. Thus, the present study aimed to evaluate non-clinical toxicity and antitumor activity in vivo and the possible antitumor mechanisms of action of AMTAC-07 in model of Ehrlich ascites carcinoma (CAE). In the non-clinical acute toxicity assay in mice, the administration of AMTAC-07 (2000 mg/kg), intraperitoneal (ip), did not cause death of the experimental animals, with the mean lethal dose (LD50) estimated to be greater than 5000 mg/kg. The use of the fish embryo toxicity test (FET test) indicated that the mean lethal concentration (LC50) of AMTAC-07 is greater than 36.8 μg/mL. For the evaluation of genotoxicity, the micronucleus test was performed in mice peripheral blood, and it was observed that AMTAC-07 (2000 mg/kg, i.p.) did not induce an increase in the number of micronucleated erythrocytes. In the CAE model, AMTAC-07 (12.5, 25 or 50 mg/kg, ip, seven consecutive days of treatment) was observed to reduce tumor volume and mass, cell viability, and total number of peritoneal tumor cells. It was observed that AMTAC-07 (50 mg/kg) did not induce cell cycle arrest. Microdensity of the vessels in the peritoneum of the animals was determined, being observed reduction of this parameter after treatment with AMTAC-07 (50 mg/kg) indicating antiangiogenic action. It was further observed that AMTAC-07 acts on the modulation of the tumor immune response by inducing increase in IL-1β, TNF-α, CCL2 and IL-4 cytokine levels. The fluorimetric assay using 2 ', 7'-diacetate dichlorofluorescein (DCFH-DA) allowed the observation that AMTAC-07 does not induce changes in the level of oxidative stress in the experimental model used. Regarding to toxicity, after antitumor treatment, it was observed that AMTAC-07 (50 mg/kg) did not induce significant changes in all parameters evaluated (metabolic, biochemical, hematological and histological parameters). The data presented, together, suggest that AMTAC-07 has low non-clinical toxicity and significant antitumor activity via antiangiogenic and immunomodulatory mechanisms. |
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Toxicidade e atividade antitumoral do derivado acridínico (E)-1’-{(4-flúorbenzilideno)-amino}-5’oxo-1,5’diidro-10H-espiro[acridina9,2’-pirrol]-4’carbonitrila (AMTAC-07)Derivados acridínicosCarcinoma ascítico de EhrlichEfeito antiangiogênicoAtividade imunomoduladoraAcridinal derivativesEhrlich's ascitic carcinomaAntiangiogenic effectImmunomodulatory activityCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIACancer is one of the leading causes of death in the world. It is now considered a human tragedy and its prevalence is steadily increasing. By 2018, cancer statistics in the United States predicted more than 1.7 million new cancers and more than 600,000 disease-related deathsAcridine derivatives are DNA intercalators and topoisomerase inhibitors, and thus the synthesis of novel acridine derivatives has been of interest in medicinal chemistry. The compound (E)-1'-{(4- fluorobenzylidene) amino}-5'oxo-1,5'-dihydro-10H-spiro [acridine-9,2'-pyrrole]- 4'carbonitrile (AMTAC-07) is an acridine derivative capable of inhibiting a topoisomerase II. However, despite data related to this mechanism of action, there are no reports in the literature describing the antitumor potential and toxicity profile of AMTAC-07. Thus, the present study aimed to evaluate non-clinical toxicity and antitumor activity in vivo and the possible antitumor mechanisms of action of AMTAC-07 in model of Ehrlich ascites carcinoma (CAE). In the non-clinical acute toxicity assay in mice, the administration of AMTAC-07 (2000 mg/kg), intraperitoneal (ip), did not cause death of the experimental animals, with the mean lethal dose (LD50) estimated to be greater than 5000 mg/kg. The use of the fish embryo toxicity test (FET test) indicated that the mean lethal concentration (LC50) of AMTAC-07 is greater than 36.8 μg/mL. For the evaluation of genotoxicity, the micronucleus test was performed in mice peripheral blood, and it was observed that AMTAC-07 (2000 mg/kg, i.p.) did not induce an increase in the number of micronucleated erythrocytes. In the CAE model, AMTAC-07 (12.5, 25 or 50 mg/kg, ip, seven consecutive days of treatment) was observed to reduce tumor volume and mass, cell viability, and total number of peritoneal tumor cells. It was observed that AMTAC-07 (50 mg/kg) did not induce cell cycle arrest. Microdensity of the vessels in the peritoneum of the animals was determined, being observed reduction of this parameter after treatment with AMTAC-07 (50 mg/kg) indicating antiangiogenic action. It was further observed that AMTAC-07 acts on the modulation of the tumor immune response by inducing increase in IL-1β, TNF-α, CCL2 and IL-4 cytokine levels. The fluorimetric assay using 2 ', 7'-diacetate dichlorofluorescein (DCFH-DA) allowed the observation that AMTAC-07 does not induce changes in the level of oxidative stress in the experimental model used. Regarding to toxicity, after antitumor treatment, it was observed that AMTAC-07 (50 mg/kg) did not induce significant changes in all parameters evaluated (metabolic, biochemical, hematological and histological parameters). The data presented, together, suggest that AMTAC-07 has low non-clinical toxicity and significant antitumor activity via antiangiogenic and immunomodulatory mechanisms.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESO câncer é uma das principais causas de morte no mundo. Atualmente, é considerado como uma tragédia humana e a sua prevalência está crescendo continuamente. Em 2018, as estatísticas do câncer nos Estados Unidos previram mais de 1,7 milhões de novos casos de câncer e mais de 600.000 mortes relacionadas à doença. Os derivados acridínicos são agentes intercaladores de DNA e inibidores de topoisomerase e, desta forma, a síntese de novos derivados acridínicos tem sido de considerável interesse na química medicinal. O composto (E)-1’-{(4-flúorbenzilideno)-amino}-5’oxo-1,5’diidro-10H-espiro[acridina-9,2’-pirrol]- 4’carbonitrila (AMTAC-07) é um derivado acridínico capaz de inibir a topoisomerase II. Todavia, apesar dos dados relacionados a esse mecanismo de ação, não há relatos na literatura que descrevam o potencial antitumoral e o perfil de toxicidade do AMTAC-07. Sendo assim, o presente trabalho objetivou avaliar a toxicidade não clínica e a atividade antitumoral in vivo e os possíveis mecanismos de ação antitumorais de AMTAC-07 em modelo de carcinoma ascítico de Ehrlich (CAE). No ensaio de toxicidade não clínica aguda em camundongos, a administração de AMTAC-07 (2000 mg/kg), via intraperitoneal (i.p.), não induziu morte dos animais experimentais, sendo a dose letal média (DL50) estimada como maior que 5000 mg/kg. O uso do teste de toxicidade em embriões de peixe (teste FET), indicou que a concentração letal média (CL50) do AMTAC-07 é superior a 88 µM. Para a avaliação da genotoxicidade foi realizado o teste do micronúcleo em sangue periférico de camundongos, sendo observado que AMTAC-07 (2000 mg/kg, i.p.) não induziu aumento no número de eritrócitos micronucleados. Em modelo de CAE, observou-se que AMTAC-07 (12,5, 25 ou 50 mg/kg, i.p., sete dias consecutivos de tratamento) reduziu o volume e massa tumorais, a viabilidade celular e a quantidade total de células tumorais peritoneais. Foi observado que o AMTAC-07 (50 mg/kg) não induziu parada do ciclo celular. Foi determinada a microdensidade dos vasos no peritônio dos animais, sendo observada redução deste parâmetro após tratamento com AMTAC-07 (50 mg/kg) indicando ação antiangiogênica. Observou-se ainda que o AMTAC-07 atua na modulação da resposta imune contra o tumor por induzir aumento nos níveis das citocinas IL-1β, TNF-α, CCL2 e IL-4. A realização de ensaio fluorimétrico utilizando o 2’,7’-diacetato diclorofluoresceína (DCFH-DA) permitiu a observação de que o AMTAC-07 não induz alterações no nível de estresse oxidativo, no modelo experimental utilizado. Em relação à toxicidade, após tratamento antitumoral, entre todos os parâmetros avaliados (parâmetros metabólicos, bioquímicos, hematológicos e histológicos), foi observado que AMTAC-07 (50 mg/kg) não induziu alterações significativas. Os dados apresentados, em conjunto, sugerem que AMTAC-07 possui baixa toxicidade não clínica e significativa atividade antitumoral via mecanismos antiangiogênicos e imunomoduladores.Universidade Federal da ParaíbaBrasilFarmacologiaPrograma de Pós-Graduação em Produtos Naturais e Sintéticos BioativosUFPBSobral, Marianna Vieirahttp://lattes.cnpq.br/1036684849301560Batista, Tatianne Mota2021-02-14T23:12:24Z2019-08-142021-02-14T23:12:24Z2019-03-29info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesishttps://repositorio.ufpb.br/jspui/handle/123456789/19371porhttp://creativecommons.org/licenses/by-nd/3.0/br/info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFPBinstname:Universidade Federal da Paraíba (UFPB)instacron:UFPB2021-08-13T20:09:37Zoai:repositorio.ufpb.br:123456789/19371Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2021-08-13T20:09:37Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Toxicidade e atividade antitumoral do derivado acridínico (E)-1’-{(4-flúorbenzilideno)-amino}-5’oxo-1,5’diidro-10H-espiro[acridina9,2’-pirrol]-4’carbonitrila (AMTAC-07) |
title |
Toxicidade e atividade antitumoral do derivado acridínico (E)-1’-{(4-flúorbenzilideno)-amino}-5’oxo-1,5’diidro-10H-espiro[acridina9,2’-pirrol]-4’carbonitrila (AMTAC-07) |
spellingShingle |
Toxicidade e atividade antitumoral do derivado acridínico (E)-1’-{(4-flúorbenzilideno)-amino}-5’oxo-1,5’diidro-10H-espiro[acridina9,2’-pirrol]-4’carbonitrila (AMTAC-07) Batista, Tatianne Mota Derivados acridínicos Carcinoma ascítico de Ehrlich Efeito antiangiogênico Atividade imunomoduladora Acridinal derivatives Ehrlich's ascitic carcinoma Antiangiogenic effect Immunomodulatory activity CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Toxicidade e atividade antitumoral do derivado acridínico (E)-1’-{(4-flúorbenzilideno)-amino}-5’oxo-1,5’diidro-10H-espiro[acridina9,2’-pirrol]-4’carbonitrila (AMTAC-07) |
title_full |
Toxicidade e atividade antitumoral do derivado acridínico (E)-1’-{(4-flúorbenzilideno)-amino}-5’oxo-1,5’diidro-10H-espiro[acridina9,2’-pirrol]-4’carbonitrila (AMTAC-07) |
title_fullStr |
Toxicidade e atividade antitumoral do derivado acridínico (E)-1’-{(4-flúorbenzilideno)-amino}-5’oxo-1,5’diidro-10H-espiro[acridina9,2’-pirrol]-4’carbonitrila (AMTAC-07) |
title_full_unstemmed |
Toxicidade e atividade antitumoral do derivado acridínico (E)-1’-{(4-flúorbenzilideno)-amino}-5’oxo-1,5’diidro-10H-espiro[acridina9,2’-pirrol]-4’carbonitrila (AMTAC-07) |
title_sort |
Toxicidade e atividade antitumoral do derivado acridínico (E)-1’-{(4-flúorbenzilideno)-amino}-5’oxo-1,5’diidro-10H-espiro[acridina9,2’-pirrol]-4’carbonitrila (AMTAC-07) |
author |
Batista, Tatianne Mota |
author_facet |
Batista, Tatianne Mota |
author_role |
author |
dc.contributor.none.fl_str_mv |
Sobral, Marianna Vieira http://lattes.cnpq.br/1036684849301560 |
dc.contributor.author.fl_str_mv |
Batista, Tatianne Mota |
dc.subject.por.fl_str_mv |
Derivados acridínicos Carcinoma ascítico de Ehrlich Efeito antiangiogênico Atividade imunomoduladora Acridinal derivatives Ehrlich's ascitic carcinoma Antiangiogenic effect Immunomodulatory activity CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Derivados acridínicos Carcinoma ascítico de Ehrlich Efeito antiangiogênico Atividade imunomoduladora Acridinal derivatives Ehrlich's ascitic carcinoma Antiangiogenic effect Immunomodulatory activity CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Cancer is one of the leading causes of death in the world. It is now considered a human tragedy and its prevalence is steadily increasing. By 2018, cancer statistics in the United States predicted more than 1.7 million new cancers and more than 600,000 disease-related deathsAcridine derivatives are DNA intercalators and topoisomerase inhibitors, and thus the synthesis of novel acridine derivatives has been of interest in medicinal chemistry. The compound (E)-1'-{(4- fluorobenzylidene) amino}-5'oxo-1,5'-dihydro-10H-spiro [acridine-9,2'-pyrrole]- 4'carbonitrile (AMTAC-07) is an acridine derivative capable of inhibiting a topoisomerase II. However, despite data related to this mechanism of action, there are no reports in the literature describing the antitumor potential and toxicity profile of AMTAC-07. Thus, the present study aimed to evaluate non-clinical toxicity and antitumor activity in vivo and the possible antitumor mechanisms of action of AMTAC-07 in model of Ehrlich ascites carcinoma (CAE). In the non-clinical acute toxicity assay in mice, the administration of AMTAC-07 (2000 mg/kg), intraperitoneal (ip), did not cause death of the experimental animals, with the mean lethal dose (LD50) estimated to be greater than 5000 mg/kg. The use of the fish embryo toxicity test (FET test) indicated that the mean lethal concentration (LC50) of AMTAC-07 is greater than 36.8 μg/mL. For the evaluation of genotoxicity, the micronucleus test was performed in mice peripheral blood, and it was observed that AMTAC-07 (2000 mg/kg, i.p.) did not induce an increase in the number of micronucleated erythrocytes. In the CAE model, AMTAC-07 (12.5, 25 or 50 mg/kg, ip, seven consecutive days of treatment) was observed to reduce tumor volume and mass, cell viability, and total number of peritoneal tumor cells. It was observed that AMTAC-07 (50 mg/kg) did not induce cell cycle arrest. Microdensity of the vessels in the peritoneum of the animals was determined, being observed reduction of this parameter after treatment with AMTAC-07 (50 mg/kg) indicating antiangiogenic action. It was further observed that AMTAC-07 acts on the modulation of the tumor immune response by inducing increase in IL-1β, TNF-α, CCL2 and IL-4 cytokine levels. The fluorimetric assay using 2 ', 7'-diacetate dichlorofluorescein (DCFH-DA) allowed the observation that AMTAC-07 does not induce changes in the level of oxidative stress in the experimental model used. Regarding to toxicity, after antitumor treatment, it was observed that AMTAC-07 (50 mg/kg) did not induce significant changes in all parameters evaluated (metabolic, biochemical, hematological and histological parameters). The data presented, together, suggest that AMTAC-07 has low non-clinical toxicity and significant antitumor activity via antiangiogenic and immunomodulatory mechanisms. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-08-14 2019-03-29 2021-02-14T23:12:24Z 2021-02-14T23:12:24Z |
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 |
https://repositorio.ufpb.br/jspui/handle/123456789/19371 |
url |
https://repositorio.ufpb.br/jspui/handle/123456789/19371 |
dc.language.iso.fl_str_mv |
por |
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por |
dc.rights.driver.fl_str_mv |
http://creativecommons.org/licenses/by-nd/3.0/br/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by-nd/3.0/br/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos UFPB |
publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos UFPB |
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reponame:Biblioteca Digital de Teses e Dissertações da UFPB instname:Universidade Federal da Paraíba (UFPB) instacron:UFPB |
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Universidade Federal da Paraíba (UFPB) |
instacron_str |
UFPB |
institution |
UFPB |
reponame_str |
Biblioteca Digital de Teses e Dissertações da UFPB |
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Biblioteca Digital de Teses e Dissertações da UFPB |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB) |
repository.mail.fl_str_mv |
diretoria@ufpb.br|| diretoria@ufpb.br |
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1801842967498981376 |