| spelling |
Rosemeire Brondi Alveshttp://lattes.cnpq.br/8833561166396452Rossimiriam Pereira de FreitasLaurent Frédéric GilAdriana Akemi OkumaAmanda Silva de MirandaÂngelo de Fátimahttp://lattes.cnpq.br/3789064721575170Gabriele de Azevedo Cardoso2024-01-08T17:52:55Z2024-01-08T17:52:55Z2023-11-01http://hdl.handle.net/1843/62480https://orcid.org/0000-0002-3193-5293Os compostos canabinoides correspondem a um grupo de substâncias, naturais ou sintéticas, capazes de interagir com os receptores endógenos do tipo 1 (CB1) e do tipo 2 (CB2) e desencadear uma resposta. As estruturas químicas desses compostos são bastante diversas, podendo ser derivados do dibenzopirano, indólicos e ésteres. O presente trabalho teve como objetivo explorar o potencial terapêutico dos compostos canabinoides para tratamento de câncer de mama. Nesse sentido foram sintetizados 22 novos derivados de canabinoides indólicos e núcleos 1,2,3-triazólicos, com rendimentos superiores a 69%. Para isso foi empregada a cicloadição 1,3-dipolar entre alcinos terminais ligados a um núcleo canabinomimético e azidas orgânicas. Esses compostos foram avaliados in vitro quanto à sua atividade antiproliferativa frente a células tumorais mamárias das linhagens MCF7 e MDA-MB-231, e frente à linhagem de células epiteliais de mama MCF10A, para avaliação da seletividade. Os compostos foram divididos em dois grupos principais, tendo o núcleo estrutural canabinomimético comum 1-alquil-3-(1-naftoil)indol ou 3-indoil-1-naftilmetanos. Dentro de cada grupo variaram-se as substituições do anel 1,2,3-triazólico na posição N-1 em: grupos benzílicos p-substituídos com grupos doadores e retiradores de densidade eletrônica, e grupo propila. 12 compostos apresentaram atividade citotóxica (IC50<100 M). O derivado 69j foi o composto mais ativo com IC50 de 2,8 μM e 4,4 μM contra as linhagens de células MCF7 e MDA-MB-231, respectivamente, e exibindo citotoxicidade 3 vezes menor em relação à linhagem celular MCF10A. O melhor resultado, que combinou atividade citotóxica e seletividade, foi observado para o derivado 69a, que apresentou alta citotoxicidade contra linhagens de células tumorais (MCF7-IC50 = 8,3±0,4 μM; MDA-MB-231-IC50 = 7,1±0,1 μM) e foi inativo frente à linhagem celular não tumoral (MCF10A) testada. Os derivados 69a e 69j foram avaliados em ensaios in sílico quanto às suas propriedades farmacocinéticas com o programa SwissADME. Os resultados mostraram que esses compostos apresentam boas propriedades segundo os parâmetros ADME previstos. Com isso, esses podem ser considerados promissores para o desenvolvimento de agentes antitumorais.Cannabinoid compounds correspond to a group of substances, natural or synthetic, capable of interacting with type 1 (CB1) and type 2 (CB2) endogenous receptors and triggering a response. The chemical structures of these compounds are quite diverse and can be derived from dibenzopyran, indoles and esters. The present work aimed to explore the therapeutic potential of cannabinoid compounds for the treatment of breast cancer. In this sense, twenty-two new derivatives of indole cannabinoids and 1,2,3-triazole ring were synthesized, with yields greater than 69%. For this purpose, 1,3-dipolar cycloaddition was used between terminal alkynes linked to a cannabinomimetic nucleus and organic azides. These compounds were evaluated in vitro for their antiproliferative activity against mammary tumor cells of the MCF7 and MDA-MB-231, and against the MCF10A breast epithelial cell, to evaluate selectivity. The compounds were divided into two main groups, with the common cannabinomimetic structural core being 1-alkyl-3-(1-naphthoyl)indole or 3-indoyl-1-naphthylmethanes. Within each group, the substitutions of the 1,2,3-triazole ring in the N-1 position were varied in psubstituted benzyl groups with different electronic properties, and propyl group. Twelve compounds showed cytotoxic activity (IC50<100 M). Derivative 69j was the most active compound with IC50 of 2.8 μM and 4.4 μM against the MCF7 and MDA-MB-231 cell lines, respectively, and exhibited 3-fold lower cytotoxicity compared to the MCF10A cell line. The best result, which combined cytotoxic activity and selectivity, was observed for derivative 69a, which showed high cytotoxicity against tumor cell lines (MCF7-IC50 = 8.3±0.4 μM; MDA-MB-231-IC50 = 7.1±0.1 μM) and was not active against the non-tumor cell MCF10A. Derivatives 69a and 69j were evaluated in silico for their pharmacokinetic properties with the SwissADME program. The results showed that these compounds present good properties according to the predicted ADME parameters, therefore, they can be considered promising for the development of antitumor agents.CNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas GeraisCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorporUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em QuímicaUFMGBrasilICEX - INSTITUTO DE CIÊNCIAS EXATASQuímica orgânicaMaconhaTriazóisAgentes antineoplásicosMamas – CâncerProdutos naturaisTestes biológicosFarmacocinéticaAlquilaçãoRessonância magnética nuclearCanabinoides indólicos1,2,3-triazóisAtividade citotóxicaCâncer de mamaSíntese e avaliação da atividade citotóxica de derivados triazólicos de canabinoides indólicosinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALTese-GabrieleCardoso2023 (1).pdfTese-GabrieleCardoso2023 (1).pdfapplication/pdf42780375https://repositorio.ufmg.br/bitstream/1843/62480/1/Tese-GabrieleCardoso2023%20%281%29.pdf8f8c708111f1ccaafe22ec5611a80bbcMD51LICENSElicense.txtlicense.txttext/plain; charset=utf-82118https://repositorio.ufmg.br/bitstream/1843/62480/2/license.txtcda590c95a0b51b4d15f60c9642ca272MD521843/624802024-01-08 14:52:56.021oai:repositorio.ufmg.br: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ório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2024-01-08T17:52:56Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
|