Síntese e avaliação da atividade citotóxica de derivados triazólicos de canabinoides indólicos

• Ano de defesa: 2023
• Autor(a) principal: Gabriele de Azevedo Cardoso
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; Brasil; ICEX - INSTITUTO DE CIÊNCIAS EXATAS; Programa de Pós-Graduação em Química; UFMG
• Palavras-chave em Português: Canabinoides indólicos; 1,2,3-triazóis; Atividade citotóxica; Câncer de mama; Química orgânica; Maconha; Triazóis; Agentes antineoplásicos; Mamas – Câncer; Produtos naturais; Testes biológicos; Farmacocinética; Alquilação; Ressonância magnética nuclear
• Link de acesso: http://hdl.handle.net/1843/62480; https://orcid.org/0000-0002-3193-5293

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.