Design, synthesis and cytotoxicity of the antitumor agent 1-azabicycles for chemoresistant glioblastoma cells
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2020
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Twelve multi-functional pyrrolizidinones, indolizidinones and pyrroliazepinones were prepared from formal aza-[3 + 2] and aza-[3 + 3] cycloadditions of five- to seven-membered heterocyclic enaminones as diverse ambident electrophiles. The antitumor activity of these alkaloid-like compounds was investigated through an initial screening performed on human glioblastoma multiform (GBM) cell lines (GL-15, U251), on murine glioma cells line (C6) and on normal glial cells. Of the compounds tested, the new pyrrolo[1,2a]azepinone, [ethyl (3-oxo-1,2-diphenyl-6,7,8,9-tetrahydro-3H-pyrrolo[1,2a]azepin-9a(5H)-yl)acetate] or (Compound-13) exhibited selective cytotoxic effects on GBM-temozolomide resistant cells. Compound-13 exerted dose-dependent cytotoxic activity by promoting arrest of cells in the G0/G1 phase of the cell cycle in the first 24 h. The apoptotic effect observed was in a time-dependent manner. Anti-migratory effect promoted by the treatment with compound-13 was also observed. Moreover, healthy mixed glial cell cultures from rat brain exhibited no cytotoxicity effect upon exposure to compound-13. Thus, the present study paves the way for the use of compound-13 as novel antitumor scaffold candidate for glioma cell therapy.
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OLIVEIRA, Mona et al. Design, synthesis and cytotoxicity of the antitumor agent 1-azabicycles for chemoresistant glioblastoma cells. Investigational New Drugs, New York, v. 38, n. 5, p. 1257-1271, 2020. DOI: 10.1007/s10637-019-00877-2. Disponível em: https://link.springer.com/article/10.1007/s10637-019-00877-2. Acesso em: 22 jan. 2024.