Published in:
01-10-2020 | Glioblastoma | PRECLINICAL STUDIES
Design, synthesis and cytotoxicity of the antitumor agent 1-azabicycles for chemoresistant glioblastoma cells
Authors:
Mona Oliveira, Lourenço Luis Botelho de Santana, José Claudio Serafim, Airam Oliveira Santos, Michelle Pereira Quintino, José Tiago Menezes Correia, Fabiano Damasceno, José Ricardo Sabino, Thiago Rubens Cardim Pires, Paulo Lucas Cerqueira Coelho, Giselle Pinto de Faria Lopes, Henning Ulrich, Silvia Lima Costa, Silvio Cunha
Published in:
Investigational New Drugs
|
Issue 5/2020
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Summary
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.