Design, synthesis and cytotoxicity of the antitumor agent 1-azabicycles for chemoresistant glioblastoma cells
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PRECLINICAL STUDIES
Design, synthesis and cytotoxicity of the antitumor agent 1-azabicycles for chemoresistant glioblastoma cells Mona Oliveira 1,2 & Lourenço Luis Botelho de Santana 3,4 & José Claudio Serafim 3,4 & Airam Oliveira Santos 3 & Michelle Pereira Quintino 3,4 & José Tiago Menezes Correia 3 & Fabiano Damasceno 3 & José Ricardo Sabino 5 & Thiago Rubens Cardim Pires 1,2 & Paulo Lucas Cerqueira Coelho 1,2 & Giselle Pinto de Faria Lopes 1,6 & Henning Ulrich 7 & Silvia Lima Costa 1,2 & Silvio Cunha 3,4 Received: 24 June 2019 / Accepted: 5 November 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019
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 dosedependent 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. Keywords Azabicyclic compounds . Formal aza-cyclo additions . Anti-tumor agent . Glioblastoma cells . Chemoresistance
Introduction Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor. It has a high recurrence rate with poor
prognosis and high resistance to chemotherapy [1]. Many cancer patients experience recurrence and ultimately death because of treatment failure between 3 and 12 months after diagnosis [2]. Radiotherapy, with concomitant adjuvant
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-019-00877-2) contains supplementary material, which is available to authorized users. * Silvia Lima Costa [email protected] * Silvio Cunha [email protected] 1
Departamento de Biofunção/Bioquímica, Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da Saúde, Salvador BA 40.110-100, Brazil
2
Departamento de Biofunção/Bioquímica, Instituto Nacional de Ciência e Tecnologia - INCT em Neurociência Translacional, Universidade Federal da Bahia, Instituto de Ciências da Saúde, Salvador, BA 40.110-100, Brazil, Salvador BA 40.170-290, Brazil
3
Instituto de Química, Universidade Federal da
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