Abstract
Leukemia is a malignant disease that originates in the bone marrow, local of blood cells production. Chemotherapy treatment is one of the alternatives to improve the survival of patients. In this context, the search for new compounds with potential cytotoxic action is justified. The present work evaluated the cytotoxic activity of 16 new synthetic analogs of 3-alkylpyridine alkaloids. The cytotoxic profiles were determined by MTT in vitro assay against THP-1 (acute monocytic leukemia), K562 (chronic myeloid leukemia) and PBMC (peripheral blood mononuclear) human cells. To investigate the mechanism of action, cell cycle analysis and alterations of TP53, p21, Bax, Bcl2, NOX-1, NOX-2, NOX-4 and p47-phox gene expressions were performed by qPCR, along with the measurement of reactive oxygen species (2’,7’-dichlorodihydrofluorescein diacetate and dihydroethidium). Compounds 4c, 5b, 5c and 6d were the most active and selective for THP-1 and compounds 7c and 11 were found to be more active for K562. All of this induced apoptosis in the tested strains. Concerning the investigation of the mechanism of action, it was observed that the pathway being activated is a p53-independent pathway. The data presented in this work indicate that 3-alkylpyridine alkaloid analogues are a potential class of compounds with cytotoxic action.
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Acknowledgements
The authors are grateful to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Pro-Reitoria de Pesquisa (PRPq) da Universidade Federal de Minas Gerais, for sponsoring this study.
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Evangelista, F.C.G., de Freitas Lopes, A., Andrade, S.N. et al. Synthetic 3-alkylpyridine alkaloid analogues as a new scaffold against leukemic cell lines: cytotoxic evaluation and mode of action. Med Chem Res 28, 1567–1578 (2019). https://doi.org/10.1007/s00044-019-02395-5
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DOI: https://doi.org/10.1007/s00044-019-02395-5