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Cytotoxicity of 4-substituted quinoline derivatives: Anticancer and antileishmanial potential

2020; Elsevier BV; Volume: 28; Issue: 11 Linguagem: Inglês

10.1016/j.bmc.2020.115511

1464-3391

Claudia A. Costa, Rayssa de Mello Lopes, Letícia S. Ferraz, Gabriela Nohemi Nuñez Esteves, Juliana Fortes Di Iório, Aline Aparecida de Souza, Isadora M. de Oliveira, Flávia Manarin, Wagner Alves de Souza Júdice, Hélio A. Stefani, Tiago Rodrigues,

Cholinesterase and Neurodegenerative Diseases

Chemical modifications of quinoline moiety have been recognized as a useful strategy to development of new drugs. Here, the cytotoxicity of a set of twenty-four 4-substituted quinolines (named HTI) was screened for their antitumor and antileishmanial potential in vitro, and the underlying mechanisms investigated. HTI 21 and HTI 22 exhibited the highest cytotoxicity, being selected to the subsequent studies. Both derivatives induced caspase-dependent apoptosis associated to the dissipation of the mitochondrial transmembrane potential (ΔΨ) and ROS generation. HTI-induced cell death was calcium dependent, associated to thiol oxidation and cysteine proteases activation. In isolated mitochondria, HTI derivatives promoted mitochondrial permeabilization by different mechanisms. The inhibition of BCL-2 by venetoclax enhanced the HTI-induced cytotoxicity. Regarding the inhibition of cysteine proteases type B of Leishmania mexicana, HTI 15 exhibited the most potent inhibitory activity through a linear non-competitive mechanism. These data highlight the therapeutic potential of 4-substituted quinolines as antitumor and antileishmanial drugs.