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

Autor: Costa CA; Centro Interdisciplinar de Investigação Bioquímica (CIIB), Universidade de Mogi das Cruzes (UMC), Mogi das Cruzes, SP, Brazil., Lopes RM; Centro Interdisciplinar de Investigação Bioquímica (CIIB), Universidade de Mogi das Cruzes (UMC), Mogi das Cruzes, SP, Brazil., Ferraz LS; Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC (UFABC), Santo André, SP, Brazil., Esteves GNN; Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC (UFABC), Santo André, SP, Brazil., Di Iorio JF; Centro Interdisciplinar de Investigação Bioquímica (CIIB), Universidade de Mogi das Cruzes (UMC), Mogi das Cruzes, SP, Brazil., Souza AA; Centro Interdisciplinar de Investigação Bioquímica (CIIB), Universidade de Mogi das Cruzes (UMC), Mogi das Cruzes, SP, Brazil., de Oliveira IM; Departamento de Química Fundamental, Instituto de Química (IQ), Universidade de São Paulo (USP), São Paulo, SP, Brazil., Manarin F; Centro de Engenharias e Ciências Exatas (CECE), Universidade Estadual do Oeste do Paraná, Toledo, PR, Brazil., Judice WAS; Centro Interdisciplinar de Investigação Bioquímica (CIIB), Universidade de Mogi das Cruzes (UMC), Mogi das Cruzes, SP, Brazil., Stefani HA; Departamento de Farmácia, Faculdade de Ciências Farmacêuticas (FCF), Universidade de São Paulo (USP), São Paulo, SP, Brazil., Rodrigues T; Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC (UFABC), Santo André, SP, Brazil. Electronic address: tiago.rodrigues@ufabc.edu.br.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Jun 01; Vol. 28 (11), pp. 115511. Date of Electronic Publication: 2020 Apr 20.
DOI: 10.1016/j.bmc.2020.115511
Abstrakt: 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.
Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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