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

Autor(es):Mostrar menos -

Costa, Claudia A. ^[1] ; Lopes, Rayssa M. ^[1] ; Ferraz, Leticia S. ^[2] ; Esteves, Gabriela N. N. ^[2] ; Di Iorio, Juliana F. ^[1] ; Souza, Aline A. ^[1] ; de Oliveira, Isadora M. ^[3] ; Manarin, Flavia ^[4] ; Judice, Wagner A. S. ^[1] ; Stefani, Helio A. ^[5] ; Rodrigues, Tiago ^[2]

Afiliação do(s) autor(es)

^[1] Univ Mogi das Cruzes UMC, Ctr Interdisciplinar Invest Bioquim CIIB, Mogi Das Cruzes, SP - Brazil

^[2] Univ Fed ABC UFABC, Ctr Ciencias Nat & Humanas CCNH, Santo Andre, SP - Brazil

^[3] Univ Sao Paulo, Inst Quim IQ, Dept Quim Fundamental, Sao Paulo, SP - Brazil

^[4] Univ Estadual Oeste Parana, Ctr Engn & Ciencias Exatas CECE, Toledo, PR - Brazil

^[5] Univ Sao Paulo, Dept Farm, Fac Ciencias Farmaceut FCF, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Bioorganic & Medicinal Chemistry; v. 28, n. 11 JUN 1 2020.
• Citações Web of Science: 0

Resumo

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 (Delta psi) 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. (AU)

• Processo FAPESP: 16/04289-3 - Síntese de derivados calcogenoaminoácidos e 4-calcogenoquinolinas via reações multicomponentes
• Beneficiário: Isadora Maria de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 18/25747-5 - Alterações de morfologia e dinâmica mitocondriais no câncer: compreensão da biologia tumoral e prospecção de novos alvos terapêuticos
• Beneficiário: Tiago Rodrigues
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/25112-4 - Avaliação de moduladores da atividade de proteases envolvidas em processos patológicos
• Beneficiário: Wagner Alves de Souza Júdice
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/24821-4 - Reações de Acoplamento Carbonilativo e Cicloadição [2+2] Intramolecular Empregando D-Glucal
• Beneficiário: Helio Alexandre Stefani
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/02205-1 - Estudo do comportamento cinético das convertases
• Beneficiário: Wagner Alves de Souza Júdice
• Modalidade de apoio: Auxílio à Pesquisa - Regular