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

Cytotoxicity of 4-substituted quinoline derivatives: Anticancer and antileishmanial potential.
Bioorg Med Chem. 2020 Apr 20;:115511
Authors: Costa CA, Lopes RM, Ferraz LS, Esteves GNN, Di Iorio JF, Souza AA, de Oliveira IM, Manarin F, Judice WAS, Stefani HA, Rodrigues T
Abstract
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.
PMID: 32336669 [Pu...

Source: Bioorganic and Medicinal Chemistry - April 19, 2020 Category: Chemistry Authors: Costa CA, Lopes RM, Ferraz LS, Esteves GNN, Di Iorio JF, Souza AA, de Oliveira IM, Manarin F, Judice WAS, Stefani HA, Rodrigues T Tags: Bioorg Med Chem Source Type: research