Anticancer properties of 5Z-(4-fluorobenzylidene)-2-(4-hydroxyphenylamino)-thiazol-4-one

Abstract

4-thiazolidinones, which are privileged structures in medicinal chemistry, comprise the well-known class of heterocycles and are a source of new drug-like compounds. Undoubtedly, the 5-bulky-substituted-2,4-thiazolidinediones - a class of antihyperglycemic glitazones, which are peroxisome proliferator-activated receptor gamma (PPARγ) agonists, are the most described group among them. As there are various chemically distinct 4-thiazolidinones, different subtypes have been selected for studies; however, their main pharmacological profiles are similar. The aim of this study was to evaluate the anticancer activity of 5 Z -(4-fluorobenzylidene)-2-(4-hydroxyphenylamino)-thiazol-4-one (Les-236) in four human cancer cell lines, A549, SCC-15, SH-SY5Y, and CACO-2, and investigate its impact on the production of reactive oxygen species (ROS) and the apoptotic process as well as cytotoxicity and metabolism in these cell lines. The cell lines were exposed to increasing concentrations (1 nM to 100 µM) of the studied compound for 6, 24, and 48 h, and later, ROS production, cell viability, caspase-3 activity, and cell metabolism were examined. The obtained results showed that the studied compound decreased the production of ROS, increased the release of lactate dehydrogenase, and decreased cell metabolism/proliferation in all the five cell lines at micromolar concentrations. Interestingly, over a wide range of concentrations (from 1 nM to 100 µM), Les-236 was able to increase the activity of caspase-3 in BJ (after 6 h of exposure), A549, CACO-2, and SCC-15 (after 48 h of exposure) cell lines which could be an effect of the activation of PPARγ-dependent pathways.

Induction of Cyp450 enzymes by 4-thiazolidinone-based derivatives in 3T3-L1 cells in vitro

“…To date, thiazolidinone-based compounds have been shown to initiate the apoptotic process in various cancerous cell lines (Szychowski et al 2017a , b , 2019 ). Caspase-3 activity assay was performed to measure the effects of Les-2194, Les-3640, Les-5935, and Les-6166 on the apoptotic process in the 3T3-L1 cell line.…”

“…Our previous study has demonstrated that 4-thiazolidinone-based derivatives (thiopyrano[2,3- d ]thiazole derivative Les-2194 and thiazolidinone-pyrazoline hybrid molecule Les-3640) cause apoptotic cell death in human squamous carcinoma cells (SCC-15) with key involvement of PPARγ (Szychowski et al 2017a , b ). Moreover, another compound studied by our team 5 Z -(4-fluorobenzylidene)-2-(4-hydroxyphenylamino)-thiazol-4-one (Les-236) has been found to exhibit broad cytotoxic and proapoptotic action in SCC-15, lung carcinoma (A549), colon adenocarcinoma (CACO-2), neuroblastoma (SH-SY5Y), and skin fibroblast (BJ) cell lines (Szychowski et al 2019 ).…”

Evaluation of Anticancer and Antibacterial Activity of Four 4-Thiazolidinone-Based Derivatives

“…One of the classes of heterocycles with promising anticancer activity is the series of 4-thiazolidinone (4-TZD) derivatives. To date, it has been described that various 4-thiazolidinones exhibit anticancer properties demonstrated in numerous in vitro and in vivo models [ 10 , 12 , 13 , 14 , 18 , 25 , 26 , 27 , 28 ]. The determination of the impact of xenobiotics on metabolic activity is one of the most relevant analyses allowing the formulation of preliminary assumptions about their application potential.…”

“…They were found to act mainly in a PPARγ-dependent manner [ 25 , 26 ]. A similar effect was produced by the action of 5 Z -(4-fluorobenzylidene)-2-(4-hydroxyphenylamino)-thiazol-4-one (Les-236), e.g., in lung carcinoma (A549) and colon adenocarcinoma (CACO-2) cell lines and in normal skin fibroblasts (BJ) [ 27 ]. However, 4-TZD-based compounds are also able to have a negative influence on healthy cells, such as mouse preadipocytes (3T3-L1 cell line), although this effect is observed only at high micromolar concentrations (100 µM of Les-2194 and Les-3640) [ 28 ].…”

An Insight into 4-Thiazolidinones

“…1,3-Dipolar cycloaddition is a preferable route for synthesis of thiazolidinones, isoxazoles and isoxazolines [9]. 1,3-Dipolar or [3+2] cycloaddition is a reaction between a molecule containing a  bond ( an alkene, alkyne, etc) known as 1,3 dipolarophile with a highly polarized ionic compound called a 1,3 dipole.…”