Synthesis and Biological Evaluation of Novel 2-imino-4-thiazolidinones as Potential Antitumor Agents for Glioblastoma

Abstract

Aims: The purpose of our study was to explore the molecular hybridization between 2-imino-4-thizolidione and piridinic scaffolds and its potential antitumor activity. Background: Glioblastoma is the most aggressive glioma tumor clinically diagnosed malignant and highly recurrent primary brain tumor type. The standard of treatment for a glioblastoma is surgery, followed by radiation and chemotherapy using temozolomide. However, the chemoresistance has become the main barrier to treatment success. 2-imino-4-thiazolidinones are an important class of heterocyclic compounds that feature anticancer activity; however the antiglioblastoma activity is yet to be explored. Objective: To synthesize and characterize a series of novel 2-imino-4-thiazolidinones and evaluate their antiglioblastoma activity. Method: The 2-imino-4-thiazolidinone (5a-p) was synthesized according to the literature with modifications. Compounds were identified and characterized using spectroscopic analysis and X-ray diffraction. The antitumor activity was analyzed by 3-(4,5- dimethyl)-2,5-diphenyltetrazolium bromide (MTT) assay both in primary astrocyte and glioma (C6). Apoptosis and cell cycle phase were determined by flow cytometry analysis. The expression of caspase-3/7 was measured by luminescence assay. Oxidative stress parameters as: determination of reactive oxygen species (ROS), superoxide dismutase (SOD) activity, catalase (CAT) activity and total sulfhydryl content quantification were analyzed by colorimetric assays according to literature. Results: Among sixteen synthesized compounds, three displayed potent antitumor activities against tested glioblastoma cell line showed IC50 values well below the standard drug temozolomide. Therefore, compounds 5a, 5l and 5p were evaluated using cell cycle and death analysis, due to potent toxicity (2.17±1.17, 6.24±0.59, 2.93±1.12µM, respectively) in C6 cell line. The mechanism of action studies demonstrated that 5a and 5l induced apoptosis significantly increase the percentage of cells in Sub-G1 phase in the absence of necrosis. Consistent with these results, caspase-3/7 assay revealed that 5l presents pro-apoptotic activity due to the significant stimulation of caspases-3/7. Moreover, 5a, 5l and 5p increased antioxidant defense and decreased reactive oxygen species (ROS) production. Conclusion: The compounds were synthesized with good yield and three of these presented (5a, 5l and 5p) good cytotoxicity against C6 cell line. Both affected cell cycle distribution via arresting more C6 cell line at Sub-G1 phase promoting apoptosis. Furthermore, 5a, 5l and 5p modulated redox status. These findings suggest that these compounds can be considered as promising lead molecules for further development of potential antitumor agents.

Synthesis, anticancer evaluation and in silico studies of novel N‐substituted arylidenethiazolidine‐2,4‐dione derivatives as adenosine monophosphate‐activated protein kinase activators

“…Interestingly, PC3 cells were found more susceptible than MDMB-231 cells against these agents. Of these derivatives, thiazolidine 2,4-dione containing indole or azaindole scaffolds (12,13,16,25) found to be more potent than thiazole-thiazolidine 2,4-dione hybrid (7). Particularly, molecular hybridization of thiazolidine 2,4-dione with N-2-(4-(trifluoromethyl)phenyl)ethanol and azaindole (compound 16) was the most effective among the series resulted in potent antiproliferative activity toward both PC3 and MDMB-231 cell lines with IC 50 4.28 μM and 2.5 μM, respectively.…”

“…For that purpose, thiazolidine 2,4-dione skeleton has been extensively utilized to obtain novel anticancer agents [11][12][13]. For instance, combination of 2,4-thiazolidinone with privileged scaffolds (Figure 1) such as pyrazole (I) [14], thiazole (II) [15], pyridine (III) [16], quinoline (IV) [17], coumarin (V) [18], and indole (VI) [19] led to potent anticancer activities against numerous cell growths. Further studies toward mechanism of action indicated that most of these privileged scaffolds-thiazolidine 2,4-dione hybrids exerted variety of mechanism such as potent inhibitors of VEGFR2-tyrosine kinases [13], apoptosis inducers through caspase-dependent pathways [16], and inhibition of carbonic anhydrases [17] as well as tubulin polymerization [20].…”

“…For instance, combination of 2,4‐thiazolidinone with privileged scaffolds (Figure 1) such as pyrazole (I) [14], thiazole (II) [15], pyridine (III) [16], quinoline (IV) [17], coumarin (V) [18], and indole (VI) [19] led to potent anticancer activities against numerous cell growths. Further studies toward mechanism of action indicated that most of these privileged scaffolds‐thiazolidine 2,4‐dione hybrids exerted variety of mechanism such as potent inhibitors of VEGFR2‐tyrosine kinases [13], apoptosis inducers through caspase‐dependent pathways [16], and inhibition of carbonic anhydrases [17] as well as tubulin polymerization [20]. Moreover, hybrids of N ‐substituted arylidenethiazolidine‐2,4‐dione with substituted furan (Figure 1, VII) [21, 22] or benzene sulfonamide derivative (VIII) [23] have also been reported as AMPK activator with significant anticancer activity.…”

Reactive astrocytes and glioblastoma: are there new targets for more effective antitumor therapy?

“…В настоящий момент основным цитостатиком, используемым для лечения таких больных, остается темозоломид. Исследования химио-и радиорезистентности клеток глиомы к этому препарату под воздействем реактивных астроцитов весьма ограниченны [45,[50][51][52][53].…”

4-Thiazolidinone-Bearing Hybrid Molecules in Anticancer Drug Design

“…The molecular hybridization approach was applied for the synthesis of pyridine–4-thiazolidinone hybrids with aim of the synthesis of potential antiglioblastoma agents by Campos et al [ 50 ]. Among sixteen synthesized compounds, derivatives 50–52 ( Figure 20 ) displayed potent antitumor activities against the tested glioblastoma cell lines and exhibited IC 50 values 2.17, 6.24, and 2.93 μM, respectively, in the C6 cell line, well below the standard drug temozolomide.…”