In:
Medicinal Chemistry, Bentham Science Publishers Ltd., Vol. 18, No. 4 ( 2022-05), p. 452-462
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
1573-4064
DOI:
10.2174/1573406417666210806094543
Sprache:
Englisch
Verlag:
Bentham Science Publishers Ltd.
Publikationsdatum:
2022
SSG:
15,3
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