期刊
CHEMISTRY & BIODIVERSITY
卷 18, 期 2, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbdv.202000800
关键词
imidazothiadiazole; cytotoxicity; TGF beta receptor kinase; melphalan; levamisole
资金
- NIH-MARC Program [T34GM008048-35]
- National Institute on Minority Health and Health Disparities (NIMHD) [5U54MD007592]
The study synthesized 22 compounds with various substitutions on imidazo[2,1-b][1,3,4]thiadiazoles and investigated their potential cytotoxic activity in leukemia cell lines. Two compounds showed the most cytotoxic effect against leukemia cells, T-lymphocyte cells, and cervix carcinoma cells, with IC50 values ranging between 0.79 and 1.6 μM. These compounds induce apoptosis through phosphatidylserine externalization and caspase-3 activation, and binding studies showed strong interactions with the active sites of TGF-beta type I receptor kinase domain.
In this study, we synthesized 22 compounds in a series with various substitution on imidazo[2,1-b][1,3,4]thiadiazole. The potential cytotoxic activity of these compounds investigated in leukemia cell lines by Differential Nuclear Staining (DNS). Our results identified two compounds, 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate and 6-(4-chlorophenyl)-2-(4-methoxybenzyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde, exhibited the most cytotoxic effect against murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa) with IC50 values ranging between 0.79 and 1.6 mu M. The results indicate that 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate is inducing phosphatidylserine externalization and caspase-3 activation which are both a hallmark of apoptosis. Docking studies showed that 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate binds within the active sites of transforming growth factor beta (TGF-beta) type I receptor kinase domain by strong hydrogen binding and hydrophobic interactions.
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