Novel thiazolidines of potential anti-proliferation properties against esophageal squamous cell carcinoma via ERK pathway
Novel thiazolidines of potential anti-proliferation properties against esophageal squamous cell carcinoma via ERK pathway
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DOI：
10.1016/j.ejmech.2022.114909
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发表时间：
2022-12-09
影响因子：
6.7
通讯作者：
Lovely，Carl J.
中科院分区：
文献类型：
--
作者：
Aziz，Marian N.;Nguyen，Linh;Lovely，Carl J.
通过开发新的2-亚氨基-5-芳亚基-噻唑烷类似物，发现了一类新的细胞外信号调节激酶(ERK)抑制剂。采用固体载体介导法，通过级联反应，以较高的产率合成了目标化合物。通过将不稳定的C5位封闭为好氧氧化，成功地实现了新的噻唑烷文库的化学和物理稳定性。通过四甲基偶氮唑盐比色法对食管鳞癌细胞系(KYSE-30和KYSE-150)和非肿瘤性食道上皮细胞系(HET-1A和NES-G4t)进行了细胞活性研究，结果表明(Z)-5-((Z)-4-bromobenzylidene)-N-(4-methoxy-2-nitrophenyl)-4，4-dimethylthiazolidin-2-imine(6G)是合成的文库中选择性最好的化合物。DAPI染色观察细胞的形态变化，观察细胞的凋亡活性。此外，我们还用蛋白质印迹法研究了噻唑烷6G选择性抑制ERK通路磷酸化的活性和选择性背后的机制和途径。分子模拟技术已经被用来证实观察到的活性。分子对接研究表明，合成的噻唑烷类化合物与报道的共晶抑制剂与ERK蛋白之间存在类似的结合作用。因此，本研究为开发具有生物活性的2-亚氨基-5-亚芳基-噻唑烷提供了一个起点。
The discovery of a new class of extracellular-signal-regulated kinase (ERK) inhibitors has been achieved via developing novel 2-imino-5-arylidene-thiazolidine analogues. A novel synthetic method employing a solid support-mediated reaction was used to construct the targeted thiazolidines through a cascade reaction with good yields. The chemical and physical stability of the new thiazolidine library has successfully been achieved by blocking the labile C5-position to aerobic oxidation. A cell viability study was performed using esophageal squamous cell carcinoma cell lines (KYSE-30 and KYSE-150) and non-tumorous esophageal epithelial cell lines (HET-1A and NES-G4T) through utilization of an MTT assay, revealing that (Z)-5-((Z)-4-bromobenzylidene)-N-(4-methoxy-2-nitrophenyl)-4,4-dimethylthiazolidin-2-imine (6g) was the best compound among the synthesized library in terms of selectivity. DAPI staining experiments were performed to visualize the morphological changes and to investigate the apoptotic activity. Moreover, western blots were used to probe the mechanism/pathway behind the observed activity/selectivity of thiazolidine6gwhich established selective inhibition of phosphorylation in the ERK pathway. Molecular modeling techniques have been utilized to confirm the observed activity. A molecular docking study revealed similar binding interactions between the synthesized thiazolidines and reported co-crystalized inhibitors with ERK proteins. Thus, the present study provides a starting point for the development of interesting bioactive 2-imino-5-arylidene-thiazolidines.