Aziz Marian N, Nguyen Linh, Chang Yan, Gout Delphine, Pan Zui, Lovely Carl J
Department of Chemistry and Biochemistry, 700 Planetarium Place, University of Texas at Arlington, TX, 76019, USA; Department of Pesticide Chemistry, National Research Centre, Dokki, Giza, 12622, Egypt.
Dept. of Biology, College of Science, University of Texas at Arlington, TX, 76019, USA; Department of Graduate Nursing, College of Nursing and Health Innovation, University of Texas at Arlington, TX, 76019, USA.
Eur J Med Chem. 2023 Jan 15;246:114909. doi: 10.1016/j.ejmech.2022.114909. Epub 2022 Nov 24.
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 thiazolidine 6g which 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.
通过开发新型的2-亚氨基-5-亚芳基噻唑烷类似物，已实现了一类新的细胞外信号调节激酶（ERK）抑制剂的发现。采用一种新型的固相载体介导反应的合成方法，通过级联反应以良好的产率构建了目标噻唑烷。通过封闭易被有氧氧化的C5位，成功实现了新噻唑烷文库的化学和物理稳定性。利用MTT法，使用食管鳞状细胞癌细胞系（KYSE - 30和KYSE - 150）和非肿瘤性食管上皮细胞系（HET - 1A和NES - G4T）进行细胞活力研究，结果表明，就选择性而言，(Z)-5-((Z)-4-溴亚苄基)-N-(4-甲氧基-2-硝基苯基)-4,4-二甲基噻唑烷-2-亚胺（6g）是合成文库中最好的化合物。进行DAPI染色实验以观察形态变化并研究凋亡活性。此外，使用蛋白质免疫印迹法探究噻唑烷6g所观察到的活性/选择性背后的机制/途径，该研究证实了其对ERK途径磷酸化的选择性抑制作用。已利用分子建模技术来确认所观察到的活性。分子对接研究揭示了合成的噻唑烷与报道中与ERK蛋白共结晶的抑制剂之间类似的结合相互作用。因此，本研究为开发有趣的生物活性2-亚氨基-5-亚芳基噻唑烷提供了一个起点。
