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Synthesis of ( Z )-3-((5-(benzylthio)-4 H -1,2,4-triazol-3-yl)imino)-5-haloindolin-2-one derivatives: combined spectroscopic and computational investigations on the level and activity of matrix metalloproteinases 2 and 9 in cancer cell lines
Journal of the Iranian Chemical Society ( IF 2.4 ) Pub Date : 2021-01-17 , DOI: 10.1007/s13738-020-02150-3
Amir Kiani , Mohsen Shahlaei , Mahdi Rahpeyma , Hadi Adibi

Angiogenesis is an essential factor for cancer progression. Although more attention is paid in angiogenesis on its role in cancer biology, many other non-neoplastic diseases are also angiogenic-dependent. Recently, there is motivation to control cancer via inhibition of angiogenesis. Isatin-based scaffolds have been extensively used as anticancer agents in the recent years. Although some biological properties of isatin-based scaffolds are determined, their effects on angiogenesis are rare. So, we investigated the antiangiogenic effects of isatin-1,2,4-triazole conjugates. (Z)-3-((5-(benzylthio)-4H-1,2,4-triazol-3-yl)imino)-5-haloindolin-2-one macromolecules 1a1l were synthesized and characterized, and the buffered solutions were used for evaluation of their cytotoxicity (cell viability) by MTT assay in vitro against U87MG (human glioblastoma astrocytoma) and A2780 (human ovarian carcinoma) cancer cell lines. Also, the effects of the compounds 1a1l on supernatants activities and levels of matrix metalloproteinases (MMP-2 and MMP-9) were assayed using enzyme-linked immunosorbent assay (ELISA) and gelatin zymography. The compounds 1j1l have the greatest cytotoxicity against studied cell lines. Moreover, our observations indicated that 1j1l decreased the supernatants activity of MMP-2 and MMP-9 more than the others and all of the tested compounds considerably decreased the supernatant levels of MMP-9. The molecular mechanism of 1j binding to MMP-2 and MMP-9 was investigated by fluorescence quenching, absorption spectroscopy, FT-IR, molecular docking and molecular dynamics (MD) simulation procedures.



中文翻译:

(Z)-3-((5-(苄硫基)-4 H -1,2,4-三唑-3-基)亚氨基)-5-卤代吲哚-2-酮衍生物的合成:结合光谱和计算研究癌细胞系中基质金属蛋白酶2和9的水平和活性

血管生成是癌症进展的必要因素。尽管在血管生成中更多地关注了其在癌症生物学中的作用,但许多其他非肿瘤性疾病也依赖于血管生成。近来,存在通过抑制血管生成来控制癌症的动机。近年来,基于Isatin的支架已被广泛用作抗癌剂。尽管确定了基于伊斯汀的支架的某些生物学特性,但它们对血管生成的影响却很少。因此,我们研究了isatin-1,2,4-三唑共轭物的抗血管生成作用。(Z)-3-((5-(苄硫基)-4 H -1,2,4-三唑-3-基)亚氨基)-5-卤代吲哚-2-一大分子1a1l合成并表征,并将缓冲液用于体外MTT检测对U87MG(人类胶质母细胞瘤星形细胞瘤)和A2780(人类卵巢癌)癌细胞系的细胞毒性(细胞生存力)。同样,使用酶联免疫吸附测定(ELISA)和明胶酶谱分析法测定化合物1a1l对上清液活性和基质金属蛋白酶(MMP-2和MMP-9)水平的影响。化合物1j - 1l对已研究的细胞系具有最大的细胞毒性。此外,我们的观察表明1j1l降低了MMP-2和MMP-9的上清液活性,并且所有测试化合物均大大降低了MMP-9的上清液水平。通过荧光猝灭,吸收光谱,FT-IR,分子对接和分子动力学(MD)模拟程序研究了1j与MMP-2和MMP-9结合的分子机理。

更新日期:2021-01-18
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