Division of Pharmaceutical Chemistry, Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India.
Division of Pharmaceutical Chemistry, Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India.
Biomed Pharmacother. 2017 May;89:162-176. doi: 10.1016/j.biopha.2017.01.108. Epub 2017 Feb 20.
Hepatocellular carcinoma is the most common primary malignancy of the liver with poor prognosis. In this study novel, Schiff's bases of 2-aminopyridine (SSSC-26 to 31) and 2-aminobenzothiazole (SSSC-32 to 37) were designed, synthesised and evaluated for antioxidant potential using DPPH method, and anti-hepatocellular carcinoma property using diethylnitrosamine (DEN) induced hepatocellular carcinoma rat model. The in-silico pharmacokinetic, rule of five and toxicity studies reveals that all the leads have an excellent intrinsic quality and sufficient structural features necessary for an oral activity. Molecular docking studies of all compounds into the ligand binding pocket of checkpoint kinase1 and vascular endothelial growth factor receptor-2 was also performed using Schrodinger software suite v8.5, and which have shown good Glide scores. Further compounds were synthesised based on the docking score and ADMET profile. The 1,1-diphenyl-2-picrylhydrazil (DPPH) scavenging study was carried out, and results showed that SSSC-29 (IC-63.60) and SSSC-33 (IC-60.32) were having good anti-oxidant potential in comparison with ascorbic acid (IC-55.27). SSSC-33 further evaluated for anti-cancer potential against diethylnitrosamine (200mg/kg bw) induced hepatocellular carcinoma in rats. The biochemical, histopathological and morphological data showed that SSSC-33 can reverse the changes occurred in the cancerous liver significantly. All these findings suggested that SSSC-33-((benzo[d]thiazol-2-ylimino) methyl)phenol) could be a potential compound in combating the oxidative damage of hepatic cells occurred due to the development of hepatocellular carcinoma induced by a chemical carcinogen, DEN.
肝细胞癌是肝脏最常见的原发性恶性肿瘤，预后不良。在这项研究中，设计、合成了 2-氨基吡啶（SSSC-26 至 31）和 2-氨基苯并噻唑（SSSC-32 至 37）的新型席夫碱，并使用 DPPH 法评价其抗氧化潜力，使用二乙基亚硝胺（DEN）诱导的肝癌大鼠模型评价其抗肝癌特性。基于体内药物代谢动力学、五规则和毒性研究表明，所有先导化合物都具有出色的内在质量和足够的结构特征，为口服活性提供了必要的条件。还使用 Schrodinger 软件套件 v8.5 对所有化合物进入细胞周期蛋白激酶 1 和血管内皮生长因子受体-2 的配体结合口袋进行了分子对接研究，结果显示对接评分良好。根据对接评分和 ADMET 概况进一步合成了化合物。进行了 1,1-二苯基-2-苦基肼（DPPH）清除实验，结果表明，与抗坏血酸（IC-55.27）相比，SSSC-29（IC-63.60）和 SSSC-33（IC-60.32）具有良好的抗氧化潜力。进一步评价 SSSC-33 对二乙基亚硝胺（200mg/kg bw）诱导的大鼠肝癌的抗癌潜力。生化、组织病理学和形态学数据表明，SSSC-33 可以显著逆转癌变肝脏的变化。所有这些发现表明，SSSC-33-（（苯并[d]噻唑-2-基亚氨基）甲基）苯酚）可能是一种潜在的化合物，可用于对抗化学致癌剂 DEN 诱导的肝癌引起的肝细胞氧化损伤。
