Jahan Humera, Choudhary Muhammad I, Atta Amber, Khan Khalid M, Ur-Rahman Atta-
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
Med Chem. 2018;14(5):516-523. doi: 10.2174/1573406413666171020120528.
Anthranilic acid derivatives are important pharmacophores in drug discovery. Several of them are currently being used, such as mefenamic acid and meclofenamates, possess analgesic, anti-inflammatory and antipyretic activities. Some anthranilic acid-based scaffolds have also been reported for the management of metabolic disorders.
The aim of the current study was to investigate the antiglycation potential of 2-anilino benzoic acid derivatives against (N-phenylanthranilic acid) fructose- human serum albumin (HSA) glycation. The study also analyzed the effects of newly identified antiglycation inhibitors on AGEs-mediated intracellular reactive oxygen species production, and associated impaired proliferation of the hepatocytes.
The present study focuses on the antiglycation activity of 2- anilinobenzoic acid derivatives 1-18 in in-vitro human serum albumin (HSA)- fructose model. These derivatives were also identified as non-toxic to 3T3 mouse fibroblast cell-line using metabolic assay. The effect of the most promising derivative 1, 2- (2, 4- dinitroanilino)benzoic acid, was studied in a dose dependent manner, co-incubated with fructose-derived AGEs (0- 200 μg/mL), on rat hepatocytes proliferation and associated intracellular generation of ROS via MTT assay and DCFH-DA technique, respectively.
We found that derivative 1 ameliorates the elevated intracellular oxidative stress and associated diminished proliferation of the hepatocytes in response to AGEs.
In conclusion, we identify novel 2- anilino benzoic acid derivatives as antiglycation agents through in-vitro and cellular-based models.
邻氨基苯甲酸衍生物是药物研发中重要的药效基团。其中一些目前正在使用，如甲芬那酸和甲氯芬那酸盐，具有镇痛、抗炎和解热活性。一些基于邻氨基苯甲酸的支架也被报道用于治疗代谢紊乱。
本研究旨在研究2-苯胺基苯甲酸衍生物对（N-苯基邻氨基苯甲酸）果糖-人血清白蛋白（HSA）糖基化的抗糖基化潜力。该研究还分析了新鉴定的抗糖基化抑制剂对晚期糖基化终产物（AGEs）介导的细胞内活性氧生成以及相关肝细胞增殖受损的影响。
本研究聚焦于2-苯胺基苯甲酸衍生物1-18在体外人血清白蛋白（HSA）-果糖模型中的抗糖基化活性。使用代谢测定法还确定这些衍生物对3T3小鼠成纤维细胞系无毒。以剂量依赖方式研究了最有前景的衍生物1,2-（2,4-二硝基苯胺基）苯甲酸与果糖衍生的AGEs（0-200μg/mL）共同孵育对大鼠肝细胞增殖以及通过MTT测定法和DCFH-DA技术分别测定的相关细胞内活性氧生成的影响。
我们发现衍生物1改善了AGEs引起的细胞内氧化应激升高以及相关的肝细胞增殖减少。
总之，我们通过体外和基于细胞的模型鉴定了新型2-苯胺基苯甲酸衍生物作为抗糖基化剂。
