A Series of Ferulic Acid Amides Reveals Unexpected Peroxiredoxin 1 Inhibitory Activity with in vivo Antidiabetic and Hypolipidemic Effects.
Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes (T2DM). Ferulic acid is known for attenuating the insulin resistance and reducing the blood glucose in T2DM rats. In this work, we designed and synthesized a library of new ferulic acid amides (FAA), which could be considered as ring opening derivatives of the antidiabetic PPARγ agonists Thiazolidinediones (TZDs). However, since these compounds displayed weak PPAR transactivation capacity, we employed a proteomics approach to unravel their molecular target(s) and identified the peroxiredoxin 1 (PRDX1) as a direct binding target of FAAs. Interestingly, PRDX1, a protein with antioxidant and chaperone activity, has been implied in the development of T2DM by inducing hepatic insulin resistance. SPR, mass spectrometry-based studies, docking experiments and in vitro inhibition assay confirmed that compounds VIe and VIf bound PRDX1 and induced a dose-dependent inhibition. Furthermore, VIe and VIf significantly improved hyperglycemia and hyperlipidemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats as confirmed by histopathological examinations. These results provide guidance for developing the current FAAs as new potential antidiabetic agents.
['Yasmin|Sabina|S|', 'Cerchia|Carmen|C|', 'Badavath|Vishnu Nayak|VN|', 'Laghezza|Antonio|A|', 'Dal Piaz|Fabrizio|F|', 'Mondal|Susanta K|SK|', 'Atlı|Özlem|Ö|', 'Baysal|Merve|M|', 'Vadivelan|Sankaran|S|', 'Shankar|S|S|', 'Siddique|Mohd Usman Mohd|MUM|', 'Pattnaik|Ashok Kumar|AK|', 'Singh|Ravi Pratap|RP|', 'Loiodice|Fulvio|F|', 'Jayaprakash|Venkatesan|V|', 'Lavecchia|Antonio|A|0000-0002-2181-8026']
D000577:Amides D000818:Animals D001713:Biphenyl Compounds D002470:Cell Survival D003373:Coumaric Acids D003921:Diabetes Mellitus, Experimental D004305:Dose-Response Relationship, Drug D004791:Enzyme Inhibitors D006801:Humans D007003:Hypoglycemia D007004:Hypoglycemic Agents D000960:Hypolipidemic Agents D008297:Male D008958:Models, Molecular D015394:Molecular Structure D054464:Peroxiredoxins D010851:Picrates D051381:Rats D017207:Rats, Sprague-Dawley D017208:Rats, Wistar D013311:Streptozocin D013329:Structure-Activity Relationship D014407:Tumor Cells, Cultured
Ferulic acid amides Peroxiredoxin 1 Type 2 diabetes Hyperglycemia Hyperlipidemia