A Series of Ferulic Acid Amides Reveals Unexpected Peroxiredoxin 1 Inhibitory Activity with in vivo Antidiabetic and Hypolipidemic Effects

Yasmin S., Cerchia C., Badavath V. N., Laghezza A., Dal Piaz F., Mondal S. K., ...Daha Fazla

CHEMMEDCHEM, cilt.16, sa.3, ss.484-498, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 16 Sayı: 3
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1002/cmdc.202000564
  • Dergi Adı: CHEMMEDCHEM
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Biotechnology Research Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Index Chemicus (IC)
  • Sayfa Sayıları: ss.484-498
  • Anahtar Kelimeler: Type 2 diabetes, Ferulic acid amides, Peroxiredoxin 1, Hyperglycemia, Hyperlipidemia, DENSITY-LIPOPROTEIN CHOLESTEROL, BIOLOGICAL EVALUATION, INSULIN-RESISTANCE, INDUCE DIFFERENTIATION, ACCURATE DOCKING, GENE-EXPRESSION, PPAR-ALPHA, CANCER, ANTIOXIDANT, DERIVATIVES
  • Anadolu Üniversitesi Adresli: Evet

Özet

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 PPAR gamma 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.