94 / 2021-10-11 14:36:18

Design and synthesis of natural product-motivated PPAR-γ ligand and in vitro anti-inflammatory activity

exocyclic enone, PPAR-γ agonist, metabolic stability, anti-inflammatory

Previously, we reported a chiral exocyclic enone jasmonate derivative (+)-(R,E)-6a1 that function as a potential PPAR-γ agonist. The exocyclic enone moiety of (+)-(R,E)-6a1 is required for covalent bonding with the Cys²⁸⁵ residue and the hydrogen bonds with Tyr⁴⁷³ residue is essential for ligand/ PPAR-γ recruitment in the PPAR-γ ligand-binding domain (LBD). However, the in-silico analysis showed that (+)-(R,E)-6a1 forms a similar fashion as does rosiglitazone and 15d-PGJ₂ but lack of a key interaction with Tyr⁴⁷³. Meanwhile, in an attempt to improve the metabolic stability of (+)-(R,E)-6a1 in the biological system, a series of its novel analogs which resistant to enzymatic hydrolysis and possess hydrogen bonds with Tyr⁴⁷³ were synthesized. Since PPAR-γ agonist suppresses inflammatory response, (+)-(R,E)-5f1 suppressed the expression of pro-inflammatory factors, including inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and LPS-evoked nuclear factor kappa B (NF-κB) p65 submit phosphorylation in macrophages, suggesting that (+)-(R,E)-5f1 may exert anti-inflammatory activity through the NF-κB inhibition pathway.