Highlights

New PPAR-γ ligands were designed based on (+)-(R,E)-6a1.

Synthetic analogs were evaluated for PPAR-γ activation by luciferase reporter assay.

Synthetic analogs were evaluated for stability to enzymatic hydrolysis using porcine liver esterase.

Compound (+)-(R,E)-5f showed potent in vitro anti-inflammatory activity via inhibition of the NF-κB pathway.

Abstract

In our previous study, a PPAR-γ agonist (+)-(R,E)-6a1 was elaborated as an anti-inflammatory lead. However, in silico analysis showed that (+)-(R,E)-6a1 lacks key hydrogen bonding with Tyr⁴⁷³ of PPAR-γ LBD (ligand binding domain). To facilitate additional hydrogen bonding with Tyr⁴⁷³, a more polar head group was introduced to the structure of (+)-(R,E)-6a1, and we also attempted to synthesize enzymatically stable derivatives. Of the synthetic derivatives, compound (+)-(R,E)-5f showed highest PPAR-γ transcriptional activity and reasonable metabolic stability. Compound (+)-(R,E)-5f suppressed the expression of pro-inflammatory mediators such as inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α). Reduction of nitric oxide (NO), and ROS was also observed. Compound (+)-(R,E)-5f was found to suppress the NF-κB pathway by inhibiting phosphorylation of IKK (IκB kinase), and this may lead to subsequent inhibition of IκBα (inhibitor of NF-κBα) phosphorylation and inhibition of NF-κB activation. These results indicate that (+)-(R,E)-5f exerts anti-inflammatory activity via NF-κB pathway inhibition, and may serve as a potential anti-inflammatory lead.