Oxidization synthesis and bioactivity study of tricyclic and tetracyclic genipin derivatives with collins reagent as anti-inflammatory agents

Tricyclic and tetracyclic genipin derivatives were investigated with variety of oxidized agents to give the corresponding oxidized genipin products with α,β-unsaturated aldehyde moiety. Based on the experimental results, Collins reagent (complex of chromium(VI) oxide with pyridine in CH₂Cl₂) was examined as the better favorable oxidized selective agent. On the other hand, the oxidized tricyclic and tetracyclic genipins were also evaluated for stability using UV–visible spectroscopy and tested for their effects on NO production in LPS-induced RAW 264.7 cells. Most of oxidized tricyclic and tetracyclic genipin aldehyde derivatives were substantially improved ≥4.0-fold inhibiting activity than allyl alcoholic genipin starting materials. On the other hand, SAR study indicated oxidized compound 3g possessed the best inhibitory activity (IC₅₀ = 2.60 μM) in comparison with reference standard Celecoxib (IC₅₀ = 22.6 μM) and Indomethacin (IC₅₀ = 156 μM). Furthermore, potential compounds (IC₅₀ ≤ 10 μM) were also chosen for safety profile study and oxidized compounds 3a–j showed significant safety, except for compound 3f possessed the cell toxicity (12.5 μM). The mechanism of compound 3g in reducing cyclooxygenase-2 (COX-2) during inflammation was further demonstrated through Western blot analysis. To sum-up, the potential drug candidate 3g, significantly exhibited better anti-inflammatory effect than Indomethacin.