Design, biological evaluation, and molecular modelling insights of cupressic acid derivatives as promising anti-inflammatory agents

Abstract

The major labdanes in the oleogum resin of Araucaria heterophylla (Salisb.) Franco, 13-epi-cupressic acid (1) and acetyl-13-epi-cupressic acid (2) were used to prepare seven new (3–9), along with one known (10) derivatives. RAW264.7 cells were used to evaluate the anti-inflammatory activity of the derivatives (1–10) via measuring the level of COX-2 expression and IL-6. Pre-treated RAW264.7 cells with 1–10 (except for derivative 7) at 25 µM for 24h exhibited downregulation of COX-2 expression in response to LPS stimulation. Moreover, pre-treatment with compounds 1, 2, or 3 significantly attenuated the LPS-stimulated IL-6 level in RAW264.7 cells (p < 0.05). A docking study was conducted against phospholipase A2 (PLA2), a crucial enzyme in initiating the inflammatory cascade. The significant structural features of compounds (1–10) as PLA2 inhibitors included the carbonyl group at C-4 (free or substituted) and the hydrophobic diterpenoid skeleton. This study suggested 13-epi-cupressic acid as a scaffold for new anti-inflammatory agents.

Keywords

• Cupressic acid derivatives
• labdane diterpenoids
• RAW264.7 cell line
• COX-2 gene expression
• anti-inflammatory leads