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 <i>Araucaria heterophylla</i> (Salisb.) Franco, 13-epi-cupressic acid (<b>1</b>) and acetyl-13-epi-cupressic acid (<b>2</b>) were used to prepare seven new (<b>3</b>-<b>9</b>), along with one known (<b>10</b>) derivatives. RAW264.7 cells were used to evaluate the anti-inflammatory activity of the derivatives (<b>1</b>-<b>10</b>) <i>via</i> measuring the level of <i>COX-2</i> expression and IL-6. Pre-treated RAW264.7 cells with <b>1</b>-<b>10</b> (except for derivative <b>7</b>) at 25 µM for 24h exhibited downregulation of <i>COX-2</i> expression in response to LPS stimulation. Moreover, pre-treatment with compounds <b>1</b>, <b>2</b>, or <b>3</b> significantly attenuated the LPS-stimulated IL-6 level in RAW264.7 cells (<i>p</i> < 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 (<b>1</b>-<b>10</b>) 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.