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

Author contributions

A.F.S.; Conceptualisation, investigations, data interpretation. D.M.E.; Methodology, investigations. F.F.E.; Biological investigation. M.A.A. and M.A.; Methodologies, resources. F.M.A.B.; In silico investigation. A.F.S., D.M.E., F.F.E., and F.M.A.B.; writing-original draft. All authors review, editing, and approving the final manuscript.

Disclosure statement

No potential conflict of interest was reported by author(s).

Additional information

Funding

This study is supported via funding from Prince Sattam bin Abdulaziz University project number [PSAU/2023/R/1444].