Synthesis and Structure–Activity Relationship of Pyxinol Derivatives as Novel Anti-Inflammatory Agents

Abstract

Pyxinol, the main metabolite of 20<i>S</i>-protopanaxadiol in human liver, was chosen as a novel skeleton for the development of anti-inflammatory agents. Pyxinol derivatives modified at C-3, C-12, or C-25 and selected stereoisomers were designed, prepared, and investigated for <i>in vitro</i> anti-inflammatory activities. Structure-activity relationship (SAR), focused on skeleton, was analyzed based on their ability to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) synthesis. The preliminary SAR results signified that the biological activity of the pyxinol derivatives is largely dependent on the <i>R</i>/<i>S</i> stereochemistry of pyxinol skeleton and the hydroxy at C-3 is a modifiable position. Among the tested compounds, the 3-oximinopyxinol (<b>4a</b>) exhibited the most potent NO-inhibitory activity and was even comparable to the steroid drug. Furthermore, compound <b>4a</b> also significantly decreased LPS-induced TNF-α and IL-6 synthesis and iNOS and COX-2 expressions via the NF-κB pathway. This study proves that pyxinol is an interesting skeleton for anti-inflammatory drug discovery.