A new class of potent liver injury protective compounds: Structural elucidation, total synthesis and bioactivity study

Abstract

A new class of potent liver injury protective compounds, phychetins A−D (1−4) featuring an unique 6/6/5/6/5 pentacyclic framework, were isolated and structurally characterized from a Chinese medicinal plant Phyllanthus franchetianus. Compounds 2−4 are three pairs of enantiomers that were initially obtained in a racemic manner, and were further separated by chiral HPLC preparation. Compounds 1−4 were proposed to be originated biosynthetically from a coexisting lignan via an intramolecular Friedel–Crafts reaction as the key step. A bioinspired total synthesis strategy was thus designated, and allowed the effective syntheses of compounds 2−4 in high yields. Some of compounds exhibited significant anti-inflammatory activities in vitro via suppressing the production of pro-inflammatory cytokine IL-1β. Notably, compound 4, the most active enantiomeric pair in vitro, displayed prominent potent protecting activity against liver injury at a low dose of 3 mg/kg in mice, which could serve as a promising lead for the development of acute liver injury therapeutic agent.

Keywords

• Phychetins
• Phyllanthus franchetianus
• Structural elucidation
• Total synthesis
• Liver injury protection
• Anti-inflammation