(+)/(−)-Yanhusamides A−C, three pairs of unprecedented benzylisoquinoline-pyrrole hetero-dimeric alkaloid enantiomers from Corydalis yanhusuo

Abstract

A chemical investigation on the aqueous extract of Corydalis yanhusuo tubers led to the isolation and structural elucidation of three pairs of trace enantiomeric hetero-dimeric alkaloids, (+)/(−)-yanhusamides A−C (1−3), featuring an unprecedented 3,8-diazatricylco[5.2.2.02,6]undecane-8,10-diene bridged system. Their structures were exhaustively characterized by X-ray diffraction, comprehensive spectroscopic data analysis, and computational methods. Guided by the hypothetical biosynthetic pathway for 1−3, a gram-scale biomimetic synthesis of (±)-1 was achieved in 3 steps using photoenolization/Diels−Alder (PEDA) [4+2] cycloaddition. Compounds 1‒3 exhibited potent inhibition of NO production induced by LPS in RAW264.7 macrophages. The in vivo assay showed that oral administration of 30 mg/kg of (±)-1 attenuated the severity of rat adjuvant-induced arthritis (AIA). Additionally, (±)-1 induced a dose-dependent antinociceptive effect in the acetic acid-induced mice writhing assay.

Keywords

• (+)/(−)-Yanhusamides A−C
• Hetero-dimeric alkaloids
• Corydalis yanhusuo
• Anti-inflammatory
• Analgesic activity