Asperinamide A, an anti-inflammatory prenylated indole alkaloid possessing an unprecedented bicyclo[2.2.2]diazaoctane fused with substituted piperidine scaffold from Aspergillus sp. TE-65L

Abstract

Prenylated indole alkaloids (PIAs) containing a bicyclo[2.2.2]diazaoctane ring have gained extensive attention due to their chemical (especially stereochemical), biosynthetic/synthetic, and bioactive interests. In the present study, An unprecedented PIA (namely asperinamide A, 1), featuring a 6/6/5/6/6/6/5 heptacyclic scaffold fused with bicyclo[2.2.2]diazaoctane and substituted piperidine, hitherto unknown among this family of PIAs, along with its biosynthetic-related analogues sclerotiamide (2) and (+)-stephacidin A (3), were isolated from the Nicotiana tabacum-derived endophytic fungus Aspergillus sp. TE-65L. Their structures were unambiguously determined by detailed NMR, mass spectra, and X-ray crystallographic analysis. A detailed plausible biosynthetic analysis for compounds 1–3 was proposed, which revealed that the unique substituted piperidine ring may be formed through a radical-mediated rearrangement. Compound 1 showed significant anti-inflammatory activity targeting the TLR4-MD2 site in the TLR4/NF-κB signaling pathway.