Diterpenoids with a novel 6/5-5 spiro tricyclic skeleton from Orthosiphon wulfenioides and their NLRP3 inflammasome inhibitory activity

Abstract

Wulfenioidins A–C (1–3) with an unprecedented 6/5-5 tricyclic skeleton featuring the unusual spiro[4.4]nonane were isolated from the whole plant of Orthosiphon wulfenioides. Their structures were elucidated by X-ray diffraction, quantum chemical calculations, and extensive spectroscopic methods. Putative biosynthetic pathways of 1–3 were proposed. Compound 3 showed a potent inhibitory effect against the NLRP3 inflammasome with an IC₅₀ value of 1.05 μM and significantly blocked the NLRP3 inflammasome-induced pyroptosis by inhibiting caspase-1 activation, GSDMD-NT production, and IL-1β secretion in J774A.1 cells.