Lindenane sesquiterpenoid dimers with NLRP3 inflammasome inhibitory activities from Chloranthus holostegius var. shimianensis

Abstract

Thirteen previously undescribed lindenane sesquiterpenoid dimers (LSDs), named chlorahololides G–S (1–13), were isolated from the whole plants of Chloranthus holostegius var. shimianensis, along with ten known analogues (14–23). The structures and absolute configurations of compounds 1–13 were elucidated through comprehensive spectroscopic analysis, NMR and electronic circular dichroism (ECD) calculations, and X-ray single-crystal diffraction. Chlorahololide G (1) represents the first instance of LSDs formed via a C-15–C-9′ carbon-carbon single bond, whose plausible biosynthetic pathway was also proposed. Chlorahololides I and J (3 and 4) were deduced to be rare 8,9-seco and 9-deoxy LSDs with C-11–C-7′ carbon-carbon bond, respectively. The inhibitory activity against NLRP3 inflammasome activation was evaluated for all isolates, with six compounds (5, 7, 8, 17, 22, and 23) exhibiting significant effects, and IC50 values ranging from 2.99 to 8.73 µM. Additionally, a preliminary structure-activity relationship analysis regarding their inhibition of NLRP3 inflammasome activation was summarized. Compound 17 exhibited dose-dependent inhibition of nigericin-induced pyroptosis in J774A.1 cells. Molecular docking studies suggested a strong interaction between compound 17 and NLRP3.

Keywords

• Chloranthus holostegius var. shimianensis
• Lindenane sesquiterpenoid dimers
• Chlorahololides G–S
• NLRP3 inflammasome inhibition
• Pyroptosis