# NMR-Guided Discovery of Luvunga D: A Novel Propellane-Type Limonoid from Luvunga scandens That Functions as a Non-Classical Ferroptosis Inhibitor

## TL;DR

Researchers discovered a new compound from Luvunga scandens that inhibits a type of cell death called ferroptosis through a unique mechanism.

## Contribution

The study introduces Luvunga D, a novel propellane-type limonoid with non-classical ferroptosis inhibition activity.

## Key findings

- Luvunga D inhibits RSL3-induced ferroptosis in liver cells with an EC50 of 16.1 µM.
- The compound suppresses lipid peroxidation without acting as a direct antioxidant or iron chelator.
- A proposed biosynthetic pathway explains the formation of isoobacunoic acid and propellane-type limonoids.

## Abstract

Recent phytochemical investigations have demonstrated that Luvunga scandens is a rich source of structurally diverse secondary metabolites; however, its potential antioxidant-active constituents and their underlying mechanisms remain largely unexplored. In this study, an NMR-guided fractionation strategy applied to the rhizomes and leaves of L. scandens led to the isolation of ten limonoids, including three new compounds, Luvungas B–D (3, 4, and 8). Their structures and absolute configurations were determined through extensive spectroscopic analysis, X-ray diffraction, and ECD calculations. Based on the isolated analogues, a biosynthetic pathway is proposed, featuring the metabolic bifurcation of a key acyclic intermediate into the isoobacunoic acid and propellane-type lineages. Biological evaluation revealed that 8 inhibits RSL3-induced ferroptosis in HepaRG liver cells with an EC50 of 16.1 µM. Mechanistic studies demonstrated that, unlike classical antioxidants, compound 8 mitigates lipid peroxidation without exhibiting direct radical-scavenging or iron-chelating activities. These findings suggest that 8 suppresses ferroptosis via non-canonical mechanisms.