In a recent study, researchers isolated two novel bis-β-triketone hybrids, Corymbinols A (1) and B (2a/2b), from the fruits of Corymbia citriodora. Corymbinol A demonstrated a 31% inhibition of cuproptosis in HepG2 cells at a concentration of 20 μM, suggesting its potential as a non-toxic therapeutic option against liver cancer.

Cuproptosis is a recently identified mechanism of cell death that is dependent on copper and is closely associated with neurodegenerative diseases such as Alzheimer's and Huntington's. While copper chelators can help mitigate cuproptosis, developing specific inhibitors has proven challenging.

To tackle this issue, a collaborative research team from the South China National Botanical Garden and the Kunming Institute of Botany, both at the Chinese Academy of Sciences (CAS), isolated and characterized these two bis-β-triketone hybrids—Corymbinols A and B—from the fruits of Corymbia citriodora.

The researchers employed NMR, electronic circular dichroism (ECD), and X-ray crystallography techniques to elucidate the complex structures of these compounds. Corymbinol A features a novel 6/6/10/6/6 pentacyclic scaffold formed through a hetero-Diels–Alder (HDA) cycloaddition between hedycaryol (a sesquiterpene) and dual β-triketone units. In contrast, Corymbinol B consists of enantiomeric bis-β-triketone-dihydrochalcone conjugates.

In a HepG2 cell model induced by elesclomol (ES) and CuCl₂, Corymbinol A exhibited moderate inhibition of cuproptosis at 20 μM, which partially reversed cell death caused by copper accumulation. It also restored the expression levels of mitochondrial iron-sulfur cluster proteins (ACO2 and SDHB), which are key markers of cuproptosis. Mechanistic studies indicate that Corymbinol A disrupts copper-mediated protein toxicity without acting as a copper chelator, providing a unique therapeutic strategy.

The study further proposed a biosynthetic pathway for these compounds, originating from β-triketone monomers found in Myrtaceae plants. This research enhances the chemical diversity of phloroglucinol derivatives and underscores their potential in targeting copper-driven diseases.

The findings were published in Organic Letters, and this work was supported by the National Natural Science Foundation of China and the Science and Technology Service Network Program of CAS.

Novel skeletal structures of Corymbinols A and B isolated from C. citriodora fruits.（Imaged by QIU et al）

Proposed biosynthetic pathway (left) and cuproptosis-inhibitory activity of Corymbinol A (right).（Imaged by QIU et al）