Enantiomeric meroterpenoids from Rhododendron capitatum and their anti-inflammatory activity

Area of Science:

• Natural Products Chemistry
• Medicinal Chemistry
• Pharmacognosy

Background:

• The genus Rhododendron is a rich source of bioactive secondary metabolites.
• Meroterpenoids, compounds derived from both mevalonate and acetate pathways, exhibit diverse biological activities.
• Investigating the chemical constituents of Rhododendron capitatum can lead to the discovery of novel bioactive compounds.

Purpose of the Study:

• To isolate and characterize meroterpenoids from Rhododendron capitatum.
• To elucidate the structures of new compounds using advanced spectroscopic and crystallographic methods.
• To evaluate the biological activities of isolated compounds, focusing on hypoxia-inducible factor-1α (HIF-1α) inhibition and anti-inflammatory effects.

Main Methods:

• Isolation of compounds using various chromatographic techniques.
• Structure elucidation through comprehensive spectroscopic analyses (NMR, MS) and X-ray crystallography.
• Determination of absolute configurations using modified Mosher's method and electronic circular dichroism (ECD) calculations.
• In vitro assays including hypoxia-inducible factor-1α (HIF-1α) responsive element (HRE) luciferase assay and assessment of macrophage-mediated inflammatory response.

Main Results:

• Ten enantiomeric pairs of meroterpenoids were isolated, including six new compounds: (+/-)-capitanoids A-F, (+)-ranhuadujuanine B, (-)-rubiginosin G, and (-)-anthopogochromene B.
• (+/-)-Capitanoid A represents the first reported meroterpenoids with a 1,2,3,3a,10,10a-hexahydrobenzo[b]cyclopenta[e][1,4]dioxepine system.
• (+/-)-Capitanoid F are the first tris-normonoterpene-containing meroterpenoids discovered in the Rhododendron genus.
• Several compounds, including (+/-)-rubiginosin G, (+/-)-anthopogochromene B, and (-)-rhodonoid B, inhibited the HIF-1α pathway.
• (+)-Anthopogochromene B and (-)-rhodonoid B suppressed macrophage-mediated inflammation by downregulating IL-1β.

Conclusions:

• The study successfully identified and characterized ten meroterpenoids from Rhododendron capitatum, expanding the known chemical diversity of this genus.
• The discovery of novel meroterpenoids with unique structural features, such as the 6/7/5 heterocyclic system and tris-normonoterpene moiety, contributes significantly to natural products chemistry.
• The identified compounds, particularly (+)-anthopogochromene B and (-)-rhodonoid B, show promising anti-inflammatory and HIF-1α inhibitory activities, suggesting potential therapeutic applications.