Labdane and ent-halimane diterpenoids with STAT3-inhibitory activity from Leonurus sibiricus

Area of Science:

• Natural Product Chemistry
• Medicinal Chemistry
• Cancer Biology

Background:

• Leonurus sibiricus is a source of bioactive compounds.
• Naturally occurring antitumor agents are actively sought.
• Interleukin-6 (IL-6) signaling is implicated in cancer progression.

Purpose of the Study:

• To isolate and characterize novel diterpenoids from Leonurus sibiricus.
• To evaluate the inhibitory activity of isolated compounds against IL-6-stimulated STAT3 activation.
• To investigate the potential of compound 1 as an antitumor agent for nasopharyngeal carcinoma.

Main Methods:

• Isolation and structural elucidation of diterpenoids using spectroscopic analyses and electronic circular dichroism.
• In vitro evaluation of inhibitory activity against STAT3 using a luciferase reporter assay.
• Assessment of antiproliferative, cell migration, invasion, epithelial-mesenchymal transition, and ferroptosis effects of compound 1 in cancer cell lines.

Main Results:

• Ten new diterpenoids, including a rare 10-epi labdane scaffold, were isolated.
• Compound 1 exhibited significant inhibition of IL-6-stimulated STAT3 activation (IC50 = 20.31 μM).
• Compound 1 demonstrated antiproliferative effects, particularly in CNE cells, and modulated key cancer hallmarks including migration, invasion, EMT, and ferroptosis.

Conclusions:

• Compound 1 effectively inhibits the JAK2/STAT3 pathway by binding to STAT3.
• Compound 1 shows potential as a lead compound for the development of novel therapeutics against nasopharyngeal carcinoma.
• Further research into compound 1's mechanism of action and in vivo efficacy is warranted.