Antiproliferative Activity and Target Analysis of 18β-Glycyrrhetinic Acid Derivatives Modified With α, β-Unsaturated...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Molecular Biology

Background:

• Cancer presents significant therapeutic challenges due to multidrug resistance and poor prognosis.
• 18β-glycyrrhetinic acid (18β-GA) demonstrates potential in cancer treatment but suffers from low bioavailability.
• Developing effective antitumor agents remains a critical unmet need.

Purpose of the Study:

• To synthesize novel 18β-GA derivatives with enhanced anticancer properties.
• To investigate the antiproliferative activity and potential molecular targets of these new compounds.
• To address the limitations of 18β-GA by improving its therapeutic potential.

Main Methods:

• Molecular hybridization strategy to create α, β-unsaturated carbonyl modified 18β-GA derivatives.
• In vitro antiproliferative assays against HCT-116, SH-SY5Y, and HepG2 cancer cell lines.
• Reverse target finding and in silico molecular docking to identify and validate STAT3 as a key target.

Main Results:

• Compounds 9a, 9g, and 9i displayed significant antiproliferative effects, with IC50 values between 1.52–3.46 μM.
• STAT3 was identified as the likely molecular target for the most active derivatives.
• In silico analysis confirmed strong binding affinity of these derivatives to STAT3.

Conclusions:

• Novel 18β-GA derivatives exhibit potent anticancer activity.
• These compounds show promise as STAT3 inhibitors for cancer therapy.
• The developed derivatives may overcome the bioavailability limitations of the parent compound.