Synthesis and antitumor evaluation of oleanolic acid acylhydrazone derivatives

Area of Science:

• Natural Product Chemistry
• Medicinal Chemistry
• Cancer Biology

Background:

• Cancer remains a leading global cause of mortality, necessitating innovative therapeutic strategies.
• Oleanolic acid (OA), a natural compound, exhibits promising antitumor properties.
• Structural modification of OA can potentially enhance its anticancer potency.

Purpose of the Study:

• To synthesize novel oleanolic acid derivatives with improved antitumor activity.
• To evaluate the cytotoxic effects of these derivatives against various cancer cell lines.
• To elucidate the molecular mechanisms underlying the activity of potent OA derivatives.

Main Methods:

• Synthesis of oleanolic acid acylhydrazone derivatives via modification at the C28 carboxylic acid group.
• Structural characterization using NMR spectroscopy, HRMS, and X-ray diffraction.
• Cytotoxicity assessment via CCK-8 assay against A549, AGS, and K562 cell lines.
• Network pharmacology analysis and molecular docking to identify molecular targets and binding interactions.

Main Results:

• Several synthesized OA derivatives exhibited superior cytotoxic activity compared to cisplatin.
• Compound 28 demonstrated potent inhibition against A549 and K562 cells (IC50 values 8.34 µM and 6.25 µM, respectively).
• Compound 16 showed significant efficacy against AGS cells (IC50 value 7.93 µM).
• Network pharmacology identified key proteins (SRC, PLCG1, EGFR, GRB2, IL1B, HSP90AB1) as potential targets.
• Molecular docking confirmed strong binding affinities between active compounds and identified targets.

Conclusions:

• The structural optimization of oleanolic acid yielded potent anticancer derivatives.
• Compounds 16 and 28 represent promising lead candidates for further development as antitumor agents.
• This study provides a foundation for the rational design of novel oleanolic acid-based cancer therapies.