Hydroxyl-substituted double Schiff-base condensed 4-piperidone/cyclohexanones as potential anticancer agents with...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Cancer Biology

Background:

• Schiff-base derivatives are explored for their therapeutic potential.
• Cytotoxicity and apoptosis induction are key mechanisms in anticancer drug development.
• Targeting apoptosis-related proteins like Bcl-2 is a strategy in cancer therapy.

Purpose of the Study:

• To synthesize and characterize novel hydroxyl-substituted double Schiff-base 4-piperidone/cyclohexanone derivatives.
• To evaluate the in vitro and in vivo anticancer activity of these derivatives.
• To elucidate the mechanism of action for the most potent compound.

Main Methods:

• Synthesis and full characterization (1H NMR, IR, elemental analysis) of compounds.
• In vitro cytotoxicity assays against various human carcinoma and non-malignant cell lines.
• Western blot, flow cytometry, and molecular docking to determine mechanism of action.
• In vivo efficacy study using HepG2 xenografts in a mouse model.

Main Results:

• Synthesized derivatives 3a-e, 4a-e, 5a-d, and 6a-c.
• 4-Piperidinone derivatives exhibited superior cytotoxicity compared to cyclohexanone analogs.
• Compound 5c demonstrated significant apoptosis induction by modulating Bax and Bcl-2 expression.
• Molecular docking revealed favorable binding of 5c to the Bcl-2 protein active site.
• Compound 5c suppressed HepG2 tumor growth in vivo without significant toxicity.

Conclusions:

• Hydroxyl-substituted 4-piperidone derivatives, especially 5c, possess significant anticancer properties.
• Compound 5c effectively promotes cancer cell apoptosis and inhibits liver tumor growth.
• 5c is a potential anticancer agent for the early treatment of liver cancers.