Basic N-interlinked imipramines show apoptotic activity against malignant cells including Burkitt's lymphoma

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Oncology

Background:

• Tricyclic antidepressants like imipramine and desipramine have limited use in cancer therapy.
• Developing novel derivatives with enhanced anti-cancer properties is crucial for overcoming drug resistance.

Purpose of the Study:

• To synthesize and evaluate novel ethylene glycol N-interlinked imipramine dimers as potential anti-cancer agents.
• To investigate the mechanism of cell death induced by these imipramine derivatives.

Main Methods:

• Synthesis of imipramine dimers via amide coupling and lithium aluminium hydride reduction.
• Assessment of cellular viability inhibition and cell death mechanisms in various cancer cell lines.
• Evaluation of inhibition of the human serotonin transporter (hSERT).

Main Results:

• Synthesized imipramine dimers demonstrated potent inhibition of cancer cell viability.
• These dimers induced cell type-specific death mechanisms, effective even in chemoresistant Burkitt's lymphoma cells.
• Basic amine analogues enhanced compound potency; imipramine dimers showed moderate hSERT inhibition (micromolar IC50 values).

Conclusions:

• Newly designed imipramine derivatives possess significant potential as anti-cancer therapeutics.
• The anti-cancer activity is independent of hSERT inhibition, suggesting a novel mechanism of action.
• These compounds offer a promising avenue for treating malignant cells, including those resistant to conventional chemotherapy.