Design, synthesis and multidrug resistance reversal activity evaluation of 8-oxocoptisine derivatives

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Cancer Research

Background:

• Multidrug resistance (MDR) significantly limits the efficacy of cancer chemotherapy.
• 8-Oxocoptisine has demonstrated potential in overcoming MDR in human cancer cells.
• Developing novel MDR reversal agents is crucial for improving treatment outcomes.

Purpose of the Study:

• To synthesize and evaluate novel 8-oxocoptisine derivatives for their MDR reversal activity.
• To identify potent MDR modulators with minimal cytotoxicity.
• To explore preliminary structure-activity relationships (SARs) of these derivatives.

Main Methods:

• Synthesis of fifteen 8-oxocoptisine derivatives.
• Assessment of growth inhibition against cancer cells.
• Evaluation of MDR reversal effects against P-glycoprotein (P-gp)-mediated MDR in MCF-7/ADM cells.
• Comparison with verapamil as a reference compound.

Main Results:

• 12, 13-dinitro-8-oxocoptisine (6c) exhibited potent MDR reversal activity, increasing adriamycin (ADM) sensitivity by 213-fold at 10 μM.
• Compound 6c demonstrated weak intrinsic growth inhibition, suggesting a specific MDR reversal mechanism.
• The activity of 6c was comparable to the established MDR modulator verapamil.

Conclusions:

• 12, 13-dinitro-8-oxocoptisine (6c) is a highly promising candidate for reversing P-gp-mediated MDR.
• The developed derivatives offer potential therapeutic strategies to overcome chemotherapy resistance.
• Further SAR studies are warranted to optimize these novel MDR reversal agents.