Flavonoid Oxime Carbamate Derivatives: Reversal of Multidrug Resistance in Cancer Cells

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Cancer Research

Background:

• Multidrug resistance (MDR) in cancer, primarily mediated by efflux transporters like P-glycoprotein (P-gp/ABCB1), significantly compromises treatment efficacy.
• Tangeretin, a natural polymethoxyflavonoid, serves as a lead compound for developing novel MDR modulators.

Purpose of the Study:

• To synthesize and evaluate novel tangeretin derivatives, specifically oxime carbamates, for their potential to overcome P-gp-mediated multidrug resistance in cancer.
• To identify potent MDR reversal agents derived from tangeretin that can restore cancer cell sensitivity to chemotherapeutics.

Main Methods:

• Synthesis of 23 novel oxime carbamate derivatives of tangeretin using carbonyldiimidazole or isocyanates.
• Structural elucidation of synthesized compounds using 1D and 2D NMR spectroscopy.
• Evaluation of MDR reversal potential via rhodamine-123 accumulation assays, chemosensitivity experiments, and ATPase assays in P-gp-expressing cells.

Main Results:

• Most synthesized tangeretin derivatives exhibited significant P-gp inhibitory activity at non-cytotoxic concentrations.
• Compounds 19, 20, and 22, featuring aliphatic substituents, demonstrated potent MDR reversal effects at 2 μM.
• Several derivatives showed synergistic effects with doxorubicin in drug combination assays and acted as ATPase inhibitors.

Conclusions:

• Novel tangeretin-derived oxime carbamates are effective P-gp inhibitors and possess significant MDR reversal capabilities.
• These compounds hold potential as adjuncts to chemotherapy for overcoming multidrug resistance in cancer treatment.
• The structure-activity relationship suggests that specific substituents enhance the MDR reversal efficacy of tangeretin derivatives.