Design, synthesis and biological evaluation of biaryl amide derivatives as modulators of multi-drug resistance

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Multi-drug resistance (MDR) significantly hinders cancer treatment efficacy.
• Overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and MDR-associated protein 1 (MRP1), is a key mechanism of MDR in cancer cells.

Purpose of the Study:

• To systematically investigate structure-activity relationships of biaryl amide compounds.
• To identify potent agents capable of reversing MDR mediated by ABC transporters.
• To evaluate the efficacy of a novel compound, D2, in overcoming MDR in cancer.

Main Methods:

• Structure-activity relationship (SAR) studies and structural optimization of biaryl amide derivatives.
• In vitro evaluation of compound D2's ability to reverse MDR in paclitaxel- and cisplatin-resistant cancer cell lines (A2780/T, A2780/CDDP, A549/T).
• Assessment of D2's direct binding to P-gp, its effect on P-gp and MRP1 expression, and its impact on P-gp-mediated drug efflux using rhodamine 123 (Rh123) accumulation assays.

Main Results:

• Structural optimization led to the identification of D2, a potent resistance reversal agent.
• Compound D2 demonstrated significant reversal of MDR to paclitaxel and cisplatin in multiple resistant cell lines.
• D2 was found to directly bind to P-gp, downregulate P-gp and MRP1 expression, and inhibit P-gp-mediated efflux of Rh123.

Conclusions:

• Compound D2 effectively overcomes MDR induced by P-gp.
• D2 exhibits promising potential as a therapeutic agent to enhance the efficacy of chemotherapy in drug-resistant cancers.
• Further investigation into D2's mechanism and therapeutic application is warranted.