Novel Flavonoid Dimers for Reversing Cancer Drug Resistance

Design, synthesis and characterization of highly potent flavonoid dimers in reversing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP)-mediated cancer drug resistance

Multidrug resistance (MDR) in cancer is a major problem in chemotherapy. We have designed small molecules to reverse it. Membrane proteins P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) pump drugs out of cancer cells and reduce chemotherapy efficacy. We have designed, synthesized and characterized novel diet-derived flavonoid dimers which can target P-gp and BCRP’s dimeric structure. Due to the unique design of dimeric in structure which can specifically bind to the pseudodimeric P-gp and BCRP, these flavonoid dimers can inhibit P-gp and BCRP, and reverse cancer drug resistance with very high potency (inhibiting BCRP at < 1 nM) and low toxicity (therapeutic index of 1x10⁵ ).

Special Features and Advantages

Reverse cancer resistance to multiple drugs
High potency in inhibiting breast cancer resistance protein with effective concentration 50 (EC₅₀) lower than 1 nM
Low toxicity towards normal fibroblast (IC₅₀ > 100 µM)
High therapeutic index of over 1 x 10⁵
High throughput synthesis of flavonoid dimer library for future activity screening

Applications

Prevent drug efflux by drug-resistant cancer cells
Reverse multidrug resistance in tumor

Awards

Gold Medal – 41st International Exhibition of Inventions of Geneva, Switzerland (April 2013)
Special Award from the Romanian Delegation (April 2013)
Silver Award – 6th China International Invention Exhibition Awards (2008)

Principal Investigator

Dr Larry M. C. Chow, Prof. Tak-hang Chan

Department of Applied Biology and Chemical Technology

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Novel Flavonoid Dimers for Reversing Cancer Drug Resistance

Design, synthesis and characterization of highly potent flavonoid dimers in reversing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP)-mediated cancer drug resistance