Enhanced reversal of ABCG2‐mediated drug resistance by replacing a phenyl ring in baicalein with a meta‐carborane

Success of chemotherapy is often hampered by multidrug resistance. One mechanism for drug resistance is the elimination of anticancer drugs through drug transporters, such as breast cancer resistance protein (BCRP; also known as ABCG2), and causes a poor 5‐year survival rate of human patients. Co‐treatment of chemotherapeutics and natural compounds, such as baicalein, is used to prevent chemotherapeutic resistance but is limited by rapid metabolism. Boron‐based clusters as meta‐carborane are very promising phenyl mimetics to increase target affinity; we therefore investigated the replacement of a phenyl ring in baicalein by a meta‐carborane to improve its affinity towards the human ABCG2 efflux transporter. Baicalein strongly inhibited the ABCG2‐mediated efflux and caused a fivefold increase in mitoxantrone cytotoxicity. Whereas the baicalein derivative 5,6,7‐trimethoxyflavone inhibited ABCG2 efflux activity in a concentration of 5 μm without reversing mitoxantrone resistance, its carborane analogue 5,6,7‐trimethoxyborcalein significantly enhanced the inhibitory effects in nanomolar ranges (0.1 μm) and caused a stronger increase in mitoxantrone toxicity reaching similar values as Ko143, a potent ABCG2 inhibitor. Overall, in silico docking and in vitro studies demonstrated that the modification of baicalein with meta‐carborane and three methoxy substituents leads to an enhanced reversal of ABCG2‐mediated drug resistance. Thus, this seems to be a promising basis for the development of efficient ABCG2 inhibitors.