Design, Synthesis and Characterization of ABCG2 Inhibitors with a Focus on Water Solubility and Stability in Plasma

ATP-binding cassette (ABC) transporters are gatekeepers at all major tissue barriers, e.g. the intestinal barrier or the blood-brain barrier (BBB). On one hand, these proteins extrude endogenous substrates and on the other hand, they protect cells against the entry of numerous xenobiotics, including a variety of drugs such as anticancer agents or neuropharmaceuticals. The three main drug transporters are ABCB1, ABCC1 and ABCG2, with ABCG2 being predominant at the human BBB. They constitute a severe impediment for the oral bioavailability and brain penetration of drugs, and confer multidrug resistance (MDR) to cancer cells. Thus, inhibitors of ABCG2 are required as molecular tools for examinations on the patho(physiological) role of this transporter and as potential drugs to overcome tissue barriers (especially the BBB) and MDR in cancer. So far, the discovery of ABCG2 inhibitors had largely been driven by potency, while drug-like properties – imperative for application in vivo – had been overlooked. Moreover, the mechanism of transport inhibition had been enigmatic. Therefore, the present thesis aimed at creating novel ABCG2 inhibitors with improved drug-like properties, especially stability in blood plasma and water solubility, and at elucidating the underlying transport inhibition mechanism. Tariquidar analogs had been described as potent and selective ABCG2 inhibitors. Yet, their susceptibility to hydrolysis limited their applicability in vivo. Chapter 2 of this thesis comprises the synthesis (performed by Prof. König’s group) and characterization (performed by our group, including the author of this thesis) of new tariquidar-related inhibitors, obtained by bioisosteric replacement of the labile moieties in the previous tariquidar analog UR-ME22-1. CuAAC (“click” reaction) gave access to a triazole core as a substitute for the labile amide group and the unstable ester moiety was replaced by acyl groups. An HPLC assay proved enhanced stability in blood plasma. Compounds UR-MB108 and UR-MB136 inhibited ABCG2 in ...