2‐Carboranylquinazoline: The Path to an ABCG2 Inhibitor

Abstract

The role of ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR) in anti-cancer therapy is often challenging, frequently leading to inefficiency of treatments. Cancer cells exploit efflux transporters, like the breast cancer resistance protein (BCRP, ABCG2), to secrete chemotherapeutic substances. In this study, an N-phenyl-2-carboranylquinazolin-4amine ( 8) was designed as inorganic-organic hybrid BCRP inhibitor. In particular, the ABCG2-transporter inhibitor-prominent scaffold N-phenylquinazolin-4-amine was combined with a boronÀ carbon cluster (carborane) moiety. Introducing a carborane at 2-position of the quinazoline scaffold resulted in an increased inhibitory activity towards human ABCG2 (hABCG2) compared to its recently published regioisomer Ncarboranyl-2-phenyl-quinazolin-4-amine. The carboranylquinazoline 8 further showed the ability to reverse hABCG2-mediated drug resistance in MDCKII-hABCG2 cells by lowering the IC 50 value of the BCRP-substrate mitoxantrone, similar to the standard reference and strong inhibitor Ko143, without exhibiting intrinsic toxicity in the lower micromolar ranges. These results make compound 8 a promising scaffold for the design of further BCRP inhibitors.

Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin

“…There are three major strategies for handling ABC transporter-induced resistance: (1) pharmacological inhibition of ABCG2 activity, (2) inhibition of ABCG2 expression, and (3) circumventing the ABCG2-mediated resistance by using agents that are poor substrates [29]. In our previous work [30][31][32] we have followed the strategy of synthesizing novel compounds able to inhibit the human ABCG2 protein. With the incorporation of a meta-carborane (closo-dicarbadodecaborane, C 2 B 10 H 12 ) moiety as a pharmacophore into a (poly(methoxylated)) 2-phenylquinazolin-4-amine scaffold (Figure 1), potent, non-toxic inhibitors of BCRP were obtained; furthermore, a strong reversion of ABCG2-mediated mitoxantrone resistance in MDCKII-hABCG2 cells was achieved [32,33].…”