Carborane-Based Derivatives as Inhibitors of the Breast Cancer Resistance Protein (ABCG2).

Many chemotherapies are still severely restricted due to cancer cells' resistance to antineoplastic agents. Alongside the constant alteration of cancer itself, neoplastic cells tend to develop a multidrug resistance (MDR), intrinsic or acquired. MDR can result from several unrelated biochemical mechanisms. Altered cell membrane transporters are one of the most extensively implicated causes of MDR, decreasing intracellular drug concentrations to non-therapeutic levels. The upregulation of integral membrane transporters, the ATP-binding cassette transporters (ABCs), is strongly related to increased efflux of chemotherapeutic agents. One of the main efflux transporters associated with MDR is the ABCG2 or Breast Cancer Resistance Protein (BCRP). Thus, selective inhibition of the efflux transporter-mediated excretion of anti-cancer agents represents a valid approach to overcome MDR. This chapter summarizes advances in the design and structural modification of target protein-known scaffolds, such as 5,6,7-trihydroxyflavones, quinazolines, as well as a novel, thus far ABCG2-unrelated scaffold, isoquinolinone. In combination with a carborane moiety (C2B10H12) as a central pharmacophore and methoxy-based substitution patterns, the modifications can allow enhanced affinities and metabolic stability through the boron-carbon cluster and further allow insight into the pattern-induced relationship between structure and activity. Borcalein and 5,6,7-trimethoxyborcalein, a carborane derivative of 5,6,7-trihydroxyflavone (baicalein) and 5,6,7-trimethoxyflavone, respectively, and a small library of polymethoxylated and carborane-functionalized 2-phenylquinazolin-4-amine derivatives and related carboranylquinazoline amide derivatives are covered in this chapter. A comparison of the most active carborane derivatives with their respective organic phenyl and adamantyl analogs is also included. Biological studies showed reduced toxicity, enhanced inhibitory efficacy, and, most importantly, reversal of drug resistance for most carborane derivatives, rendering such compounds interesting for further studies.