Synthesis and Investigation of Tetrahydro-β-carboline Derivatives as Inhibitors of the Breast Cancer Resistance Protein (ABCG2)

The
breast cancer resistance protein (ABCG2) transports chemotherapeutic
drugs out of cells, which makes it a major player in mediating multidrug
resistance (MDR) of cancer cells. To overcome this mechanism, inhibitors
of ABCG2 can be used. Only a few potent and selective ABCG2 inhibitors
have been discovered, i.e., fumitremorgin C (FTC), Ko143, and the
alkaloid harmine, which contain a tetrahydro-β-carboline or
β-carboline backbone, respectively. However, toxicity and or
instability prevent their use in vivo. Therefore, there is a need for further potent inhibitors. We synthesized
and pharmacologically investigated 37 tetrahydro-β-carboline
derivatives. The inhibitory activity of two compounds (51, 52) is comparable to that of Ko143, and they are selective
for ABCG2 over ABCB1. Furthermore, they are able to reverse the ABCG2-mediated
resistance toward SN-38 and inhibit the ATPase activity. The cytotoxicity
data show that their inhibitory effect is substantially higher than
their toxicity.