Synthesis and investigation of tetrahydro-β-carboline derivatives as inhibitors of the Breast Cancer Resistance Protein (ABCG2).

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Synthesis and investigation of tetrahydro-β-carboline derivatives as inhibitors of the Breast Cancer Resistance Protein (ABCG2).

J Med Chem. 2016 Jun 9;

Authors: Spindler A, Stefan K, Wiese M

Abstract
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 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.

PMID: 27280693 [PubMed - as supplied by publisher]