Hybrids of Harmine and Quinoline-Based Antimalarials Show a Strong Antiproliferative Effect on Glioblastoma Cells and reverse ABC Transporters-Mediated Drug Resistance

Glioblastomas are the most aggressive tumors of the nervous system, whose treatment success is associated with many problems, including resistance to therapy and the permeability of the blood-brain barrier (BBB). The blood-brain barrier is equipped with ATP-binding cassette (ABC) transporters that play an important function by excreting toxic compounds. Two transporters in particular, ABCB1 (P-glycoprotein) and ABCG2 (BCRP), play an important role both at the BBB and in the development of drug resistance, leading to low intracellular drug concentrations. We investigated the antiproliferative activity of fifteen hybrids comprising harmine and quino-line-based antimalarials with triazole- and ureido-type linkers on neuroblastoma and glioblastoma cell lines. We also investigated their inhibitory effect on the ABCB1 and ABCG2 transporters using cell-based functional assays. We demonstrated that all hybrids showed significantly stronger anti-proliferative effect on glioblastoma cells than the parent compounds and also than the reference drug temozolomide. In addition, a number of derivatives showed remarkable inhibitory effects on ABC transporters, with ureido-type derivatives, harmiprime PU-9 and harmiquine MU-9 exerting the most pronounced dual inhibitory effect on both transporters. These results indicate that hy-brids of harmine and quinoline scaffolds have potential for glioblastoma drug discovery and for the discovery of new dual (ABCB1/ABCG2) inhibitors.