Cancer is the second most common cause of death globally. The number of patients and the number of deaths due to cancer increase each year. An estimated 21.7 million new cancer diagnoses and 13 million cancer deaths are expected in 2030. Cancer is a large group of diseases in which, due to changes in the genome, normal cells lose control of the regulatory mechanisms of growth and reproduction, which leads to uncontrolled cell division and growth. In the case of metastasis, the cells are released from the primary source of the tumor into the blood or lymphatic circulation and thus pass to other organs and tissues.
Overexpression of the voltage-gated Kv10.1 potassium channels was detected in 70% of different tumor types. Tumor cells overexpressing Kv10.1 channels acquire cancer progression capacity, which means that Kv10.1 plays an important role in cell proliferation, differentiation, tumorigenesis, migration, and apoptosis of cancer cells. By inhibiting these channels, tumor growth is reduced, so Kv10.1 potassium channels are a potential target for cancer treatment. Various analogues of the diarylamine Kv10.1 inhibitor 7b, which was recently discovered at the Faculty of Pharmacy, University of Ljubljana, were prepared as a part of the master's thesis. Compound 7b with an IC50 of 5 µM was modified at several positions to provide a compound with improved inhibitory and selective action on Kv10.1 potassium channels. Functional groups were changed at the central diarylamine scaffold at the positions R1, R2 and R3. This sought to determine the effect on the inhibitory activity of NH2, NO2 and H as R1, H and CF3 as R2, and the effect of dimethylamine, methylamide, aniline and the morpholine ring at the R3 site. In determining the structure activity relationship, we have used already prepared and evaluated compounds having a carboxyl group and a methyl ester as R1 and a proton on the aliphatic portion of the compound (R4). From the results of the patch-clamp assay, it was found that only two of the thirteen compounds synthesized, 8b and 14b, had only slightly improved inhibitory action (8b 81% and 14b 87% vs 7b 61% at 10 µM concentration) on Kv10.1 channels, selectivity however, was not achieved by any modification of the compound. In view of the obtained results, we also made some suggestions for further optimisation of compounds with the goal to improve their potency and achieve antiproliferative activity in cancer cell lines.
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