Voltage-gated potassium ion channels KV1.3 play a crucial role in biological processes by regulating the flow of ions across various cellular membranes. They are found in most human cells and are particularly active in the immune and nervous systems, where they contribute to the regulation of action potential duration, frequency, and repolarization, as well as membrane potential, proliferation, migration, apoptosis, and cell volume. Increased expression of KV1.3 has been detected in immune system cells, such as macrophages and effector T lymphocytes, indicating their significant role in immune and inflammatory responses. Inhibiting KV1.3 channels is an innovative therapeutic approach for treating various diseases, including multiple sclerosis, diabetes, rheumatoid arthritis, asthma, and different types of cancer.
As part of the development of KV1.3 channel inhibitors as antitumor agents at the Faculty of Pharmacy, University of Ljubljana, we synthesized seven new furan-based inhibitors and evaluated their activity on Kv1.3 ion channels. In our study, we investigated the relationship between the structure of the compounds and their inhibitory activity, using known benzamide KV1.3 inhibitors as a basis. In the initial compound, we replaced the 2-methoxybenzene group with a 3-substituted furan while retaining the 3-substituted thiophene and the amide bridge. The compound was further modified through a hydroxyl group on cyclohexane with various substituents. Five of the prepared compounds (7, 8D1, 8D2, 10, and 11) did not exhibit significant inhibitory effects on KV1.3 channels, as determined using the patch-clamp technique on L929 mouse fibroblasts. If compounds do not inhibit channel activity, they consequently do not influence related cellular processes, and therefore, they were not evaluated on cancer cells. Compounds 12 and 13 were designed for selective mitochondrial targeting and inhibition of mitochondrial KV1.3 channels. Both compounds contain a triphenylphosphonium ion (TPP+), which enables targeted delivery to mitochondria. Their activity was assessed on B16F10 mouse melanoma cancer cells, but neither compound exhibited anticancer effects. Based on the results, we conclude that these compounds do not have sufficient affinity for KV1.3 channels, which is reflected in the absence of anticancer activity. The findings from our research contribute new data to the KV1.3 inhibitor database and enhance our understanding of the relationship between structure and function.
|
