Synthesis of benzamide-based inhibitors of the Kv1.3 voltage gated potassium ion channel

Napetostno odvisni kalijevi kanali imajo pomembno vlogo pri delovanju celice, saj v celični membrani vzpostavljajo mirovni membranski potencial in določajo dolžino trajanja akcijskega potenciala. Prav tako so vpleteni v celične procese proliferacije in aktivacije, uravnavanja celičnega volumna in v apoptozo celice. Napetostno odvisni kalijevi kanali podtipa KV1.3 se nahajajo v mnogih celicah v telesu, kjer so vpleteni v različne fiziološke in patofiziološke procese. Ker ima veliko celic, ki so pomembno vpletene v rakave, avtoimunske in kronične vnetne bolezni, povečano izražanje KV1.3 kanalov, so kalijevi kanali lahko pomembni označevalci odkrivanja bolezni in nova tarča za zdravljenje teh bolezni. Z zaviralci kalijevih KV1.3 kanalov bi lahko zmanjšali prekomerne delitve rakavih celic in spodbudili njihovo apoptozo ter s tem preprečili širjenje tumorja. V magistrski nalogi smo sintetizirali pet potencialnih zaviralcev napetostno odvisnih kalijevih kanalov KV1.3. Za spojino vodnico smo izbrali spojino I (IC50 = 920 nM), ki je objavljen zaviralec tega kanala. Na podlagi strukture spojine I smo sintetizirali druge podobne spojine in preverili, ali uspešno zavirajo delovanje kanala in kateri strukturni deli spojine so pomembni za zaviralno delovanje (SAR). Ena izmed petih potencialnih zaviralcev, spojina 3, ki je vsebovala tetrahidropiranski obroč v strukturi, je pokazala 87 % zaviralno delovanje na KV1.3 kanale, zato smo ji določili IC50 vrednost (IC50 = 4,3 μM). Za uspešno zaviranje KV1.3 kanala sta pri spojini 3 najverjetneje najbolj pomembna tetrahidropiranski obroč in benzenov obroč, ki ima na meta mestu vezano metilno skupino. Ostale sintetizirane spojine niso uspešno zavirale kanala KV1.3.Voltage-gated potassium channels are significantly involved in cell function. They participate in establishing resting membrane potential and in determination of the duration of the action potential. They are also involved in cellular processes as proliferation, activation, cell volume regulation, and cell apoptosis. Voltage-gated potassium channels KV1.3 are broadly expressed in many cells in human body, where they are significantly involved in physiological and pathophysiological processes. Cells that play important roles in cancer, autoimmune and chronic inflammatory diseases, may have increased expression of KV1.3 channel. Potassium channels KV1.3 could be important markers for these diseases and new targets for the treatment of these diseases. Potassium channel KV1.3 inhibitors offer potential to reduce the division of cancer cells, to promote their apoptosis, and to prevent tumor to spread. In this master degree we synthesized five potential inhibitors of voltage-gated potassium channels KV1.3. Compound I (IC50 = 920 nM), which is the published inhibitor of this channel, was selected as the lead compound. We designed and synthesized other similar compounds based on the structure of compound I and tested whether they successfully inhibited the channel function. We determined which structural parts of the new compounds were important for inhibitory activity on KV1.3 channels. One of the five potential inhibitors, compound 3, which incorporated tetrahydropyran ring in the structure, showed 87% inhibitory activity on the KV1.3 channel, therefore we determined its IC50 value for KV1.3 (IC50 = 4.3 μM). Tetrahydropyran and benzene ring, substituted with methyl group at meta site, in compound 3 are probably the most important structural parts that are important for successful inhibition of the KV1.3 channel. Other synthesized compounds did not successfully inhibit the KV1.3 channel