Centralna tehniška knjižnica Univerze v Ljubljani (CTK)
  • Načrtovanje in sinteza novih zaviralcev napetostno odvisnih kalijevih kanalov KV 1.3 in KV 10.1 s protitumornim delovanjem = Design and synthesis of novel voltage-gated potassium channel KV 1.3 and KV 10.1 inhibitors with anticancer activity : doktorska disertacija
    Gubič, Špela
    Voltage-gated potassium channels are proteins found in cell membranes. They include channels KV1.3 and KV10.1 (hEAG1), which are significantly involved in cancer development. High expression of ... KV10.1 (hEAG1) has been found in more than 70% of human cancers. KV1.3 is directly involved in promoting cancer cell proliferation, and inhibition of the channel in mitochondria can selectively induce cancer cell apoptosis. As part of our work, we have developed new benzamide-thiophene-based KV1.3 inhibitors. Since the cryo-electronic (cryo-EM) structure of the channel was not known at the time of development, new inhibitors were designed based on the structure of the known benzamide KV1.3 inhibitor. Two new benzamide hit compounds were identified by ligand-based virtual screening. New thiophene-based inhibitors were developed by structural optimization of the hit compounds and by preparation of a large number of new analogues, which were also patented. The most selective among them was the tetrahydropyran-type compound, which exhibited KV1.3 inhibitory activity in the mid nanomolar range. Cyclohexane-type compounds with two chiral centres and with hydroxyl or carbamate groups showed the most potent KV1.3 inhibition in the low nanomolar range in T cells, affecting their activation, intracellular Ca2+ levels, and colony formation. KV1.3 is involved in proliferation of healthy and cancer cells. The new benzamide compounds either inhibited the growth of Panc-1 cells or were cytotoxic to them. Certain benzamide compounds also had a cytotoxic effect on Colo357 cells. Only one compound showed specific anticancer activity without effects on non-cancer hTERT-RPE1 cells. KV1.3 is also found in the inner mitochondrial membrane (mitoKV1.3). Since a crucial step for selectively inducing apoptosis in cancer cells is for the compounds to enter mitochondria in large numbers, we developed new benzamide-based mitoKV1.3 inhibitors. The latter were prepared by attaching the triphenylphosphonium+ (TPP+) group to benzamide KV1.3 inhibitors with two chiral centers. The mitochondrial benzamide inhibitors greatly reduced the number of live Colo357 cells in the 2D and 3D cell models. The two compounds induced apoptosis at 5 μM in the 2D and 3D cell models. Both compounds also significantly decreased the number of live B16F10 mouse melanoma cells expressing mitoKV1.3. On the other hand, the two compounds had a significantly less potent effect on B16F10 mouse melanoma cells not expressing mitoKV1.3. Like KV1.3, the hEAG1 channel is also significantly involved in cancer cell proliferation. Because it is found in healthy tissues only in the central nervous system, it is an almost ideal IV target for the development of new anticancer drugs. We developed new diphenylamine hEAG1 inhibitors by structurally optimising previously published diphenylamine inhibitors. Our new inhibitors showed improved potency compared to previsouly published compounds. The best compound had a better ratio of IC50 values for hEAG1 and hERG than known compounds of the same structural type. The compounds inhibited the growth of breast cancer cells MCF-7, which highly express hEAG1, and Panc-1 cells, which have high hERG expression. As part of the doctoral work, we have developed new structural types of KV1.3 and KV10.1 inhibitors, which represent an important contribution to the development of new drugs and immunosuppressants. The KV1.3 and KV10.1 inhibitors have a new mechanism of action, as there are no drugs with such a mechanism of action on the market so far. The PhD thesis represents an original contribution to the field of research on the involvement of ion channels in cancer processes.
    Vrsta gradiva - disertacija ; neleposlovje za odrasle
    Založništvo in izdelava - Ljubljana : [Š. Gubič], 2022
    Jezik - angleški
    COBISS.SI-ID - 133516291

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Centralna tehniška knjižnica Univerze v Ljubljani
prosto - na dom, čas izposoje: 14 dni
Signatura – lokacija, inventarna št. ... Status izvoda
0000052047/0000002639 Skladišče
IN: 320230117 52047/2639 Skladišče
IN: 320230117 		prosto - na dom, čas izposoje: 14 dni
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