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Vpliv strukture terciarnih aminov na antiproliferativno delovanje piperidinskih zaviralcev C-končne domene proteina Hsp90
ID Veberič, Barbara (Avtor), ID Tomašič, Tihomir (Mentor) Več o mentorju... Povezava se odpre v novem oknu

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Izvleček
Proteini so strukturno najbolj zapletene in vsestranske molekule, ki so vključene v skoraj vsak biološki proces. Sestavljeni so iz aminokislinskih verig, ki morajo zavzeti ustrezno konformacijo, da protein postane funkcionalen. Pravilno zvijanje proteinov ni pomembno samo za zagotavljanje ustrezne funkcije, temveč tudi za preprečevanje manifestacije in napredovanja številnih bolezni – tudi raka. Za normalno proteinsko homeostazo skrbijo šaperoni, ki preprečujejo nepravilne povezave med aminokislinami in pospešujejo pravilno zvijanje celičnih proteinov. Protein toplotnega šoka Hsp90 je šaperon odgovoren za pravilno zvijanje več sto proteinov, med drugim tudi mnogih onkoproteinov, ki imajo ključen pomen pri maligni transformaciji. Zaradi svoje vloge v patofiziologiji raka je potencialna tarča novih kemoterapevtikov – zaviralcev ATPazne aktivnosti Hsp90. Prvi zaviralci Hsp90 so zavirali vezavo ATP na N-končni domeni proteina. Zaradi toksičnosti, slabe biološke uporabnosti in indukcije odziva toplotnega šoka je bil njihov terapevtski potencial omejen, kar je vodilo v razvoj alosteričnih zaviralcev z vezavnim mestom na C-končni domeni Hsp90. V okviru magistrske naloge smo proučili vpliv strukture terciarnih aminov na antiproliferativno delovanje piperidinskih zaviralcev C-končne domene proteina Hsp90. Kot izhodišče za sintezo končnih spojin smo uporabili spojino s potrjenim alosteričnim zaviranjem Hsp90. Na ta način smo ohranili lastnosti, za katere vemo, da so pomembne za tvorbo interakcij s tarčo. Z variiranjem aminskega dela izhodiščne molekule smo pripravili pet novih spojin, katerih substituenti, pripeti na piperidinski amin, se med seboj razlikujejo v mnogih lastnostih, med drugim tudi v polarnosti, velikosti in zmožnosti tvorbe interakcij s tarčnim vezavnim mestom. Antiproliferativno delovanje končnih spojin smo določili s testom MTS metabolne aktivnosti celic v človeški celični liniji raka dojke MCF-7 ter na podlagi rezultatov proučili odnos med strukturo in delovanjem. Na novo sintetizirane končne spojine so v večini šibkeje aktivne v primerjavi z izhodiščno spojino in že predhodno sintetiziranimi spojinami. Kot najbolj optimalni substituenti na piperidinskem aminu sta se izkazali metilna in benzilna skupina, kar so pomembne ugotovitve za nadaljnjo optimizacijo.

Jezik:Slovenski jezik
Ključne besede:kemoterapevtiki, molekularni šaperoni, piperidin, protein toplotnega šoka Hsp90, rak, zaviralci C-končne domene Hsp90
Vrsta gradiva:Magistrsko delo/naloga
Organizacija:FFA - Fakulteta za farmacijo
Leto izida:2021
PID:20.500.12556/RUL-124678 Povezava se odpre v novem oknu
Datum objave v RUL:07.02.2021
Število ogledov:1698
Število prenosov:269
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Sekundarni jezik

Jezik:Angleški jezik
Naslov:Effects of tertiary amines structure on antiproliferative activity of piperidine-based Hsp90 C-terminal domain inhibitors
Izvleček:
Proteins are structurally the most complex and versatile molecules involved in almost every biological process. They consist of amino acid chains that must fold in a proper conformation for a protein to become functional. Appropriate protein folding is not only important to ensure the right function, but also to prevent the manifestation and progression of many diseases, including cancer. Normal protein homeostasis is ensured by molecular chaperones, which prevent improper connections between amino acids and facilitate protein folding. Heat shock protein 90 (Hsp90) is a molecular chaperone responsible for the correct folding of hundreds of proteins, including many oncoproteins that have a crucial role in malignant transformation. Because of its role in the pathophysiology of cancer, it is a potential target for new chemotherapeutics – inhibitors of Hsp90 ATPase activity. The first Hsp90 inhibitors blocked ATP binding at the N-terminal domain of the protein. Due to toxicity, poor bioavailability, and induction of heat-shock response, their therapeutic potential has been limited, leading to the development of allosteric inhibitors of Hsp90 C-terminal domain. In the context of this master's thesis, we studied the influence of tertiary amines structure on antiproliferative activity of piperidine-based Hsp90 C-terminal domain inhibitors. Our starting point for the synthesis of the focused library of final compounds was known allosteric Hsp90 C-terminal domain inhibitor. In this way, we retained properties that were identified as important for forming interactions with the target. By varying the amine portion of the parent molecule, five new compounds were obtained. The substituents attached to the piperidine amine of those compounds differ in many properties, including polarity, size, and ability to form different types of interactions. The antiproliferative activity of the final compounds was evaluated in vitro in MCF-7 breast cancer cell lines using colorimetric MTS cell proliferation test. Based on the results, the relationship between structure and activity of final compounds was examined. The newly synthesized final compounds were, in majority, found to be less active compared to the parent compound and the previously synthesized compounds. The methyl and benzyl groups proved to be the most optimal substituents on the piperidine amine. These results provide important information for further optimization of this class of Hsp90 inhibitors.

Ključne besede:cancer, chemotherapeutics, heat-shock protein Hsp90, Hsp90 C-terminal inhibitors, molecular chaperones, piperidine

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