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Sinteza piperidinskih alosteričnih zaviralcev proteina toplotnega šoka 90
Zver, Patricija (Author), Tomašič, Tihomir (Mentor) More about this mentor... This link opens in a new window

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Abstract
Rakava obolenja ostajajo eden od vodilnih vzrokov umrljivosti po vsem svetu. Čeprav je zdravljenje v zadnjih desetletjih precej napredovalo, ostajata neselektivnost učinkovin in pojav neželenih učinkov velik problem. Iskanje novih tarč in razvoj protitumornih učinkovin tako predstavljata pomembno področje raziskav. Protein toplotnega šoka 90 (Hsp90) je evolucijsko ohranjen šaperon, ki predstavlja velik delež proteinov v celici. Sestavljen je iz N-končne, srednje in C-končne domene. Vključen je v različne biokemijske procese vzdrževanja proteostaze, hkrati sodeluje pri oblikovanju in vzdrževanju konformacije proteinov. Njegovo delovanje je odvisno od hidrolize ATP, preko katere dobi potrebno energijo za izvajanje funkcije kot šaperon. Od aktivnosti Hsp90 je odvisnih veliko proteinov, ki sprožijo različne neoplastične procese. Hsp90 je zato postal obetavna tarča v razvoju protitumornih učinkovin, saj z zaviranjem njegovega delovanja blokiramo več različnih poti kancerogeneze. Zaviralci N-končne domene Hsp90 so v kliničnih raziskavah že dalj časa, vendar v večini sprožijo odziv toplotnega šoka, kar vodi bodisi v toksičnost ali neučinkovitost terapije. Zato je bilo pomembno odkritje alosteričnega vezavnega mesta na C-končni domeni, saj imajo zaviralci le-te boljše lastnosti. Največjo oviro pri razvoju novih zaviralcev C-končne domene predstavlja neraziskana struktura vezavnega mesta. S študijami odnosa med strukturo in delovanjem se postopoma odkrivajo ključni strukturni elementi zaviralcev, potrebni za njihovo aktivnost. V okviru magistrske naloge smo sintetizirali nove potencialne zaviralce Hsp90 s piperidinskim skeletom, ki se vežejo v C-končno domeno encima. Želeli smo izboljšati njihovo protitumorno delovanje in poglobiti znanje o odnosu med strukturo in delovanjem. V okviru eksperimentalnega dela magistrske naloge smo sintetizirali šest različnih analogov referenčne spojine, pridobljene s pomočjo virtualnega rešetanja. Med osrednja obroča smo uvedli amidno vez ter ugotovili vpliv razdalje med fenolnim obročem in bazičnim aminom. Proučili smo vlogo hidroksilne skupine na distančniku, z modifikacijo fenolnega obroča pa raziskali vpliv različnih substituentov na zaviralno aktivnost spojin. Končne spojine smo testirali na celičnih linijah raka jeter HepG2 in raka dojk MCF-7 ter tako določili citotoksične IC50. Pet spojin je izkazalo močnejše delovanje (IC50= 14 – 29 µM) napram izhodiščni spojini (IC50= 45 µM), spojina 12 pa se je izkazala kot neaktivna. Ugotovljena nova spoznanja o razmerju med strukturo in delovanjem nam tako odpirajo veliko možnosti za nadaljnje raziskovanje.

Language:Slovenian
Keywords:piperidin, protein toplotnega šoka Hsp90, protitumorne učinkovine, šaperon, zaviralci C-končne domene Hsp90
Work type:Master's thesis/paper (mb22)
Organization:FFA - Faculty of Pharmacy
Year:2019
Views:349
Downloads:208
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Secondary language

Language:English
Title:Synthesis of piperidine-based allosteric heat shock protein 90 inhibitors
Abstract:
Cancer is the second leading cause of death worldwide. Although there are many types of cancer treatment available, the lack of drug selectivity and their side effects are becoming an increasing health problem. Pharmaceutical companies are exploring novel molecular targets and developing antitumour drugs acting by novel mechanisms. Heat shock protein 90 (Hsp90) is one of the most abundant cell proteins. It contains three domains: N-terminal, middle and C-terminal domain. It is an ATP dependent molecular chaperone that plays a pivotal role in proteostasis. Hsp90 is responsible for folding, maturation and activation of many proteins called co-chaperones and clients. Most of them can trigger neoplastic changes. This is the reason why Hsp90 has become a promising target in the development of antitumour drugs as we can block many cancer pathways by inhibiting its activity. Hsp90 N-terminal domain has been a focus of research as an attractive anticancer target, but N-terminal inhibitors have often been found as toxic and displayed unwanted side effects. Discovery of another binding site on the C-terminal domain of Hsp90 enables alternative strategy for anticancer therapy. However, complexity and absence of co-crystal structure of C-terminal domain in complex with ligand make development of new Hsp90 C-terminal inhibitors difficult. In this master’s thesis, we synthesized new potential allosteric Hsp90 C-terminal domain inhibitors based on the piperidine scaffold and studied structure-activity relationship. In the context of the experimental work of this master’s thesis we synthesized six analogues of the virtual screening hit. We introduced amide bond between central rings and evaluated the influence of chain length between the phenol and the basic amine. We explored the role of hydroxyl group in the central part and studied the effect of different substituents on the phenol moiety on compound activity against cancer cell lines. The final compounds were evaluated in vitro for their cytotoxicity in HepG2 liver cancer and MCF-7 breast cancer cell lines. Five of them showed higher activity (IC50= 14 – 29 µM) as the activity of previously discovered virtual screening hit (IC50= 45 µM), while compound 12 was found to be inactive. The results of structure-activity relationship pave the way to further optimisation of this structural class of Hsp90 C-terminal inhibitors.

Keywords:anticancer drugs, chaperone, Hsp90 C-terminal inhibitors, Hsp90 heat shock protein, piperidine

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