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Sinteza in biološko vrednotenje derivatov 3,4-diklorobenzena kot alosteričnih zaviralcev proteina toplotnega šoka 90 s protitumornim delovanjem
ID Toplak, Anja (Avtor), ID Tomašič, Tihomir (Mentor) Več o mentorju... Povezava se odpre v novem oknu

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Izvleček
Rakava obolenja ostajajo eden vodilnih vzrokov umrljivosti prebivalstva po vsem svetu, saj njihovo zdravljenje zaradi zapletene biologije rakave celice predstavlja enega največjih izzivov sodobne medicine. V zadnjih desetletjih se je kot izjemno obetavna tarča za razvoj novih, selektivnih protitumornih učinkovin izkazal protein toplotnega šoka 90 (Hsp90). Šaperon Hsp90 je odgovoren za pravilno zorenje in delovanje več kot dvesto različnih celičnih proteinov, med katerimi pa jih je mnogo udeleženih tudi v signalnih poteh, ki vodijo v nastanek raka. S farmakološkim zaviranjem Hsp90 lahko povzročimo hkratno razgradnjo različnih onkogenov in mutiranih proteinov, s čimer blokiramo več signalnih poti kancerogeneze, kar vodi v smrt rakavih celic. Prvi znani zaviralci Hsp90 so delovali preko vezave v vezavno mesto za ATP na N-končni domeni proteina, vendar je njihova slabost, da v večini sprožijo odziv toplotnega šoka, kar vodi v toksičnost oz. neučinkovitost terapije. Zato je bilo ključno odkritje alosteričnega vezavnega mesta na C-končni domeni Hsp90. Ker mehanizem delovanja zaviralcev C-končne domene proteina Hsp90 ni povezan z indukcijo odziva toplotnega šoka, je C-končna domena postala nova pomembna tarča razvoja protitumornih učinkovin. V sklopu magistrske naloge smo uspešno sintetizirali šest novih potencialnih 3,4-diklorobenzenskih alosteričnih zaviralcev C-končne domene proteina Hsp90, ki smo jih pripravili z modifikacijo referenčne spojine. Z namenom poglobitve poznavanja odnosa med strukturo in delovanjem smo vlogo hidroksilne skupine na piperidinskem obroču v distančniku proučevali z uvedbo amidne vezi, ki smo jo med drugim vpeljali tudi med oba osrednja obroča. Prav tako smo morfolinski obroč zamenjali s piperidinskim in z modifikacijo bazičnega centra raziskali vpliv različnih substituentov na delovanje spojin. S spreminjanem dolžine verige med osrednjim fenolom in bazičnim centrom smo obenem ovrednotili tudi vpliv razdalje na delovanje analogov. Vsem končnim spojinam smo s testom MTS ovrednotili njihov vpliv na proliferacijo rakavih celic, pri čemer smo kot in vitro model uporabili človeški celični liniji raka jeter HepG2 in raka dojk MCF-7. Zbrani rezultati biološkega testiranja so pokazali, da vseh šest končnih spojin zavira proliferacijo celic, vendar ima le spojina 13 (IC50(HepG2) = 10,7 μM, IC50(MCF-7) = 8,7 μM) močnejše antiproliferativno delovanje v primerjavi z referenčno spojino (IC50(HepG2) = 24,7 μM, IC50(MCF-7) = 44,7 μM). Rezultati magistrske naloge predstavljajo pomemben doprinos k razumevanju odnosa med strukturo in delovanjem alosteričnih zaviralcev Hsp90 ter prispevajo k nadaljnji optimizaciji do spojin z izboljšanim antiproliferativnim delovanjem.

Jezik:Slovenski jezik
Ključne besede:derivati 3, 4-diklorobenzena, protein toplotnega šoka Hsp90, protitumorne učinkovine, rak, zaviralci C-končne domene Hsp90
Vrsta gradiva:Magistrsko delo/naloga
Organizacija:FFA - Fakulteta za farmacijo
Leto izida:2020
PID:20.500.12556/RUL-122412 Povezava se odpre v novem oknu
Datum objave v RUL:10.12.2020
Število ogledov:965
Število prenosov:179
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Sekundarni jezik

Jezik:Angleški jezik
Naslov:Synthesis and biological evaluation of 3,4-dichlorobenzene derivatives as allosteric heat shock protein 90 inhibitors with anticancer activity
Izvleček:
Cancer remains one of the leading causes of mortality worldwide, since its treatment is one of the greatest challenges of modern medicine due to the complex biology of cancer cells. In recent decades, heat shock protein 90 (Hsp90) has proven to be an extremely promising target for the development of a new, selective antitumour agents. The Hsp90 molecular chaperone is responsible for the proper maturation and function of more than two hundred different cellular proteins, many of which are also involved in the signalling pathways that lead to cancer. By pharmacologically inhibiting the Hsp90 protein, we can cause the simultaneous degradation of various oncogenes and mutated proteins, thereby simultaneously blocking multiple carcinogenesis signalling pathways, leading to cancer cell death. The first known Hsp90 inhibitors have interacted with the ATP binding site at the N-terminal domain of the protein, but these mostly induce a heat shock response leading to toxicity or ineffectiveness of therapy. Due to the limited therapeutic potential of these inhibitors, the discovery of an allosteric binding site at the C-terminal domain of the protein was crucial. Because the mechanism of action of Hsp90 C-terminal domain inhibitors is not related to the induction of a heat shock response, the C-terminal domain has become a new important target for the development of antitumor agents. As part of the master's thesis, we successfully synthesized six new potential 3,4-dichlorobenzene-based allosteric Hsp90 C-terminal domain inhibitors, which were prepared by modifying the reference compound. In order to deepen the knowledge about the structure-activity relationship, the role of the hydroxyl group on the piperidine ring in the spacer was studied by introducing an amide bond, which was also introduced between the two central rings. We also replaced the morpholine ring with piperidine and investigated the effect of various substituents on the inhibitory activity of the compounds by modifying the basic center. By varying the chain length between the central phenol and the basic center, we also evaluated the effect of distance on the inhibitory activity of the analogues. Subsequently, all final synthesized compounds were evaluated by the MTS test for their effect on cancer cell proliferation, using the human liver cancer HepG2 and breast cancer MCF-7 cell lines as in vitro models. The collected results of biological testing showed that all six final compounds inhibited cell proliferation, but only compound 13 (IC50(HepG2) = 10.7 μM, IC50(MCF-7) = 8.7 μM) displayed more potent antiproliferative activity compared to the reference compound (IC50(HepG2) = 24.7 μM, IC50(MCF-7) = 44.7 μM). The results of the master's thesis represent an important contribution to the understanding of the structure-activity relationship and contribute to further optimization to inhibitors with improved antiproliferative activity.

Ključne besede:3, 4-dichlorobenzene derivatives, antitumor agents, cancer, heat shock protein Hsp90, Hsp90 C-terminal domain inhibitors

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