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Sinteza 4,5,6,7-tetrahidrobenzotiazolnih alosteričnih zaviralcev proteina toplotnega šoka 90
ID Ferjančič Benetik, Svit (Author), ID Tomašič, Tihomir (Mentor) More about this mentor... This link opens in a new window, ID Dernovšek, Jaka (Co-mentor)

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Abstract
Proteini toplotnega šoka so ubikvitarne molekule v celici. Njihovo izražanje se poveča, ko je celica izpostavljena povišani temperaturi ali oksidativnemu stresu, ki ga povzročajo reaktivne kisikove zvrsti. Osnovna naloga teh proteinov, predvsem poddružine proteinov toplotnega šoka 90 (Hsp90), je vzdrževanje nativne konformacije celičnih proteinov. Še bolj kot zdrave delovanje Hsp90 izkoriščajo rakave celice, ki imajo zaradi spremenjenega genoma več konformacijsko nestabilnih proteinov, ključnih za ohranjanje malignosti. Zato so zaviralci Hsp90 potencialne protitumorne učinkovine, pri čemer se raziskave vse bolj usmerjajo na modulacijo delovanja tega proteina preko vezave v njegovo C-končno regijo. V sklopu magistrske naloge smo sintetizirali in optimizirali serijo C-končnih zaviralcev Hsp90 s 4,5,6,7-tetrahidrobenzotiazolnim skeletom. Načrtovali smo knjižnici spojin A in B za proučevanje odnosa med strukturo ligandov in njihovim delovanjem (SAR) na rakavih celičnih linijah. Pri knjižnici A smo se osredotočili na optimizacijo substituenta na mestu 2 osnovnega 4,5,6,7-tetrahidrobenzotiazolnega skeleta. S spremembami dolžine distančnika in uvedbo kiralnih centrov smo želeli ugotoviti predvsem, kateri položaj kationskega centra je za delovanje najugodnejši. Namen knjižnice B pa je bil primerjati različne aromatske sisteme na mestu 6 osnovnega skeleta z vidika velikosti in tvorbe dodatnih interakcij z vezavnim mestom. Na osnovi rezultatov testiranja antiproliferativnega delovanja petih končnih spojin na celični liniji raka dojke MCF-7 smo iz primerjave IC50 spojin 12c in 12a ugotovili, da je na mestu 6 aromatski sistem nujen za aktivnost spojine. Rezultati aktivnosti spojine 12b so pokazali, da je v vezavnem mestu verjetno še dodatna možnost tvorbe vodikove vezi, na vezavo pa pomembno vpliva tudi dodatna substitucija aromatskega obroča. Na mestu 2 je poleg velikosti substituenta z amino skupino pomembna tudi njegova prostorska orientacija. Od vseh testiranih spojin je imela spojina 7f najnižjo vrednost IC50 = 17 μM, kar je še vedno previsoko za potencialno zdravilno učinkovino. Vrednotenje antiproliferativnega delovanja preostalih šestih sintetiziranih spojin (spojine 7a-e, 7h) bo pomagalo razjasniti vpliv dodatnega aromata na mestu 2 in določiti ustrezno razdaljo med osnovnim skeletom in aminsko funkcionalno skupino. S temi ugotovitvami bi rezultati magistrske naloge podali še več ključnih informacij glede odnosa med strukturo liganda in delovanjem 4,5,6,7-tetrahidrobenzotiazolnih modulatorjev C-končne domene Hsp90.

Language:Slovenian
Keywords:Hsp90, 4, 5, 6, 7-tetrahidrobenzotiazol, C-končna domena, SAR, rak
Work type:Master's thesis/paper
Organization:FFA - Faculty of Pharmacy
Year:2021
PID:20.500.12556/RUL-129907 This link opens in a new window
Publication date in RUL:09.09.2021
Views:2525
Downloads:794
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Secondary language

Language:English
Title:Synthesis of 4,5,6,7-tetrahydrobenzothiazole derivatives as allosteric heat-shock protein 90 inhibitors
Abstract:
Heat-shock proteins (Hsp) are ubiquitous molecules in the cell which increases their expression when exposed to elevated temperature or oxidative stress by reactive oxygen species. The main role of these proteins, particularly of the heat shock protein 90 (Hsp90) family is to maintain the native conformation of proteins in the cell. Since cancer cells possess many conformationally unstable proteins that are critical for their survival and malignancy, they tend to utilize the chaperone function of Hsp90 even more than healthy cells. For this reason, Hsp90 inhibitors represent potential antitumor drugs with researchers increasingly focusing on modulating protein function by interacting with the C-terminal domain of Hsp90. Therefore, the aim of this Master's thesis was to synthesize and optimize Hsp90 C-terminal inhibitors bearing the 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole core. Two libraries of compounds (A and B) were designed with the aim of investigating the structure-activity relationships (SAR) of these ligands. Library A focused primarily on optimizing the amine-bearing moiety attached to position C-2 of the tetrahydrobenzothiazole scaffold. By changing the length of the spacer and introducing chiral centers to the central scaffold we aimed primarily to determine which position of the cationic center will give the strongest inhibitory activity. In library B, on the other hand, the introduction of different aromatic systems to position C-6 of the 4,5,6,7-tetrahydrobenzothiazole moiety was to be compared in order to obtain information on the size of the most potent substituents and to allow additional interactions with the residues of the binding site. Five final compounds were evaluated for their antiproliferative activity in MCF-7 breast cancer cell lines. Comparison of the IC50 values of compounds 12c and 12a confirmed that the aromatic system at position C-6 is a mandatory requirement for activity. Compound 12b showed that there is an additional possibility to form hydrogen bonds in the active site. Again, the bonding is significantly affected when the aromatic ring is substituted. At the C-2 position of the tetrahydrobenzothiazole ring, both the size and spatial orientation of the amine moiety must be considered. Of all the compounds tested, compound 7f showed the lowest IC50 value of 17 μM, which is still too high for a potential antitumor agent. The cytotoxic evaluation of the remaining six synthesized compounds 7a-e and 7h would help to clarify the effects of adding an aromatic ring to the amine moiety bound at position C-2 and give a rough estimate of the optimal length of the spacer between the amine of interest and the tetrahydrobenzothiazole scaffold. With these results this Master's thesis could provide even more key information on the structure-activity relationship of 4,5,6,7-tetrahydrobenzothiazole Hsp90 C-terminal domain modulators.

Keywords:Hsp90, 4, 5, 6, 7-tetrahydrobenzothiazole, C-terminal domain, SAR, cancer

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