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Sinteza pirolidinskih, piperidinskih in piperazinskih derivatov 6-(trifluorometil)izoksazolo[5,4-d]pirimidina kot agonistov Tollu podobnega receptorja 7 = Synthesis of pyrrolidine, piperidine and piperazine derivatives of 6-(trifluoromethyl)isoxazolo[5,4-d]pyrimidine as Toll-like receptor 7 agonists : master thesis : Uniform Master's Study Programme PharmacySmajić, BenjaminImunski sistem je osnovni obrambni sistem našega telesa in se deli na prirojeni in pridobljeni. Celice prirojene imunosti zagotavljajo prvo in osnovno linijo obrambe našega telesa pred patogeni. ... Slednje zaznajo z receptorji za prepoznavanje molekulskih vzorcev (PRR), ti pa prepoznajo z patogeni in poškodbami povezane molekulske vzorce (PAMP in DAMP). Ena izmed najbolj opisanih skupin PRR so Tollu podobni receptorji (TLR). TLR so membranski glikoproteini tipa 1 in do danes so pri vretenčarjih odkrili 13 različnih tipov TLR-jev, od tega jih 10 najdemo pri človeku. Eden izmed teh je tudi TLR7, na katerega smo se osredotočili v sklopu magistrske naloge. Nahaja se na endosomalnih membranah znotraj celic in njegovo naloga je, da prepoznava enoverižne RNA virusov. Terapevtsko bi lahko bili agonisti TLR7 uporabni pri zdravljenju astme, rakavih obolenj in virusnih okužb. Edini registrirani agonist TLR7 je imikvimod. Namen naše naloge je bil sintetizirati in biološko ovrednotiti potencialne selektivne agoniste TLR7, ki so strukturni analogi spojine, ki je izkazovala agonistično delovanje na TLR7; sinteza le – te pa je temeljila na povezavi strukturnih lastnosti spojin, ki so bile agonisti TLR7 ali pa zaviralci encima indolamin-2,3-dioksigenaze. Končne spojine smo sintetizirali po šeststopenjskem postopku z dvema različnima izhodnima spojinama. V zadnji, šesti stopnji, smo na biciklični sistem pripenjali različne pirolidinske, piperidinske ter piperazinske derivate in tako sintetizirali 10 končnih spojin. Sintetiziranim spojinam smo preverili topnost v celičnem gojišču in potencialno citotoksičnost ter tudi ovrednotili agonistično delovanje na TLR7 in TLR8. Sintetiziranim spojinam, ki so izkazovale preliminarno agonistično delovanje na TLR7 (spojine 6, 7 in 20), smo nato še določili vrednost EC50. Kot najmočnejši agonist TLR7 se je izkazal 3-(3-bromo-4-fluorofenil)-4-(3-metilpiperidin-1-il)-6-(trifluorometil)izoksazolo[5,4-d]pirimidin (spojina 20), z izračunano EC50 = 16,4 ± 0,1 µM. Nobena izmed spojin ni izkazovala agonističnega delovanja na TLR8. Na podlagi teh rezultatov lahko pridemo do zaključka, da spojine 6, 7 in 20 tvorijo dobro izhodišče za nadaljnje raziskave novih selektivnih agonistov TLR7 kot potencialnih imunomodulatornih učinkovin.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [B. Smajić], 2022Language - slovenianCOBISS.SI-ID - 124397059
Author
Smajić, Benjamin
Other authors
Sova, Matej, 1979-
Topics
Imunski sistem |
Tollu podobni receptor |
TLR7 |
agonisti |
pirimidin
Library/institution |
City | Acronym | For loan | Other holdings |
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Faculty of Pharmacy, Ljubljana | Ljubljana | FFALJ |
reading room 1 cop.
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Smajić, Benjamin | |
Sova, Matej, 1979- | 25490 |
Source: Personal bibliographies
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