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Sinteza izoksazolopirimidinskih agonistov Tollu podobnega receptorja 7 z različnimi substitucijami na izoksazolnem obroču = Synthesis of isoxazolopyrimidine Toll-like receptor 7 agonists with different substitutions on the isoxazole ring : Uniform Master's Study Programme PharmacySlokan, TjašaTollu podobni receptorji (TLR) so pomembna skupina receptorjev, ki igrajo ključno vlogo v prirojenem in pridobljenem imunskem sistemu. So obetavne tarče za zdravljenje okužb, avtoimunskih bolezni in ... raka. Pri človeku so do sedaj odkrili 10 različnih tipov TLR. V okviru magistrske naloge smo se osredotočili na TLR7, ki je endosomski receptor in prepoznava enoverižno RNA virusov. S TLR7 povzročena aktivacija imunskega sistema privede do protivnetnega, protivirusnega in protitumornega delovanja, zato TLR7 predstavlja potencialno tarčo za zdravljenje virusnih okužb, alergijske astme in rakavih obolenj. Na podlagi znanega TLR7 agonista 3-(4-fluorofenil)-4-(3-metilpiperidin-1-il)-6- (trifluorometil)izoksazolo[5,4-d]pirimidina smo načrtovali in sintetizirali 11 novih potencialnih agonistov TLR7. Za sintezo analogov 6-(trifluorometil)izoksazolo[5,4-d]pirimidina z različnimi substitucijami na izoksazolnem obroču smo uporabili šeststopenjski sintezni postopek. Končne spojine smo ovrednotili na humani celični liniji HEK293. Določili smo jim topnost v DMSO in celičnem mediju, citotoksičnost ter preverili njihovo agonistično delovanje na TLR7. Ugotovili smo, da so vse sintetizirane spojine zaradi svoje lipofilnosti slabo topne v celičnem mediju. Posledično so bili preliminarni testi agonizma izvedeni pri nizkih koncentracijah, kar je vplivalo na jakost agonističnega delovanja na TLR7. Spojine z izobutilaminskim fragmentom na pirimidinskem obroču (37, 38, 40 in 41), so se izkazale za citotoksične. Izmed vseh sintetiziranih spojin je le 3-(4-klorofenil)-4-(3-metilpiperidin-1-il)-6- (trifluorometil)izoksazolo[5,4-d]pirimidin (35) izkazoval agonistično delovanje na TLR7 z vrednostjo EC50 21,4 μM. Spojina 35 predstavlja dobro izhodišče za nadaljno optimizacijo, predvsem v smislu izboljšanja fizikalno-kemijskih lastnosti.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [T. Slokan], 2022Language - slovenianCOBISS.SI-ID - 124073987
Author
Slokan, Tjaša
Other authors
Sova, Matej, 1979- |
Strašek Benedik, Nika
Topics
Imunski sistem |
Tollu-podobni receptorji |
TLR7 |
agonist |
6-(trifluorometil)izoksazolo[5, 4- d]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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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DRS, in which the journal is indexed
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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Slokan, Tjaša | |
Sova, Matej, 1979- | 25490 |
Strašek Benedik, Nika | 52378 |
Source: Personal bibliographies
and: SICRIS
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