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Sinteza cikličnih aminskih derivatov izoksazolo[5,4-d]pirimidina z delovanjem na Tollu podobne receptorje 7 = Synthesis of cyclic amine derivatives of isoxazolo[5,4-d]pyrimidine to target Toll-like receptors 7 : master thesis : Uniform Master's Study Programme PharmacyOman, Katja, farmacevtkaTollu podobni receptorji (TLR) igrajo pomembno vlogo v prirojenem in pridobljenem imunskem sistemu, ki je prva obrambna linija telesa pred mikrobi. TLR prepoznavajo molekulske vzorce, povezane s ... patogeni in poškodbami in sprožijo hiter imunski vnetni odziv. Trenutno je pri človeku znanih 10 podtipov TLR, mi smo se v sklopu našega dela osredotočili na TLR7, endosomski receptor, ki prepoznava enoverižno RNA virusov. Imunski sistem, aktiviran preko receptorja TLR7, privede do protivnetnega, protivirusnega in protitumornega učinka, zato bi lahko bili agonisti receptorja TLR7 uporabni pri zdravljenju rakavih obolenj, astme in virusnih okužb. Tekom magistrske naloge smo sintetizirali analoge agonista TLR7. Pripravljene spojine smo okarakterizirali v bioloških testiranjih, s čimer smo pridobili nekaj novih informacij o odnosu med strukturo in delovanjem agonistov TLR7 na osnovi izoksazolo[5,4-d]pirimidina. V sklopu šeststopenjske sinteze smo iz 4-fluorbenzaldehida preko oksima, imidoil klorida, derivata izoksazola ter nato izoksazolo[5,4-d]pirimidin-4(5H)-ona in njegove pretvorbe v aril klorid, na mesto 4 heterobicikličnega ogrodja pripeli različne substituente in sintetizirali šest končnih spojin, potencialnih agonistov TLR7. Za pet spojin smo nato ocenili topnost v celičnem mediju, preverili njihovo agonistično delovanje na TLR7, za nekatere tudi na TLR8, ter za najboljšo še citotoksičnost na celični liniji HEK293. Vse spojine so bile zaradi lipofilnih fragmentov slabo topne v celičnem mediju. Spojina 12 je edina izkazovala agonistično delovanje na TLR7 z EC50 vrednostjo 15,9 ± 0,9 μM. V primerjavi z imikvimodom, trenutno edinim registriranim agonistom TLR7 (EC50 = 2,1 µM), je vrednost EC50 spojine 12 višja, kar kaže na njeno šibkejše agonistično delovanje. Zaključimo lahko, da spojina 12 predstavlja dobro izhodišče za nadaljnje raziskave novih agonistov TLR7 kot imunomodulatornih učinkovin.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [K. Oman], 2023Language - slovenianCOBISS.SI-ID - 174735363
Author
Oman, Katja, farmacevtka
Other authors
Knez, Damijan, farmacevt |
Sova, Matej, 1979-
Topics
Imunski sistem |
Rak (medicina) |
Tollu podobni receptor |
TLR7 |
sinteza spojin
Library | Call number – location, accession no. ... | Copy status |
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Faculty of Pharmacy, Lj. | Knjižnica emšf 616 OMAN KATJA Sinteza 1346 IN: 0017922 |
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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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Oman, Katja, farmacevtka | |
Knez, Damijan, farmacevt | 36438 |
Sova, Matej, 1979- | 25490 |
Source: Personal bibliographies
and: SICRIS
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