Faculty of Pharmacy, Lj. (FFALJ)
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Sinteza derivatov kinazolina in izoksazolo[5,4-d]pirimidina z agonističnim delovanjem na Tollu podobni receptor 7 = Synthesis of quinazoline and isoxazolo[5,4-d]pyrimidine derivatives with Toll-like receptor 7 agonist activity : Uniform Master's Study Programme PharmacyVičič, KarolinaVnetni odziv predstavlja obrambni mehanizem, ki se aktivira v primeru izpostavljenosti škodljivim dejavnikom. V sklopu teh procesov imata ključno vlogo prirojeni in pridobljeni imunski sistem, ki se ... med drugim aktivirata tudi preko Tollu podobnih receptorjev (TLR). Do sedaj je znanih že 10 tipov TLR, za katere je značilno, da kot ligand prepoznajo različne manjše molekule in dele mikroorganizmov. V sklopu magistrske naloge smo se osredotočili na TLR7, ki ga aktivira enovijačna RNA, s tem pa povzroči kaskado procesov, ki vodi do protivnetnega, protivirusnega in protitumornega delovanja. Uporaba agonistov TLR7 bi tako lahko igrala ključno vlogo pri zdravljenju virusnih okužb, rakavih obolenj in alergijske astme. Pri našem raziskovalnem delu smo izhajali iz strukture znanega agonista TLR7 3-(4-fluorofenil)-4-(3-metilpiperidin-1-il)-6-(trifluorometil)izoksazolo[5,4-d]pirimidina. Z optimiziranim postopkom sinteze in izolacije smo pripravili pet analogov z izoksazolo[5,4-d]pirimidinskim skeletom in dva s kinazolinskim obročem. Vseh sedem končnih spojin smo okarakterizirali, jim določili čistost in jih biološko ovrednotili. Agonistično delovanje smo preverili na celični liniji HEK293, ki izraža človeški TLR7, aktivnim spojinam pa smo določili še citotoksičnost. Na podlagi rezultatov testiranj na celični liniji HEK293smo ugotovili, da kar štiri izmed sedmih končnih spojin izkazujejo agonistično delovanje, tri spojine pa niso bile aktivne. Za doseganje agonističnega delovanja so se kot najbolj optimalne izkazale spojine z izoksazolo[5,4-d]pirimidinskim skeletom, ki so na mestu 4 substituirane s 6-členskim obročem, ta pa z manjšo stransko skupino na mestu 3. Vse štiri aktivne spojine so se v testiranih koncentracijah izkazale za necitotoksične. Izmed vseh končnih spojin se je za najbolj obetavno izkazala spojina 8, saj ima najnižjo vrednost EC50 (EC50 = 11 μM), zaradi česar predstavlja dobro izhodišče za nadaljnje načrtovanje in sintezo agonistov TLR7.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [K. Vičič], 2024Language - slovenianCOBISS.SI-ID - 199517699
Author
Vičič, Karolina
Other authors
Sova, Matej, 1979-
Topics
Imunski sistem |
Tollu podobni receptorji |
TLR7 |
agonisti |
izoksazolo[5, 4-d]pirimidin |
kinazolin |
sintezni postopki
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Knjižnica emšf 0000000543 VIČIČ KAROLINA Sinteza 0000001403 IN: 0018194 Knjižnica emšf 543 VIČIČ KAROLINA Sinteza 1403 IN: 0018194 |
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Vičič, Karolina | ![]() |
Sova, Matej, 1979- | 25490 |
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