Faculty of Pharmacy, Lj. (FFALJ)
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Sinteza in vrednotenje knjižnice elektrofilnih fragmentov kot kovalentnih zaviralcev kaspaze 1 = Synthesis and evaluation of electrophile fragment library as covalent caspase 1 inhibitors : Uniform Master's Study Programme PharmacyKemperle, Žiga, farmacevtAlzheimerjeva bolezen (AB) je nevrodegenerativna bolezen, pri kateri se pojavi postopna izguba spomina in poslabšanje kognitivnih funkcij. Poglavitni patološki znaki bolezni so plaki amiloida β (Aβ) ... in nevrofibrilarne pentlje, zelo pomembno vlogo pa ima tudi vnetje centralnega živčnega sistema – nevrovnetje. Prvi znak nevrovnetja je aktivacija mikroglije, kjer se pri provnetnem fenotipu M1 sproščajo citokini, ki aktivirajo sestavljanje inflamasoma NLRP3. Po aktivaciji inflamasoma NLRP3 se z odstranitvijo prodomene aktivira cisteinska provnetna kaspaza-1, ki cepi pro-IL-1β do njegove aktivne oblike IL-1β. Pri mišjih modelih AB farmakološko zaviranje kaspaze-1 preprečuje progresivno kopičenje plakov Aβ, zmanjšuje nevrovnetje in ohranja normalne koncentracije sinaptofizina v hipokampusu. Pri rešetanju knjižnice elektrofilnih fragmentov na UL FFA so bili odkriti trije zadetki kovalentnih bojnih glav – karbamoil fluorid, 1,3,4-oksatiazol-2-on ter imidazolid, ki so zavirali encimsko aktivnost kapsaze-1. V magistrski nalogi smo sintetizirali analoge dveh zadetkov – 1,3,4-oksatiazol-2-ona B ter karbamoil fluorida C, pri čemer smo spreminjali substituente na osnovnem ogrodju (substituenti na indolu pri analogih zadetka C) oziroma zamenjali fenilni obroč s furanom in njegovimi analogi (zadetek B). Dodatno smo na indolinu karbamoil fluoridno bojno glavo zamenjali še z nekaterimi drugimi, v literaturi opisanimi elektrofilnimi skupinami. Po postavitvi in optimizaciji sintezne poti smo uspeli pripraviti 23 spojin, za katere smo ovrednotili jakost zaviranja človeške kaspaze-1. Kaspazo-1 je zaviralo osem karbamoil fluoridov, preostali fragmenti so bili neaktivni. Na osnovi rezultatov lahko sklepamo, da je za zaviralno aktivnost ugodna predvsem prisotnost sterično majhnih 5- ali 6- substituentov (npr. fluor, nitro ali hidroksi), tolerirani pa so tudi estri acetata na mestu 3. Slednji predstavljajo tudi najboljše izhodišče za optimizacijo zaviralne aktivnosti in za rast fragmenta.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [Ž. Kemperle], 2023Language - slovenianCOBISS.SI-ID - 169748739
Author
Kemperle, Žiga, farmacevt
Other authors
Knez, Damijan, farmacevt |
Meden, Anže
Topics
Alzheimerjeva bolezen |
mikroglija |
kaspaza-1 |
kovalentni fragmenti |
SAR |
sintezni postopki
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Knjižnica emšf 0000000616 KEMPERLE ŽIGA Sinteza 0000001325 IN: 0017865 Knjižnica emšf 616 KEMPERLE ŽIGA Sinteza 1325 IN: 0017865 |
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Kemperle, Žiga, farmacevt | ![]() |
Knez, Damijan, farmacevt | 36438 |
Meden, Anže | 53584 |
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