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Sinteza zaviralcev butirilholin esteraze s piridin-2-onskim in indolnim skeletom = Synthesis of butyrylcholinesterase inhibitors with pyridine-2-one and indole scaffold : Uniform Master's Study Programme PharmacyUrbančič, TajdaAlzheimerjeva bolezen (AB) je progresivna in ireverzibilna nevrodegenerativna bolezen za katero so značilne kognitivne motnje ter številni nevropsihiatrični simptomi. Glavne morfološke spremembe, ki ... spremljajo AB, so nastanek zunajceličnih plakov, znotrajceličnih nevrofibrilarnih pentelj ter izguba nevronov, ki vsebujejo visoke koncentracije acetilholina in acetilholin esteraze (AChE), hkrati pa se povečata koncentracija in aktivnost butirilholin esteraze (BChE). Pomembno vlogo pri nevrovnetju, ki spremlja AB, ima tudi ubikvitin-proteasomski sistem. Selektivni zaviralci [beta]1i podenote imunoproteasoma tako izboljšajo upad kognitivnih sposobnosti v mišjih modelih AB. V okviru magistrske naloge smo sintetizirali selektivne zaviralce človeške (h)BChE na osnovi serije zaviralcev z indolnim ogrodjem. Spreminjali smo dolžino distančnika med indolom in N-metilamidom na eni strani ter razdaljo med fenilom in N-metilamidom na drugi strani molekule. Terciarne amide smo sintetizirali z uporabo sklopitvenega reagenta CDI in ustreznih karboksilnih kislin ter aminov, nato pa smo amide z uporabo LiAlH4 reducirali do terciarnih aminov. Sintetiziranim spojinam smo z Ellmanovo metodo določili jakost zaviranja hBChE, preverili pa smo tudi njihovo selektivnost v primerjavi s strukturno podobnim encimom hAChE. Izmed 12 sintetiziranih derivatov indola je bil najmočnejši selektivni zaviralec hBChE terciarni amin 16 z IC50 = 8,36 % 0,76 nM in faktorjem selektivnosti 3800 napram hAChE. Z analizo odnosa med strukturo in delovanjem smo potrdili, da z daljšanjem distančnika dosežemo 220-krat močnejše zaviranje hBChE, za zaviralno aktivnost pa je ugodna tudi prisotnost terciarnega amina. Zamenjava indola s piridin-2-onom, literaturno opisanim fragmentom selektivnih zaviralcev [beta]1i podenote, je vodila v popolno izgubo zaviralne aktivnosti na hBChE kot tudi na AChE, spojine pa so bile neaktivne tudi na hAChE. Terciarnih aminov s piridin-2-onom zaradi sinteznih težav nismo uspeli pripraviti, glede na aktivnost aminskih indolnih analogov pa lahko na podlagi analize odnosa med strukturo in delovanjem sklepamo, da bi amini po vsej verjetnosti zavirali hBChE v nanomolarnem območju.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [T. Urbančič], 2021Language - slovenianCOBISS.SI-ID - 78299139
Author
Urbančič, Tajda
Other authors
Gobec, Stanislav, 1970- |
Knez, Damijan, farmacevt
Topics
Alzheimerjeva bolezen |
Demenca |
Piridin |
butirilholin esteraza |
imunoproteasom |
zaviralci |
indolni skelet |
sinteza amidnih derivatov indola |
sinteza piridin-2-onov |
redukcija amida
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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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Urbančič, Tajda | ![]() |
Gobec, Stanislav, 1970- | 15284 |
Knez, Damijan, farmacevt | 36438 |
Source: Personal bibliographies
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