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Sinteza in vrednotenje heterocikličnih analogov 3-(4-fluorofenetil)piperidina z zaviralnim delovanjem na butirilholin esterazo
Turk, Nina (Author), Gobec, Stanislav (Mentor) More about this mentor... This link opens in a new window, Knez, Damijan (Co-mentor)

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Abstract
Alzheimerjeva bolezen (AB) je progresivna ireverzibilna nevrodegenerativna motnja v centralnem živčevju, ki se kaže predvsem z izgubo spomina in drugimi simptomi kognitivnega upada. Razvoj AB največkrat povezujejo s pomanjkanjem acetilholina v možganih, kopičenjem amiloida beta, nevrofibrilarnimi pentljami, nevrovnetjem in oksidativnim stresom, kljub temu pa enotne hipoteze nastanka AB še vedno ni. Trenutno se za simptomatsko zdravljenje uporabljajo zaviralci holin esteraz in memantin kot antagonist NMDA receptorjev. Za razgradnjo acetilholina v centralnem živčevju sta odgovorna encima acetilholin esteraza (AChE) in butirilholin esteraza (BChE). Z napredovanjem bolezni ima vedno večjo vlogo BChE, ki kompenzira zmanjšano aktivnost AChE, zato postaja potencialna tarča za zdravljenje AB. Naš namen je bil, da na podlagi strukture znanega selektivnega zaviralca BChE, odkritega s pomočjo programa LiSiCa, sintetiziramo analoge 1-(2-piperidin-1-il)pirolidin-2-ona. Z različnimi substituenti na mestu 3 piperidina smo želeli izboljšati vezavo spojin v acil-vezavni žep BChE. Pri sintezi smo izhajali iz nipekojske kisline, ki smo jo po uvedbi Boc zaščitne skupine preko Weinrebovega amida pretvorili v aldehid, slednjega pa v Wittigovi reakciji z Wittigovo soljo pretvorili v 3-vinilpiperidine. Spojinam smo reducirali dvojno vez v distančniku, odščitili Boc zaščitno skupino in sekundarni amin alkilirali z N-(2-bromoetil)pirolidin-2-onom. Sintetiziranim končnim spojinam smo z Ellmanovo metodo ovrednotili njihovo zaviralno delovanje na rekombinantni humani BChE (hBChE) in AChE (hAChE). Zaključimo lahko, da se je kot najmočnejši in najselektivnejši zaviralec izkazala spojina 46 z 3-trifluorometilbenzenom (IC50 = 48 nM), dobro zaviralno delovanje na BChE z vrednostmi IC50 v nanomolarnem območju so pokazale še spojine 41–44 ter derivat 47. Selektivnost v primerjavi s hAChE pri večini sintetiziranih spojin ni bila dosežena, kljub temu pa spojine predstavljajo dobro izhodišče za načrtovanje in optimizacijo selektivnih zaviralcev hBChE kot tudi ligandov z multiplim delovanjem za zdravljenje AB.

Language:Slovenian
Keywords:Alzheimerjeva bolezen, butirilholin esteraza, zaviralci butirilholin esteraze
Work type:Master's thesis/paper (mb22)
Organization:FFA - Faculty of Pharmacy
Year:2021
Views:141
Downloads:53
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Secondary language

Language:English
Title:Synthesis and evaluation of heterocyclic analogues of 3-(4-fluorophenethyl)piperidine as butyrylcholinesterase inhibitors
Abstract:
Alzheimer's disease (AD) is a progressive irreversible neurodegenerative disorder of the central nervous system characterized by memory loss and other symptoms of cognitive decline. Development of AD is often associated with acetylcholine deficiency in the brain, formation of amyloid beta aggregates, neurofibrillary tangles, neuroinflammation and oxidative stress, nonetheless, a unified hypothesis of AD pathogenesis is still lacking. Currently approved drugs for symptomatic treatment of AD are cholinesterase inhibitors and memantine as an NMDA receptor antagonist. There are two enzymes in the central nervous system responsible for the decomposition of acetylcholine, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). With the progression of AD the activity of AChE decreases. On the other hand, the activity and significance of BChE compensatively increases and this observation proposes BChE as a promising therapeutic target. The aim of the work was to synthesize analogues of 1-(2-piperidin-1-yl)pyrrolidin-2-one, which was identified with ligand-based virtual screening software LiSiCA, and thus improve BChE inhibitory potencies. By varying the substituents on the position 3 of piperidine we aimed to optimize the binding of compounds to the acyl binding pocket of BChE. The synthesis started from nipecotic acid, which was protected as tert-butylcarbamate and transformed into an aldehyde via corresponding Weinreb amide. The aldehyde obtained was combined with a Wittig salt in the Wittig reaction furnishing 3-vinylpiperidines. Following the reduction of double bond in the spacer and Boc deprotection, the secondary amine was alkylated using N-(2-bromoethyl)pyrrolidin-2-one. Final compounds synthesized were biochemically evaluated for their inhibition of isolated recombinant human BChE (hBChE) and AChE (hAChE) using the Ellman's method. To conclude, the most potent and selective BChE inhibitor was compound 46 with 3-trifluoromethylphenyl moiety (IC50 = 48 nM). Potent hBChE inhibitors with IC50 values in nanomolar range were also compounds 41–44 and 47. Most of the synthesized compounds were not as selective for BChE in comparison to AChE as expected. Nonetheless, compounds still represent a good starting point for the development and optimization of selective BChE inhibitors and multifunctional ligands for AD therapy.

Keywords:Alzheimer's disease, butyrylcholinesterase, butyrylcholinesterase inhibitors

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