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Načrtovanje, sinteza in vrednotenje derivatov 1-(2-(3-(4-fluorofenetil)piperidin-1-il)etil)pirolidin-2-ona kot selektivnih zaviralcev butirilholin esteraze
Vidic, David (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) postaja kot najpogostejša oblika demence vedno večji problem moderne družbe. Bolezen je kompleksna in kljub mnogim raziskavam glavni vzrok zanjo ni znan. Skozi zgodovino so se razvile tri najpomembnejše hipoteze: holinergična, amiloidna in tau hipoteza. Kljub mnogim raziskavam so dostopna zgolj štiri zdravila, ki blažijo simptome AB. Raziskave so pokazale, da se v poznejših stadijih AB poveča izražanje in aktivnost encima butirilholin esteraze (BChE), aktivnost in izražanje encima acetilholin esteraze (AChE) pa se zmanjša. To dognanje nakazuje, da je BChE lahko zelo perspektivna terapevtska tarča v obvladovanju AB. V okviru magistrske naloge smo načrtovali, sintetizirali in in vitro ovrednotili analoge zaviralca BChE, spojine zadetka, ki je bil odkrit s programom za virtualno rešetanje na osnovi liganda, LiSiCA. Od načrtovanih sedmih spojin ter resinteze spojine zadetka smo uspešno sintetizirali šest novih derivatov. Spojine smo okarakterizirali z jedrsko magnetno resonanco (NMR), infrardečo spektrometrijo (IR) in masno spektrometrijo visoke ločljivosti (HRMS). Čistost spojin smo določili s tekočinsko kromatografijo visoke ločljivosti (HPLC). Z Ellmanovo metodo smo določili srednjo inhibitorno koncentracijo (IC50) na encimih humana BChE (hBChE) in humana AChE (hAChE). S primerjavo IC50 vrednosti smo lahko razbrali, kako uvedene strukturne modifikacije vplivajo na jakost zaviranja – t.i. odnos med strukturo in delovanjem ter selektivnost zaviranja BChE sintetiziranih analogov v primerjavi s spojino zadetkom. Zamenjava piperidinskega obroča z manjšim pirolidinskim in večjim azepanskim je vodila do šibkejšega zaviranja hBChE. Cis 3-(4-fluorostiril)piperidinski analog 25 (IC50 = 44,2 ±4,0 nM) je v primerjavi z izhodišnim zaviralcem (IC50 = 99,8 ±8,7 nM) edini izkazoval močnejšo zaviralno aktivnost na hBChE. V sodelovanju s skupino kristlografov iz Francije smo razrešili tudi kristalno strukturo analoga 25 v aktivnem mestu encima hBChE, s čimer smo tudi na strukturnem nivoju razložili močno nanomolarno zaviranje hBChE.

Language:Slovenian
Keywords:Alzheimerjeva bolezen, holinergična hipoteza, zaviralci butirilholin esteraze, derivati piperidina.
Work type:Master's thesis/paper (mb22)
Organization:FFA - Faculty of Pharmacy
Year:2021
Views:191
Downloads:55
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Secondary language

Language:English
Title:Design, synthesis and evaluation of 1-(2-(3-(4-fluorophenethyl)piperidin-1-yl)ethyl)pyrrolidin-2-one analogues as selective butyrylcholinesterase inhibitors
Abstract:
Alzheimer's disease (AD) presents an increasingly alarming health-care problem as the leading form of dementia in modern society. AD is a complex disease and the underlying cause is not defined. Decades of research have resulted in three main hypotheses, i.e. cholinergic, amyloid and tau hypothesis. There are currently only four drugs approved for the treatment of symptoms of AD. Research shows increased activity of butyrylcholinesterase (BChE) during the later stages of AD, while the activity of acetylcholinesterase (AChE) is decreased. Altogether, BChE represents a potential target for the management of AD. Within the Master's thesis, analogues of potent BChE inhibitor discovered by ligand-based screening program LiSiCA were designed, synthesized and evaluated. Six out of seven designed analogues were successfully synthesized alongside with the hit compound. Compounds were characterized by methods of nuclear magnetic resonance (NMR), infrared spectroscopy (IR) and high resolution mass spectrometry (HRMS). Purity of synthesized compounds was determined using high performance liquid chromatography (HPLC). Median inhibitory concentration (IC50) for human butyrylcholinesterase (hBChE) and human acetylcholinesterase (hAChE) was determined using the method of Ellman. Comparing IC50 values, we were able to determine the structure activity relationships and selectivity of analogues in comparison to hit compound. Replacement of piperidine with smaller pyrrolidine or larger azepane resulted in diminished inhibitory potency on hBChE. Cis 3-(4-fluorostyryl)piperidine analogue 25 (IC50 = 44.2 ±4.0 nM) was the only compound that showed more potent inhibition over the hit compound (IC50 = 99.8 ±8.7 nM). In collaboration with the group of crystallographers from France, crystal structure of analogue 25 in the active site of hBChE was resolved, which provided the structural rationel for nanomolar inhibition of hBChE.

Keywords:Alzheimer's disease, cholinergic hypothesis, butyrylcholinesterase inhibitors, piperidine derivatives.

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