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Sinteza analogov 1-(2-(piperidin-1-il)etil)pirolidin-2-ona z zaviralnim delovanjem na butirilholin esterazo
Bajuk, Anita (Author), Pajk, Stane (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 bolezen, ki se kaže s postopnim upadom kognitivnih funkcij in s pridruženimi vedenjskimi in psihološkimi spremembami. Med največkrat omenjenimi razlogi za razvoj bolezni so nastanek zunajceličnih netopnih skupkov amiloida beta, znotrajceličnih nevrofibrilarnih pentelj, pomanjkanje acetilholina v možganih in oksidativni stres. Vsi ti procesi privedejo do propada nevronov in posledično atrofije možganov. V največji meri propadejo holinergični nevroni, zato se je razvoj terapevtikov začel z iskanjem spojin, ki bi preprečile pomanjkanje acetilholina. Trenutno registrirana zdravila samo omilijo simptome bolezni, nimajo pa velikega vpliva na potek bolezni. Registrirana zdravila so zaviralci acetilholin esteraze (AChE) (rivastigmin, donepezil, galantamin) in antagonist NMDA receptorjev (memantin). Novejše raziskave kažejo, da v poznih fazah AB zmanjšano delovanje AChE kompenzira soroden encim butirilholin esteraza (BuChE), zato je v poznih fazah AB smiselno zavirati predvsem slednjega. Na podlagi strukture znanih zaviralcev BuChE smo v sklopu magistrske naloge sintetizirali 15 analogov 1-(2-piperidin-1-il)etil)pirolidin-2-ona, pri čemer smo spreminjali substituente na mestu 3 piperidina in s tem skušali optimizirati vezavo spojin v acil vezavni žep aktivnega mesta BuChE. Pri sintezi smo izhajali iz 3-karboksipiperidina, ki smo ga najprej zaščitili v obliki terc-butilkarbamata, karboksilno skupino na mestu 3 pretvorili v Weinrebov amid, slednjega pa smo nato selektivno reducirali do karbaldehida. 3-Formilpiperidin smo kot izhodni sinton uporabili v Wittigovi reakciji za pripravo 3-vinil in 3-fenetilpiperidinov. Po kislinsko katalizirani odščiti terc-butilkarbamata smo dobili sekundarni amin, ki smo ga alkilirali z N-(2-bromoetil)pirolidin-2-onom. Končnim spojinam smo z Ellmanovo metodo preverili zaviralno delovanje na BuChE in njihovo selektivnost napram AChE. Najmočnejši zaviralec je bila spojina 48. Močnejši inhibicijo hBuChE v primerjavi s spojino vodnico C so izkazale tudi spojine 40–43, 46 in 47. Spojine so selektivno zavirale hBuChE v nanomolarnem območju in tako predstavljajo dobro izhodišče za nadaljnjo optimizacijo.

Language:Slovenian
Keywords:Alzheimerjeva bolezen, butirilholin esteraza, zaviralec, acil vezavni žep
Work type:Master's thesis/paper (mb22)
Organization:FFA - Faculty of Pharmacy
Year:2020
Views:367
Downloads:245
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Secondary language

Language:English
Title:Synthesis of 1-(2-(piperidin-1-yl)ethyl)pyrrolidin-2-one analogues as butyrylcholinesterase inhibitors
Abstract:
Alzheimer's disease (AD) is defined as a progressive, irreversible neurodegenerative disorder manifested by a gradual decline in cognitive functions and associated behavioral and psychological disturbances. Among most common pathological alterations in the development of the disease are formation of extracellular insoluble aggregates of amyloid beta, intracellular neurofibrillary tangles, acetylcholine deficiency in the brain and oxidative stress. All these processes lead to neuronal death and consequently brain atrophy. Most affected are cholinergic neurons, therefore the development of therapeutics focused on compounds that ameliorate acetylcholine deficiency. Currently approved drugs only alleviate the symptoms of the disease and have little effect on the course of the disease. Registered drugs are acetylcholine esterase (AChE) inhibitors (rivastigmine, donepezil, galantamine) and NMDA receptor antagonist (memantine). Recent studies showed that in the late stages of AD, the reduced AChE activity is compensated by structurally related enzyme - butyrylcholinesterase (BuChE). Consequently, BuChE inhibition is a promising therapeutic approach in the late stages of AD. Based on the structure of previously identified BuChE inhibitors, 15 analogues of 1-(2-piperidin-1-yl)ethyl)pyrrolidin-2-one were synthesized. Substituents on the position 3 of piperidine were altered in order to optimize the binding of compounds to the acyl binding pocket of BuChE active site. The synthesis was started from 3-carboxypiperidine, which was first protected as tert-butylcarbamate. 3-Carboxylate was transformed into Weinreb amide, which was selectively reduced into carbaldehylde. 3-Formylpiperidine was used as the main building block in Witting reaction to yield 3-vinyl and 3-phenethylpiperidines. Acid-catalysed deprotection of tert-butylcarbamate furnished secondary amine that was alkylated with N-(2-bromoethyl)pyrrolidin-2-one. Final compounds were assayed for the inhibition of BuChE and their selectivity over AChE using the Ellman’s method. The most potent inhibitor was compound 48. Derivatives 40–43, 46 in 47 also showed potent inhibition of hBuChE in comparison to lead compound C. Analogs selectively inhibited hBuChE in the nanomolar range, and thus represent a good starting point for further optimization.

Keywords:Alzheimer's disease, butyrylcholinesterase, inhibitor, acyl binding pocket

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