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Sinteza zaviralcev butirilholinesteraze
Zorman, Maša (Author), Grošelj, Uroš (Mentor) More about this mentor... This link opens in a new window

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Abstract
Butirilholinesteraza je eden izmed ključnih encimov pri uravnavanju telesnih koncentracij nevrotransmiterja acetilholina in pri metabolizmu neholinskih estrov. Naloga butirilholinesteraze je hidroliza esterske vezi, ki v primeru acetilholina povzroči prekinitev sinaptičnega signaliziranja. Prekomerno izražanje butirilholinesteraze in s tem izrazito zmanjševanje sinaptičnega signaliziranja prek acetilholina v možganih lahko negativno vpliva na nastajanje novih spominov in pomnjenje, kar se tudi dogaja pri nekaterih dementnih obolenjih, kot je Alzheimerjeva bolezen. Poleg povišane regulacije acetilholina v možganih je butirilholinesteraza korelirana tudi z nastajanjem drugih patologij, ki se pojavljajo pri Alzheimerjevi demenci, kot je akumulacija proteinskih plakov v možganih. Zaradi patološkega povišanja butirilholinesteraze tekom Alzheimerjeve bolezni raziskovalci že nekaj desetletji razvijajo zdravila, ki bi zavirala delovanje butirilholinesteraze in s tem lajšala znake bolezni. Od trenutno petih terapevtskih učinkovin, ki so na voljo za lajšanje znakov Alzheimerjeve bolezni, so kar štiri učinkovine zaviralci butirilholinesteraze. Ker za zdaj na tržišču ni učinkovin, ki bi lahko delovala neposredno na akumulacijo proteinskih plakov, so inhibitorji butirilholinesteraze trenutno najbolj obetavna zdravila za lajšanje demence. Cilj diplomske naloge je bil sintetizirati in v in vitro preizkusu testirati dva nova potencialna zaviralca butirilholinesteraze. Pri sintezi obeh zaviralcev smo za ogrodje zaviralca uporabili aminokislino triptofan, na katerega smo uspešno pripeli 2-cikloheptiletanaminsko skupino(C-terminalni del) in benzilno/butirilno skupino (N-terminalni del). Obe spojini smo preizkusili v kinetičnem testu s človeško butirilholinesterazo, kjer sta obe inhibirali encim v nanomolarnem območju.

Language:Slovenian
Keywords:Alzheimerjeva bolezen, zaviralci butirilholinesteraze, triptofanski derivati
Work type:Bachelor thesis/paper (mb11)
Tipology:2.11 - Undergraduate Thesis
Organization:FKKT - Faculty of Chemistry and Chemical Technology
Year:2019
COBISS.SI-ID:1538298307 Link is opened in a new window
Views:226
Downloads:79
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Secondary language

Language:English
Title:Synthesis of butyrylcholinesterase inhibitors
Abstract:
Butyrylcholinesterase is one of the key enzymes in the regulation of the neurotransmitter acetylcholine and in the metabolism of non-choline esters. The role of butyrylcholinesterase is to hydrolyse ester bonds, which in the case of acetylcholine, causes the termination of cholinergic synaptic signalization. The overexpression of the enzyme causes a serious decrease in cerebral acetylcholine signalization, which in turn can affect the ability of the brain to generate new memories. This is what happens during the progression of certain types of dementia, such as Alzheimer's disease. Aside from the overregulation of cerebral acetylcholine, butyrylcholinesterase correlates with other Alzheimer's disease pathologies, such as the accumulation of protein plaques. Because of the pathological increase of the enzyme during the progression of Alzheimer's disease, scientists have been trying for decades to develop drugs that would inhibit butyrylcholinesterase activity and alleviate the symptoms of the disease. Four out of five therapeutical agents that are currently available for the treatment of Alzheimer's dementia are cholinesterase inhibitors. Because there are currently no available drugs that could successfully directly target brain plaque accumulation, cholinesterase inhibitors are the most promising drugs for treating dementia on the market. The goal of this diploma was to synthesize and in vitro test two new potential butyrylcholinesterase inhibitors. The base for the new inhibitors was the amino acid tryptophan to which we successfully added a 2-cyclheptylethanamino group (C-terminus) as well as a benzyl/butyryl group (N-terminus). We tested the inhibitory strength of both compounds in a kinetic test with human butyrylcholinesterase and they both inhibited the enzyme in the nanomolar range.

Keywords:Alzheimer's disease, cholinesterase inhibitors, tryptophan derivatives

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