Načrtovanje in sinteza zaviralcev butirilholinesteraze s triptofanskim skeletom

Meden, Anže (author), Grošelj, Uroš (mentor), Gobec, Stanislav (comentor)

Oslabljen holinergični prenos ima pomembno vlogo pri Alzheimerjevi bolezni, najpogostejši obliki demence, ki je skupaj z drugimi nevrodegenerativnimi boleznimi vse pogostejša med starajočim se prebivalstvom. Z napredovanjem te bolezni vlogo glavne holinesteraze v možganih prevzame butirilholinesteraza, zato je ta obetavna tarča za razvoj novih učinkovin za simptomatsko zdravljenje Alzheimerjeve bolezni. V primerjavi z acetilholinesterazo je zaradi večjega aktivnega mesta manj substratno specifična in katalizira hidrolizo različnih estrov, med njimi tudi butiril- in sukcinilholina, kar omogoča razvoj selektivnih zaviralcev. Na osnovi strukture znanega selektivnega zaviralca butirilholinesteraze s triptofanskim skeletom smo pripravili 34 analogov s klasičnimi reakcijami peptidne kemije (zaščita, amidiranje, odščita), med temi tudi dva nova heterociklična analoga triptofana z Negishijevo reakcijo ter štiri dodatno modificirane ?-aminoamide. Sintetizirane spojine so visoko selektivne za butirilholinesterazo – skoraj vse jo zavirajo v nanomolarnem območju (najboljši zaviralec v seriji, spojina 34, ima IC50 vrednost 3,0 nM), imajo primerne fizikalnokemijske lastnosti, so preproste za sintezo in omogočajo dovolj možnosti za nadaljnjo optimizacijo kot spojine vodnice pri iskanju novih učinkovin za simptomatsko zdravljenje Alzheimerjeve bolezni. Rezultati te magistrske naloge so bili objavljeni kot del članka v reviji Chemical Communications (Meden, A. in sod. Tryptophan-Derived Butyrylcholinesterase Inhibitors as Promising Leads against Alzheimer’s Disease. Chem. Commun. 2019, 55 (26), 3765–3768. https://doi.org/10.1039/C9CC01330J).

• Language: Slovenian
• Keywords: zaviralci butirilholinesteraze, Alzheimerjeva bolezen, triptofan, a-aminoamidi
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-108342
• Publication date in RUL: 28.06.2019

Secondary language

• Language: English
• Title: Design and synthesis of tryptophan-based butyrylcholinesterase inhibitors

Abstract

Reduced cholinergic transmission has an important role in Alzheimer's disease. Along with other neurodegenerative diseases, this most common form of dementia has an ever increasing incidence among the aging population. Butyrylcholinesterase becomes the main brain cholinesterase during disease progression, which makes it a promising druggable target in the development of new drugs for symptomatic treatment of Alzheimer's disease. Butyrylcholinesterase is less substrate-specific compared to acetylcholinesterase (it catalyzes hydrolysis of different esters, including butyryl- and succinylcholine) due to larger active site, which enables development of selective inhibitors. Starting from a known selective tryptophan-based butyrylcholinesterase inhibitor, 34 analogues were prepared using time-tested peptide chemistry reactions (protection, amidation, deprotection), with two new heterocyclic tryptophan analogues prepared via Negishi reaction and four ?-aminoamides additionally modified. The synthesized compounds exhibit high selectivity for butyrylcholinesterase, almost all are nanomolar inhibitors (the best inhibitor in the series, 34, has IC50 of 3,0 nM) with appropriate physicochemical properties, they are easy to synthesize, and offer additional options for further optimization as lead compound in the search for new drugs for symptomatic treatment of Alzheimer's disease. The results of this master's thesis were published as part of an article in Chemical Communications (Meden, A et al. Tryptophan-Derived Butyrylcholinesterase Inhibitors as Promising Leads against Alzheimer’s Disease. Chem. Commun. 2019, 55 (26), 3765–3768. https://doi.org/10.1039/C9CC01330J).

• Keywords: butyrylcholinesterase inhibitors, Alzheimer’s disease, tryptophan, a-aminoamides