Dizajn, sinteza i biološka evaluacija biskarbamata kao potencijalnih selektivnih inhibitora butirilkolinesteraze

doctoral thesis

• Title (english): Design, synthesis and biological evaluation of biscarbamates as potential selective inhibitors of butyrylcholinesterase
• Author: Ana Matošević
• Mentor: Anita Bosak (mentor)
• Committee member: Jasmina Rokov Plavec (predsjednik povjerenstva)
• Committee member: Vesna Petrović-Peroković (član povjerenstva)
• Committee member: Danijela Barić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2023-01-17, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

Inhibicija butirilkolinesteraze (BChE) predstavlja novi, obećavajući pristup liječenju Alzheimerove bolesti (AB). U sklopu ove disertacije dizajnirani su i sintetizirani biskarbamati s različito supstituiranim atomima dušika karbamatnih skupina i 1-hidroksi-2-aminoetilnog lanca. Za 25 biskarbamata određena je sposobnost inhibicije ljudske BChE i acetilkolinesteraze (AChE), procijenjena je sposobnost prelaska krvno-moždane barijere pasivnim transportom, in vitro toksičnost prema jetrenim, bubrežnim i živčanim stanicama te sposobnost kelatiranja biometala Cu2+, Zn2+ i Fe2+. Svi ispitivani biskarbamati pokazali su vremenski ovisnu inhibiciju s konstantama brzine inhibicije od 103−106 mol-1 dm3 min-1i općenito većom selektivnošću prema BChE u odnosu na AChE. Za tri biskarbamata utvrđena je mogućnost prolaska krvnomoždane barijere pasivnim transportom, dok je za njih devet ta sposobnost ograničena. Većina biskarbamata nije pokazala citotoksični učinak prema odabranim staničnim linijama, dok su svi pokazali sposobnost kelatiranja najmanje jednog od ispitanih iona biometala. Radi visoke BChE selektivnosti, netoksičnosti, sposobnosti kelatiranja biometala i prolaska krvno-moždane barijere, za daljnji razvoj kao lijekova za liječenje kasnijih stadija AB istaknula su se tri spoja (3, 9 i 26).

Abstract (english)

Inhibition of butyrylcholinesterase (BChE) represents a new, promising approach to the treatment of Alzheimer's disease (AD). As part of this dissertation, biscarbamates with different substituted nitrogens of carbamate groups and 1-hydroxy-2-aminoethyl chain were designed and synthesized. For 25 biscarbamates, the ability to inhibit human BChE and acetylcholinesterase (AChE) was determined, the ability to cross the blood-brain barrier (BBB) by passive transport, in vitro toxicity to liver, kidney and neural cells and the ability to chelate biometals Cu2+, Zn2+ and Fe2+ were evaluated. All of the tested biscarbamates showed a timedependent inhibition with inhibition rate constants in 103 − 106 mol-1 dm3 min-1 range with a generally higher preference for BChE compared to AChE. For three biscarbamates it was found that they should be able to cross the BBB by passive transport, while this ability was limited for nine biscarbamates. Most of the biscarbamates did not show a cytotoxic effect against the selected cell lines. All of the biscarbamates were shown to have the ability to chelate at least one of the biometals. Due to the high BChE selectivity, non-toxicity, ability to chelate biometals and pass the BBB, three compounds (3, 9 and 26) were pointed out for further development as drugs for the treatment of later stages of AD.

• Keywords: :Alzheimerova bolest; biskarbamati; BBB; inhibicija; kelatiranje; kolinesteraze
• Keywords (english): Alzheimer`s disease; biscarbamates; BBB; chelation; cholinesterases; inhibition
• Language: croatian
• URN:NBN: urn:nbn:hr:217:838768
• Promotion: 2023
• Project: Number: IP-2018-01-7683; Title: Analiza interakcija butirilkolinesteraze s novim inhibitorima i reaktivatorima; Acronym: AnalyseBChE; Leader: Zrinka Kovarik; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Project: Number: IP-2020-02-9343; Title: Razvoj bioaktivnih molekula za tretman neurodegenerativnih bolesti; Title: Development of Bioactive Molecules for Neurodegenerative Diseases Treatment; Acronym: BioMol4ND; Leader: Anita Bosak; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Study programme: Title: Doctoral study in chemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija (doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija)
• Type of resource: Text
• Extent: 119 str. ; 30 cm
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2025-01-17
• Created on: 2023-02-03 14:31:43