Utjecaj promjene strukture derivata nikotinamida na inhibiciju kolinesteraza i citotoksičnost

master's thesis

• Title (english): The impact of structure changes of nicotinamide derivatives on cholinesterase inhibition and cytotoxicity
• Author: Gabriela Lihtar
• Mentor: Maja Katalinić (mentor)
• Committee member: Morana Dulić (predsjednik povjerenstva)
• Committee member: Iva Juranović Cindrić (član povjerenstva)
• Committee member: Biserka Prugovečki (član povjerenstva)
• Committee member: Marko Močibob (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2020-02-28, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

Acetilkolinesteraza (AChE, EC 3.1.1.7.) i butirilkolinesteraza (BChE, EC 3.1.1.8.) su
strukturno homologni enzimi koji se zbog svoje važne fiziološke uloge istražuju kao
terapijske mete za ublažavanje simptoma neurodegenerativnih bolesti. Naime, ovi enzimi
hidroliziraju acetilkolin koji prenosi živčane impulse, a čiji manjak je karakteristika ovih
bolesti. Stoga se kao lijekovi koriste reverzibilni inhibitori kolinesteraza koji onemogućuju
spomenutim enzimima da razgrade acetilkolin i time se povećava količina dostupnog
acetilkolina za nesmetan prijenos signala. U ovom istraživanju ispitan je učinak serije derivata
nikotinamida, kao reverzibilnih inhibitora kolinesteraza te njihova citotoksičnost kako bi se
dobio uvid o mogućoj upotrebi derivata nikotinamida u tretmanu neurodegenerativnih bolesti.
Svi testirani derivati reverzibilno su inhibirali obje kolinesteraze s konstantom inhibicije Ki u
mikromolarnom području, a jačina učinka ovisila je o prisutnom supstituentu na bočnom
prstenu molekule. Prema omjeru Ki, ovi spojevi su selektivniji prema AChE. Dobiveni
rezultati stanične toksičnosti ne svrstavaju ove spojeve u visokotoksične i time ne
predstavljaju prepreku za daljnji razvoj inhibitora kolinesteraza baziranih na nikotinamidu.

Abstract (english)

Acetylcholinesterase (AChE, EC 3.1.1.7.) and butyrylcholinesterase (BChE, EC 3.1.1.8.) are
structurally homologous enzymes that, due to their important physiological roles are studied
as therapeutic targets for mitigation symptoms of neurodegenerative diseases. Namely, they
hydrolyse the neurotransmitter acetylcholine which deficit characterises these conditions.
Specifically for this purpose, reversible cholinesterase inhibitors are used to stop
acetylcholine degradation and to ensure smooth signal transmission. In this study, the effect
of a series of nicotinamide derivatives, were examined as reversible cholinesterase inhibitors
as well as their cytotoxicity, to gain insight into the possible use of nicotinamide derivatives
in the treatment of neurodegenerative diseases. All the derivatives that were tested reversibly
inhibited both cholinesterases with the inhibition constants Ki in the micromolar range, and
the effect intensity was dependent on the substituent present on the side ring of the molecule.
According to the Ki ratio, these compounds are more selective towards AChE. The
cytotoxicity results do not classify these compounds as highly toxic and thus do not constitute
a barrier for the further development of nicotinamide-based cholinesterase inhibitors.

• Keywords: acetilkolinesteraza; butirilkolinesteraza; neurodegenerativne bolesti; nikotinamid; reverzibilni inhibitori
• Keywords (english): acetylcholinesterase; butyrylcholinesterase; neurodegenerative diseases; nicotinamide; reversible inhibitors
• Language: croatian
• URN:NBN: urn:nbn:hr:217:133018
• Study programme: Title: Graduate university studies in chemistry; specializations in: Research programme; Course: Research programme; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra kemije (magistar/magistra kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2022-02-28
• Created on: 2020-03-19 13:42:49