Odnos strukture i citotoksičnosti oksimskih reaktivatora fosfilirane acetilkolinesteraze

doctoral thesis

• Title (english): Structure – cytotoxicity relationship of oxime reactivators of phosphylated acetylcholinesterase
• Author: Antonio Zandona
• Mentor: Maja Katalinić (mentor)
• Committee member: Ines Primožič (predsjednik povjerenstva)
• Committee member: Zrinka Kovarik (član povjerenstva)
• Committee member: Jasmina Rokov Plavec (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2021-06-14, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

Primjenom novog pristupa analizi baziranog na staničnim testovima in vitro proveden je probir pet serija strukturno povezanih oksima. Odabrani citotoksični bispiridinijevi i 3-hidroksi-2-piridinski oksimi inducirali su aktivaciju apoptoze, putom ovisnom o mitohondriju, aktivacijom enzima kaspaze 9 i/ili 3 uz oštećenje DNA i aktivaciju MAPK kinaze ili fosforilaciju acetil-CoA karboksilaze. Nasuprot tome, imidazolijevi i kinuklidinijevi oksimi uzrokovali su nereguliranu smrt stanice, nekrozu, pucanjem stanične membrane popraćenu oksidacijskim stresom, oštećenjem mitohondrija te smanjenom fosforilacijom izvanstanično reguliranih kinaza ERK1/2, uključenih u regulaciju diobe stanice. Kao potencijalne nove meta djelovanja ovih oksima, predviđene molekulskim modeliranjem farmakofora, istaknute su: beta-sekretaza 1, važna u nastajanju amiloid-β peptida kod Alzheimerove bolesti, aldehid dehidrogenaza A1, koja ima ulogu u Parkinsonovoj bolesti te citokrom P450cam iz Pseudomonas putida, što sugerira mogućnost inhibicije i ljudskih citokroma P450 sustava. Ovakav probir dao je smjernice za poboljšanje i razvoj strukture novih oksima, koje se mogu koristiti u bilo kojem istraživanju oblikovanja novih lijekova.

Abstract (english)

Using a new approach to the analysis of in vitro cell-based assays, five series of structurally related oximes were tested. The selected cytotoxic bispyridinium and 3-hydroxy-2-pyridine oximes induced apoptosis via the mitochondrial-dependent pathway by caspase 9 and/or 3 activation accompanied with DNA damage, MAPK kinase activation or acetyl-CoA carboxylase phosphorylation. In contrast, imidazolium and quinuclidine oximes caused unregulated cell death, necrosis, and cell membrane burst accompanied by oxidative stress, mitochondrial damage, and decreased phosphorylation of extracellularly regulated ERK1/2 kinases involved in the regulation of cell division. The potential new targets of these oximes, predicted by computational modeling of pharmacophores, are: beta-secretase 1, important in the formation of amyloid-β peptide in Alzheimer's disease, aldehyde dehydrogenase A1, which plays a role in Parkinson's disease and cytochrome P450cam from Pseudomonas putida. This suggests the possibility of inhibition of human cytochrome P450 systems. Such screening provided guidelines for improving the development of the structure of new oximes, which can be used in any research for designing new drugs.

• Keywords: dizajn spojeva; integritet membrane; kaspaze; oksidacijski stres; stanična smrt; stanični testovi; toksičnost
• Keywords (english): caspase; cell assays; cell death; compound design; membrane integrity; oxidative stress; toxicity
• Language: croatian
• URN:NBN: urn:nbn:hr:217:997120
• Promotion: 2021
• 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: 127 str. ; 30 cm
• File origin: Born digital
• Access conditions: Open access
• Created on: 2021-06-30 11:39:30