Title Novi heterostilbeni kao potencijalni inhibitori ili reaktivatori kolinesteraza – sinteza i fotokemija Title (english) New heterostilbenes as potential cholinesterase inhibitors or reactivators – synthesis and photochemistry Author Milena Mlakić Mentor Irena Škorić (mentor)Committee member Dragana Vuk (predsjednik povjerenstva)Committee member Sandra Babić (član povjerenstva)Committee member Anita Šalić (član povjerenstva)Committee member Ilijana Odak Committee member Danijela Barić (član povjerenstva)Granter University of Zagreb Defense date and country 2023-11-10, Croatia Scientific / art field, NATURAL SCIENCES Universal decimal classificationUDC ) 54 - Chemistry. Crystallography. Mineralogy Abstract U ovoj disertaciji, predložena je sinteza novih stilbenskih derivata koje u svojim strukturama sadrže heterocikličke jezgre furana, tiofena, triazola, tiazola i piranona. Sinteza je uspješno provedena koristeći Wittigovu reakciju, McMurryjevu reakciju i Buchwald-Hartwigovu reakciju aminiranja. Na sintetiziranim konjugiranim molekulama provedena su fotokemijska osvjetljavanja u svrhu dobivanja novih elektrociklizacijskih fotoprodukata. Na novim derivatima provedena su ispitivanja njihove biološke aktivnosti kao potencijalnih inhibitora enzima kolinesteraza s protuupalnim i antioksidacijskim djelovanjem ili kao reaktivatora kolinesteraza. Kao modelne molekule služile su poznati stilbenski derivati s izraženom biološkom aktivnošću kao što su rezveratrol, pterostilben i drugi. Heterostilbenski derivati sadrže i heterocikličke jezgre koje su ključne u metabolizmu živih stanica, a od iznimne su važnosti i za razvoj agenasa protiv neurodegenerativnih bolesti, kod kojih vodeću ulogu igraju upravo enzimi kolinesteraze. Kako se različiti heterostilbenski derivati već primjenjuju i u izradi nelinearnih optičkih materijala (NLO), detaljno su se uz fotokemijsku reaktivnost i nastajanje fotociklizacijskih produkata ispitivalo i fotofizičko ponašanje novih heterostilbena. Sinteza se provodila konvencionalnim pristupom, ali i suvremenim sintetskim pristupom, primjenom protočne kemije i protočne fotokemije, u cilju povećanja produktivnosti i ekonomičnosti procesa. Na temelju računalnih metoda ispitalo se potencijalno vezivanje novih struktura u aktivna mjesta enzima kolinesteraza, ali i elektronska struktura molekula. U velikom broju novih struktura istaknuo se određeni broj molekula koje su pokazale jako dobru inhibicijsku aktivnost prema enizimima kolinesterazama, ali i antioksidacijsku i protuupalnu aktivnost. Heterostilbenski derivati s najboljim preliminarnim rezultatima daju smjernice za daljnji tijek istraživanja u pronalaženju novih inhibitora ili reaktivatora enzima kolinesteraza s dodatnim antioksidacijskim i protuupalnim učinkom ili pogodnim fotofizičkim karakteristikama. Biološka ispitivanja su provedena u suradnji sa Sveučilištem u Mostaru i tvrtkom Selvita, a računalna ispitivanja i fotofizika, te spektroskopska mjerenja provedena su u suradnji s Institutom Ruđer Bošković. Ispitivanja na kompleksiranju novih spojeva s biometalima, te tumačenja fotokatalitičkih oksigenacija provedena su u suradnji sa Sveučilištem Pannonia u Veszprému. Biološka ispitivanja reaktivacije kolinesteraza ispitivana su u suradnji s kolegama s Instituta za medicinska istraživanja i medicinu rada. Računalna ispitivanja fotokemije i fotofizike pobuđenih molekula u korelaciji s eksperimentalnim LFP rezultatima provedena su u suradnji sa Sveučilištem u Yaleu. Analize spojeva i sinteza spojeva u protočnim reaktorima provedene su u suradnji s kolegama s Fakulteta kemijskog inženjerstva i tehnologije Sveučilišta u Zagrebu i iz tvrtke Pliva.
Abstract (english) In this dissertation, the synthesis of new stilbene derivatives containing in their structures het-erocyclic nuclei of furan, thiophene, triazole, thiazole and pyranone was designed, and success-fully carried out using the Wittig reaction, the McMurry reaction and the Buchwald-Hartwig amination reaction. Photochemical illumination was performed on the synthesized conjugated derivatives in order to obtain new electrocyclization photoproducts. New derivatives were tested for their biological activity as potential cholinesterase enzyme inhibitors with anti-in-flammatory and antioxidant activity or as cholinesterase reactivators. Known stilbene deriva-tive with pronounced biological activity such as resveratrol, pterostilbene and others served as model compounds. Heterostilbene molecules contain heterocyclic nuclei that are crucial in the metabolism of living cells, and are of exceptional importance for the development of agents against neurodegenerative diseases, in which enzymes cholinesterases play a leading role. As different heterostilbene derivatives are already used in the production of nonlinear optical ma-terials (NLO), photochemical reactivity and the formation of photocyclization products were also investigated in detail, as well as the photophysical behavior of the new heterostilbenes. The synthesis was carried out with a conventional approach, but also with a modern synthetic approach, using flow-chemistry and flow-photochemistry, in order to increase the productivity and economy of the process. On the basis of computer methods, the potential binding of new structures to the active sites of enzyme cholinesterases, as well as the electronic structure of the molecules, were examined. Among the large number of new structures, a certain number of molecules stood out with very good inhibitory activity towards enzyme cholinesterases, but also antioxidant and anti-inflammatory activity. Heterostilbene derivatives with the best pre-liminary results provide guidelines for further research in finding new enzyme cholinesterase inhibitors or reactivators with additional antioxidant and anti-inflammatory effects or suitable photophysical characteristics. Biological tests were carried out in cooperation with the University of Mostar and the company Selvita, while computational study, photophysics and spectroscopic measurements were carried out in cooperation with the Ruđer Bošković Institute. Tests on the complexation of compounds with biometals, and interpretations of the photocatalytic oxygenation were carried out in coop-eration with the Pannonia University in Veszprém. Biological tests of cholinesterase reactiva-tion were investigated in collaboration with colleagues from the Institute for Medical Research and Occupational Medicine. Computational study on the photochemistry and photophysics of excited molecules in correlation with experimental results were carried out in cooperation with Yale University. Analyzes of compounds and synthesis of compounds using flow-reactors were carried out in collaboration with colleagues from the Faculty of Chemical Engineering and Technology at University of Zagreb and from the Pliva company.
Keywords
Alzheimerova bolest
antioksidacija
fotokemija
heterostilbeni
inhibicija
kolinesteraze
molekulsko pristajanje
protuupalna aktivnost
reaktivacija
spektroskopska karakterizacija
Keywords (english)
Alzheimer's disease
antioxidation
photochemistry
heterostilbenes
inhibition
cholinesterase
molecular docking
anti-inflammatory activity
reactivation
spectroscopic characterisation
Language croatian URN:NBN urn:nbn:hr:149:822291 Promotion 2023 Study programme Title: Chemical Engineering and Applied Chemistry - Doctoral course Type of resource Text Extent 360 str. ; 30 cm File origin Born digital Access conditions Open access Terms of use Created on 2023-12-01 13:21:34
