Photochemical synthesis and functionalization of benzobicyclo[3.2.1]octadienes as potential cholinesterase inhibitors

doctoral thesis

• Title (croatian): Fotokemijska sinteza i funkcionalizacija benzobiciklo[3.2.1]oktadiena kao potencijalnih inhibitora kolinestaraza
• Author: Ana Grgičević
• Mentor: Irena Škorić (mentor)
• Committee member: Dragana Vuk (predsjednik povjerenstva)
• Committee member: Marijana Hranjec (član povjerenstva)
• Committee member: Nikola Basarić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2020-10-09, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry; Organic Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

A continuous flow-photochemistry setup was evaluated with the aim to enable a more efficient protocol for the synthesis of benzobicyclo[3.2.l]octadiene skeleton by intramolecular [2+2]-photocycloaddition reaction. This was the first application of the flow-photochemistry on β-heteroaryl-o-divinylbenzenes and o-vinylphenyl substituted butadienes. Numerous compounds with the bicyclo[3.2.l]-skeleton are proven as potent inhibitors of dopamine and serotonin transporters and also play a crucial role in the treatment of central nervous system and Alzheimer’s disorders. Some of the previously prepared photoproducts showed good cholinesterase inhibition activity, but the main disdvantages were high lipophilicity values and low solubility. Further functionalization of photoproducts was explored in order to achieve better ADME properties. New amines were synthesised using amination reaction, while the addition to the isolated double bond resulted in new epoxides, alcohols and ethers. The furan ring as part of benzobicyclo[3.2.1]-core was suitable substrate for the synthesis of new oximes and oxime ethers and acyl derivatives. Photochemical and especially photophysical behavior of the butadiene derivatives where p-fluorophenyl, p-dimethylaminophenyl, and p-nitrophenyl rings were incorporated into mono- or di-arylbutadiene analogues were investigated and explored. Triazole moiety is important structural part of biologically active compounds and their photochemical reactivity can be different from the corresponding compounds with the phenyl ring. In continuation of the work the investigation was extended by introduction of the triazole ring into the o-divinylbenzene moiety.

Abstract (croatian)

Kontinuirani flow-fotokemijski sustav razvijen je s ciljem da se omogući učinkovitija metoda sinteze benzobiciklo[3.2.1]oktadienskog skeleta intramolekulskom [2+2]-fotocikladicijom. Ovo je prva primjena flow-fotokemije na β-heteroaril-o-divinilbenzenima i o-vinilfenil-supstituiranim butadienima. Brojni spojevi s biciklo[3.2.l]-skeletom pokazali su se kao snažni inhibitori transportera dopamina i serotonina, a imaju i ključnu ulogu u liječenju centralnog živčanog sustava i Alzheimerove bolesti. Neki prethodno pripremljeni fotoprodukti pokazali su dobru inhibicijsku aktivnost na kolinesteraze, ali su imali visoke vrijednosti lipofilnosti i nisku topivost. Daljnja funkcionalizacija fotoprodukata istražena je kako bi se postigla bolja ADME svojstva, te su novi amini sintetizirani reakcijom aminacije, dok su adicijom na izoliranu dvostruku vezu priređeni su novi epoksidi, alkoholi i eteri. Furanski prsten kao dio benzobiciklo[3.2.1]-skeleta bio je pogodan supstrat za sintezu novih oksima i oksimskih etera i acilnih derivata. Fotokemijska i fotofizikalna svojstva butadienskih derivata u kojima je p-fluorfenilni, p-dimetilaminofenilni, and p-nitrofenilni prsten dio mono- i diarilbutadienskih analoga, su također istražena. Triazolni prsten je važna strukturna podjedinica biološki aktivnih spojeva i fotokemijska svojstva se mogu razlikovati od spojeva koji sadrže fenilni prsten. Istraživanje je prošireno uvođenjem triazolnog prstena na o-divinilbenzen.

• Keywords: ADME properties; benzobicyclo[3.2.1]octadienes; cholinesterase; continuous-flow photochemistry; functionalized polycyclic skeleton; physico-chemical properties
• Keywords (croatian): ADME svojstva; benzobiciklo[3.2.1]oktadieni; kolinesteraze; kontinuirana flow-fotokemija; funkcionalizirani policiklički skelet; fizikalno-kemijska svojstva
• Language: english
• URN:NBN: urn:nbn:hr:149:906955
• Promotion: 2020
• Study programme: Title: Chemical Engineering and Applied Chemistry - Doctoral course; 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: 204 str. ; 30 cm
• File origin: Born digital
• Access conditions: Access restricted to students and staff of home institution
• Created on: 2023-06-07 13:37:04