Dizajn i sinteza novih azaindolnih derivata kao mogućih inhibitora FYN kinaze

master's thesis

• Title (english): The design and synthesis of novel azaindole derivatives as possible inhibitors of FYN kinase
• Author: Helena Križan
• Mentor: Dijana Pešić (mentor)
• Committee member: Ines Primožič (predsjednik povjerenstva)
• Committee member: Iva Juranović Cindrić (član povjerenstva)
• Committee member: Aleksandra Maršavelski (član povjerenstva)
• Committee member: Nikola Cindro (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2024-10-25, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

FYN kinaza je član obitelji SRC tirozin-kinaza, prepoznata kao prikladna meta za antitumorske lijekove te lijekove za neurodegenerativne bolesti, posebice Alzheimerovu bolest. Analizom literaturno dostupnih podataka o inhibitorima SRC obitelji kinaza racionalnim pristupom dizajnirani su, a zatim i sintetizirani, novi azaindolni derivati kao mogući inhibitori FYN kinaze. Na komercijano dostupan 4- klor-7H-pirolo[2,3-d]pirimidin uvedeni su 2-(trimetoksisilil)etoksimetilna zaštitna skupina i (2,4- dimetoksifenil)metanamin. Potom je uslijedila acilacija pomoću 3-metoksipropanoil-klorida i deprotekcija u trifluoroctenoj kiselini. Dobiveni azaindol poslužio je kao reaktant u Ullmanovoj reakciji, usporedno s fotoredoks reakcijom, koja se pokazala boljim pristupom. Pripravljeni spojevi pročišćeni su dostupnim kromatografskim tehnikama i okarakterizirani analitičkim metodama (UPLC-UV/MS, 1D i 2D NMR). U računalnom dijelu rada molekulskim uklapanjem uspoređeno je vezanje produkata, ATP- a i staurosporina u FYN kinaznu domenu te produkta dobivenog u fotoredoks reakciji u nekoliko kinaza SRC obitelji.

Abstract (english)

FYN kinase is a member of the SRC family of tyrosine kinases and has been recognized as a suitable target for anticancer drugs as well as drugs for neurodegenerative diseases, especially Alzheimer's disease. By analyzing the available data on inhibitors of the SRC family of kinases using a rational approach, new azaindole derivatives were designed, and then synthesized, as possible inhibitors of FYN kinase. 2-(trimethoxysilyl)ethoxymethyl protective group and
(2,4-dimethoxyphenyl)methanamine were introduced to the commercially available 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. This was followed by acylation using 3-methoxypropionyl chloride and deprotection in trifluoroacetic acid. The resulting azaindole served as a reactant in the Ullmann reaction, in parallel with the photoredox reaction, which proved to be the better approach. The prepared compounds were purified using available chromatographic techniques and characterized by analytical methods (UPLC-UV/MS, 1D and 2D NMR). In the computational part, molecular docking was used to compare the binding of the products, ATP, and staurosporine to the FYN kinase domain, as well as the product obtained in photoredox reaction to several kinases of the SRC family.

• Keywords: otoredoks; FYN kinaza; inhibitori; Ullmanova reakcija
• Keywords (english): FYN kinase; inhibitors; photoredox; Ullman reaction
• Language: croatian
• URN:NBN: urn:nbn:hr:217:787739
• Study programme: Title: Graduate university studies in chemistry; specializations in: Graduate university studies in chemistry; Course: Graduate university studies in chemistry; Study programme type: university; Study level: graduate; Academic / professional title: sveučilišni/a magistar/magistra kemije (sveučilišni/a magistar/magistra kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-11-08 09:51:49