Dizajn i sinteza novih azaindolnih derivata kao mogućih inhibitora FYN kinaze ; The design and synthesis of novel azaindole derivatives as possible inhibitors of FYN kinase

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. ; 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 ...