Asimetrična alilna dearomatizacija u sintezi potencijalnih kinaznih inhibitora

master's thesis

• Title (english): Asymmetric allylic dearomatization reaction in potential kinase inhibitor synthesis
• Author: Ela Radošević
• Mentor: Sanja Koštrun (mentor)
• Committee member: Ines Primožič (predsjednik povjerenstva)
• Committee member: Iva Juranović Cindrić (član povjerenstva)
• Committee member: Željka Soldin (član povjerenstva)
• Committee member: Ivan Kodrin (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2020-11-27, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

SRC-kinaze su enzimi koji su uključeni u regulaciju mnogobrojnih staničnih funkcija, od rasta, diobe, metabolizma, pa do apoptoze stanica. U sklopu ovog diplomskog rada provedena je analiza literaturno dostupnih kristalnih struktura kompleksa poznatih inhibitora sa SRC-kinazom. Proučavnjem njihovih interakcija unutar aktivnog mjesta, metodom molekulskog uklapanja dizajnirani su njihovi analozi koji sadrže fragment bogat sp3 hibridiziranim ugljikovim atomima. Za sintezu su odabrani spojevi koji su imali najbolje rezultate u molekularnom uklapanju te je za njih provedena retrosintetska analiza. Nadalje, provedena je višestupanjska sinteza spoja N-benzil-6-brom-4-vinil-1,3,4,9-tetrahidro-β-karbolina temeljena na reakciji asimetrične alilne dearomatizacije katalizirane iridijem. Zatim su sintetizirani fragmenti ponatiniba i PP2 liganda te je 3-etinilimidazo[1,2-b]piridazinski fragment ponatiniba uspješno povezan s sp3 bogatim fragmentom, dok sinteza analoga jednog od najaktivnijih inhibitora SRC kinaza, PP2 liganda, nije bila uspješna.

Abstract (english)

SRC-kinases are enzymes that are involved in many cellular functions, from cell growth, division and metabolism to cell apoptosis. In this diploma thesis analysis of literally available crystal structures of SRC-kinase with different inhibitors was performed. By studying interactions between active site and known inhibitors, by means of molecular docking method, new analogues that contain a fragment rich in sp3 hybridized carbon atoms were designed. Compounds with the best docking scores were chosen for the synthesis and the retrosynthetic analysis of selected compounds was successfully done. Furthermore, in this diploma thesis N-benzyl-6-bromo-4-vinyl-1,3,4,9-tetrahydro-β-carboline was prepared in five steps relaying on iridium catalyzed asymmetric allyl dearomatization. Hinge binder fragments of ponatinib and PP2 ligand were synthesized and 3-ethynylimidazo[1,2-b]pyridazine fragment was successfully coupled to sp3 rich fragment. Synthesis of the PP2 analogue, one of the most active SRC-kinase inhibitors, was not successful.

• Keywords: CADA reakcija; kinazni inhibitori; racionalni dizajn; SRC-kinaza
• Keywords (english): CADA synthesis; kinase inhibitors; SRC kinase; rational design
• Language: croatian
• URN:NBN: urn:nbn:hr:217:796237
• Study programme: Title: Graduate university studies in chemistry; specializations in: Research programme; Course: Research programme; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra kemije (magistar/magistra kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2020-12-10 13:15:20