Novi derivati citozina: sinteza "klik" reakcijom, strukturna karakterizacija, in silico analiza i antitumorska ispitivanja

master's thesis

• Title (english): The novel cytosine derivatives: synthesis by "click" reaction, structural characterization, in silico analysis and antitumor evaluations
• Author: Moris Mihovilović
• Mentor: Tatjana Gazivoda Kraljević (mentor)
• Committee member: Tatjana Gazivoda Kraljević (predsjednik povjerenstva)
• Committee member: Maja Stipković Babić (član povjerenstva)
• Committee member: Svjetlana Krištafor (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2015-07-08, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry; Organic Chemistry

Abstract

Cilj ovog istraživanja bio je pripraviti derivate N-4-benzoilcitozinas 1,2,3-triazolnim supstituentima u položajima N-1 i N-3 radi njihovih citostatskih ispitivanja in vitro na staničnim linijama zloćudnih tumorskih linija porijeklom iz čovjeka: HeLa (adenokarcinom vrata maternice), CaCo-2 (adenokarcinom debelog crijeva), Raji (Burkittov limfom) i K562 (kronična mijeloidna leukemija u blastičnoj krizi). N-1 propargilirani i N,N-1,3-dipropargilirani derivati N-4-benzoilcitozina (2, 4 i 5) pripravljeni su reakcijom alkiliranja N-4-benzoil-5-jodcitozina ili N-4-benzoilcitozina s propargil-bromidom uz K2CO3 kao bazu. Huisgenovom 1,3-dipolarnom cikloadicijom potpomognutom mikrovalovima N,N-1,3-dipropargiliranog derivata N-4-benzoil-citozina (5) s odgovarajućim azidima uz katalizator sintetizirani su N,N-1,3-ditriazolilni derivati citozina (6-12). Oksidacijom propargilnog supstituenta na položaju N-3 citozinskog prstena dobiveni su N-3-(2-oksopropil)-N-1-triazolilni derivati (13-20) kao nusprodukti. Strukturna karakterizacija novopripravljenih spojeva provedena je 1H i 13C NMR spektroskopijom i masenom spektrometrijom, a moguće biološke mete i farmakološka djelovanja novopripravljenih spojeva predviđene su in silico analizom. Od svih analiziranih spojeva najbolje predviđene biološke aktivnosti imaju N,N-1,3-dipropargilirani N-4-benzoil-5-jodcitozin (2), derivat N-4-benzoil-ditriazolilcitozina koji na 1,2,3-triazolnom prstenu u položaju 1 ima p-trifluormetilfenilni supstituent (6) i derivat N-4-benzoil-N-3-(2-oksopropil)-N-1-triazolilcitozina koji na 1,2,3-triazolnom prstenu u položaju 1 ima benzilni supstituent (17).

Abstract (english)

The aim of this research was to synthesize N-4-benzoyl-cytosine derivatives with 1,2,3-triazole substituents on N-1 and N-3 in order to perform cytostatic evaluations in vitro against malignant human tumor cell lines: HeLa (cervical adenocarcinoma), CaCo-2 (colon adenocarcinoma), Raji (Burkitt lymphoma) i K562 (chronic myeloid leukemia in blast crisis). N-1 propargylated and N,N-1,3-dipropargylated N-4-benzoylcytosine derivatives (2, 4 i 5) were prepared by alkylation of N-4-benzoy-5-iodocytosine or N-4-benzoylcytosine with propargyl-bromide and K2CO3 as the base. The microwave assisted Huisgen 1,3-bipolar cycloaddition of the N,N-1,3-dipropargylated N-4-benzoylcytosine derivative (5) with the corresponding azides and catalyst gave N,N-1,3-ditriazole cytosine derivatives (6-12). Byproducts of this reaction, N-3-(2-oxopropyl)-N-1-triazole derivatives (13-20) were obtained by oxidation of the N-3 propargyl substituent. Structural characterization of the newly synthesized compounds was performed by 1H i 13C NMR spectroscopy and mass spectrometry, and the possible biological targets and pharmacological activity of the prepared molecules were predicted by in silico analysis. Of all the analysed compounds, the best results show N,N-1,3-dipropargylated N-4-benzoyl-5-iodocytosine (2), N-4-benzoyl-ditriazolecytosine derivative with a p-trifluoromethylphenyl supstituent on the 1,2,3-triazole ring (6) and N-4- benzoyl -N-3-(2-oxopropyl)-N-1-triazolecytosine derivative with a benzyl supstituent on the 1,2,3-triazole ring (17).

• Keywords: derivati citozina; 1 2 3-triazol; "klik“ kemija; in silico analiza; 1H i 13C NMR spektroskopija
• Keywords (english): cytosine derivatives; 1 2 3-triazole; "click“ chemistry; in silico analysis; 1H and 13C NMR spectroscopy
• Language: croatian
• URN:NBN: urn:nbn:hr:149:883700
• Study programme: Title: Applied Chemistry - Graduate study; specializations in: Environmental chemistry and green technologies, Advanced materials and technologies, Applied organic chemistry; Course: Applied organic chemistry; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra primijenjene kemije (magistar/magistra primijenjene kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2016-12-07 13:10:02