Sinteza, strukturna karakterizacija i biološka aktivnost novih derivata citozina i 7-deazapurina

master's thesis

• Title (english): Synthesis, structural characterization and biological activities of novel cytosine and 7-deazapurine derivatives
• Author: Mande Miošić
• Mentor: Tatjana Gazivoda Kraljević (mentor)
• Committee member: Tatjana Gazivoda Kraljević (predsjednik povjerenstva)
• Committee member: Silvana Raić-Malić (član povjerenstva)
• Committee member: Svjetlana Krištafor (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2015-07-14, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry; Organic Chemistry

Abstract

Zbog važnosti citozina i 7-deazapurina kao bioloških i kemoterapijskih agenasa, razvoj novih derivata iz okosnica njihove strukture bitan je za razvoj novih potencijalnih lijekova.
U ovom radu opisana je sinteza novih C-5 alkinilnih derivata citozina (9-16) i C-6 supstituiranih derivata 7-deazapurina (17-25). "Klik" reakcijom potpomognutom mikrovalovima N-1-propargiliranog derivata citozina (2) s odgovarajućim azidima uveden je 1,2,3-triazolni prsten u položaj N-1 pri čemu su sintetizirani spojevi 3-8. C-5 alkinilni derivati citozina 9-16 pripravljeni su Pd-kataliziranom Sonogashira-inom reakcijom unakrsnog spajanja 5-jod-N-1-metiltriazolilnih derivata citozina 3-8 s odgovarajućim alkinima, koji su potom reakcijom N-heteroanulacije in situ prevedeni u derivate 7-deazapurina (17-25). Strukturna i spektroskopska karakterizacija derivata citozina i 7-deazapurina provedena je 1H-NMR, te UV/Vis i fluorescencijskom spektroskopijom. Rezultati spektroskopskih istraživanja pokazuju da ciklizacija i povećanje konjugacije kod spojeva 10, 14 i 16 poboljšavaju spektroskopske karakteristike, osobito fluorescencije. Farmakološki učinci i moguće biološke mete predviđeni su in silico analizom (PASS). Kako bi se odredili mogući mehanizmi bioloških djelovanja spojeva ispitana je interakcija odabranih spojeva s ct-DNA, a iz rezultata UV/Vis i fluorimetrijskih spektara vidljivo je da se spojevi 7 i 8 najbolje vežu za ct-DNA. Citostatska aktivnost in vitro novosintetiziranih spojeva ispitat će se na staničnim tumorskim linijama porijeklom iz čovjeka HeLa (adenokarcinom vrata maternice), CaCo-2 (adenokarcinom debelog crijeva), Raji (Burkittov limfom) i K562 (kronična mijeloidna leukemija u blastičnoj krizi.

Abstract (english)

Due to biological and chemotherapeutic importance of cytosine and 7-deazapurine, development of novel derivatives from their backbones is important for the potential development of new drugs.
This paper describes the synthesis of C-5 alkynyl cytosine derivatives (9-16) and C-6 substituted 7-deazapurine derivatives (17-25). N-1 cytosine derivatives (3-8) were synthesized using "click" reaction of N-1-propargylcytosine derivate (2) with corresponding azides under microvawe irradiation. C-5 alkynyl cytosine derivatives (9-16) were synthesized by Pd-catalysed Sonogashira cross-coupling reaction of 5-iodo-N-1-methyltriazolylcytosine derivatives (3-8) with corresponding alkynes, which are then converted into 7-deazapurine derivatives (17-25) by N-heteroannulation in situ. Structural and spectroscopic characterization of cytosine and 7-deazapurine derivatives was conducted using 1H-NMR, UV/Vis and fluorescence spectroscopy. Results of spectroscopic studies show that cyclization and increase of conjugation for compounds 10, 14 and 16 have better spectroscopic characteristics, especially fluorescence. Pharmacological effects and possible biologycal targets were provided using in silico analysis (PASS). Possible mechanisms of biological activity was performed by interaction of selected compounds with the ct-DNA, and the results of UV/Vis and fluorescence spectroscopy show that compounds 7 and 8 have the best interaction. Cytostatic evaluation will be preformed in vitro against human malignant tumor cells: HeLa, CaCo-2, Raji and K562.

• Keywords: C-5-alkinilni derivati citozina; derivati 7-deazapurina; Sonogashira-ina reakcija; "klik" reakcija; biološka aktivnost; ct-DNA
• Keywords (english): C-5 alkynyl cytosine derivatives; 7-deazapurine derivatives; Sonogashira cross-coupling; "click" reaction; biologycal activity; ct-DNA
• Language: croatian
• URN:NBN: urn:nbn:hr:149:693027
• 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: 2016-12-19 13:57:59