Priprava, redoks svojstva i biološka aktivnost ferocenskih derivata nukleobaza

doctoral thesis

• Title (english): Preparation, redox properties and biological activity of ferrocene-nucleobase derivatives
• Author: Mateja Toma
• Mentor: Valerije Vrček (mentor)
• Mentor: Senka Djaković (komentor)
• Committee member: Davor Šakić (predsjednik povjerenstva)
• Committee member: Zrinka Rajić (član povjerenstva)
• Committee member: Katja Ester (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of organic chemistry); Zagreb
• Defense date and country: 2022-11-03, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry; Organic Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

U okviru ove doktorske disertacije pripravljeni su, te eksperimentalnim i teorijskim metodama istraženi,
novi ferocenski derivati različito supstituiranih purinskih nukleobaza s karbonilnom poveznicom između
heterocikličkog i organometalnog dijela. Ferocenoil-purinski derivati 1-31 pripravljeni su reakcijom između
purinskog aniona i ferocenoil-klorida pri čemu su, ovisno o C6 ili C2 supstituentima na nukleobazi, nastali N7 i
N9 regioizomeri, ili isključivo N9 produkti. Pripravljeni su spojevi karakterizirani spektroskopskim i
elektrokemijskim metodama (NMR, IR, UV-Vis, CV i SWV) te spektrometrijom masa (MS), ispitano je njihovo
in vitro citotoksično djelovanje na L929 staničnim linijama i na humanim tumorskim staničnim linijama (A549,
HepG2, PANC-1, MCF-7) te sposobnost stvaranja ROS-a kao mogućeg mehanizma citotoksičnosti. Teorijskim su
pristupom uz upotrebu DFT izračuna opisana fizikalno-kemijska svojstava ferocenskih derivata nukleobaza,
definirani su pogodni modeli za opis njihovih elektrokemijskih svojstva,te je objašnjen reakcijski mehanizma
njihova nastanka i opisana transacilacija u organskim otapalima. Pripravljeni su spojevi elektrokemijski aktivni i
stvaraju ROS acelularno i celularno. Spojevi 11 i 12 pokazali su izraženi citotoksični učinak na svim ispitanim
staničnim linijama, a slijede spojevi 3 i 4, dok je spoj 26 selektivno citotoksičan za HepG2 stanice. Rezultati ovog
istraživanja dobiveni povezivanjem eksperimentalnog i teorijskog pristupa, proširuju spektar pripravljenih i
ispitanih redoks aktivnih ferocenoil-purinskih spojeva kao potencijalnih citostatskih agenasa.

Abstract (english)

In the framework of this doctoral dissertation, new ferrocene derivatives containing variously substituted purine
nucleobases with a carbonyl bond between the two parts were prepared and investigated by the experimental and
theoretical methods. Ferrocenoyl-purine derivatives 1-31 were prepared by nucleophilic substitution reaction on
the carbon atom of the carbonyl group of ferrocenoyl-chloride with purine nucleobase anion generated by the
deprotonation with a strong base. Regioselectivity and regiospecificity of reaction were strongly influenced by the
C6 or C6, C2 substituents of the purine ring. The compounds were characterized by spectroscopic, spectrometric,
and electrochemical methods (NMR, IR, UV-Vis, MS, CV and SWV) and screened in an in vitro cytotoxic assay
against L929 cell lines and human cancer cell lines (A549, HepG2, PANC-1, MCF-7). The ability to generate ROS
was measured as a possible mechanism of cytotoxic action. Using a theoretical approach by the means of DFT
calculations, the physicochemical properties of ferrocene-nucleobase derivatives were predicted and described,
the reaction mechanism of their formation was resolved as well as the transacylation in DMSO. Prepared
compounds showed to be electrochemically active and form ROS in both acellular and cellular media. Compounds
11 and 12 showed enhanced cytotoxic effect against all tested cell lines, followed by compounds 3 and 4, while
compound 26 showed selective cytotoxic effect against HepG2 cell line. The results of this study obtained by
combination of experimental and theoretical approaches, expand the range of prepared and tested redox active
ferrocenoyl-purine compounds as potential cytostatic agents.

• Keywords: nukleobaze; ferocenski derivati; redoks svojstva; ROS; citotoksični učinak; DFT izračuni
• Keywords (english): nucleobases; ferrocene derivatives; redox properties; ROS; cytotoxic activity; DFT calculations
• Language: croatian
• URN:NBN: urn:nbn:hr:163:923376
• Promotion: 2022
• Study programme: Title: Pharmacy and biochemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor znanosti (doktor znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2022-11-08 12:05:34