Title Priprava kinon-metida i ispitivanje njihova biološkog učinka Title (english) Preparation of quinone methods and investigation of their biological effects Author Matija Sambol Mentor Nikola Basarić (mentor)Committee member Vesna Petrović-Peroković (predsjednik povjerenstva)Committee member Ines Primožič (član povjerenstva)Committee member Ivo Piantanida (član povjerenstva)Granter University of Zagreb Defense date and country 2018-12-19, Croatia Scientific / art field, NATURAL SCIENCES Universal decimal classificationUDC ) 54 - Chemistry. Crystallography. Mineralogy Abstract U okviru ovog rada provedene su višestupanjske sinteze homobifunkcionalnih i heterobifunkcionalnih spojeva, prekursora kinon-metida (QM). Homobifunkcionalni spojevi sastoje se od dvije jednake fenolne, naftolne ili antrolne QM prekursorske podjedinice povezane fleksibilnim alkilnim lancem. Heterobifunkcionalni spojevi sastoje se od naftolne QM prekursorske podjedinice i 1,8-naftalimida kao DNA interkalatorske podjedinice. Navedene podjedinice su povezane fleksibilnim alkilnim lancem. Homobifunkcionalni spojevi pripravljeni su Grignardovim reakcijama iz komercijalno dostupnih dibromalkana i O-zaštićenih karbaldehida fenola, naftola i antrola. Generiranje QM u fenolnoj podseriji postignuto je dodatkom fluorida, a u naftolnoj i antrolnoj podseriji fotoaktivacijom. Heterobifunkcionalni spojevi pripremljeni su višestupanjskom, konvergentnom sintezom koja uključuje pripravu O-zaštićenog 3-brom-2-naftola i priprave ω-formilalkil-1,8-naftalimida i ω-formilalkil-4-dietilamin-1,8-naftalimida. Ključni korak u pripravi je Grignardova reakcija O-zaštićenog 3-brom-2-naftola i ω-formilalkil-1,8-naftalimida ili ω-formilalkil-4-dietilamin-1,8-naftalimida. Fotokemijska reaktivnost i fotofizička svojstva homobifunkcionalne i heterobifunkcionalne serije spojeva ispitane su reakcijama fotosolvolize te primjenom spektroskopskih tehnika – UV-vis i fluorescencijske spektroskopije te laserske pulsne fotolize. Za QM generirane iz homobifunkcionalnih spojeva ispitana je sposobnost križnog povezivanja lanaca molekule DNA alkalnom gel-elektroforezom. Nekovalentno vezanje heterobifunkcionalnih spojeva na molekulu DNA ispitano je CD i fluorimetrijskim titracijama. Nadalje, ispitana je antiproliferativna aktivnost na humanim staničnim linijama karcinoma. Homobifunkcionalni spojevi ne reagiraju s DNA, ali pokazuju antiproliferativnu aktivnost nakon osvjetljavanja, vjerojatno zbog generiranja QM. Kod heterobifunkcionalnih spojeva nakon elektronske pobude dolazi do prijenosa energije bez zračenja (FRET-a) s naftola na naftalimid, što smanjuje mogućnost generiranja QM. Usprkos tome, spojevi pokazuju pojačanu citotoksičnost nakon osvjetljavanja. Posebno je zanimljiva 4-dietilamin-1,8-naftalimidna podserija heterobifunkcionalnih spojeva koji su selektivno citotoksični na staničnoj liniji humanog karcinoma pluća (H460).
Abstract (english) This thesis describes multi-step synthesis of homobifunctional and heterobifunctional quinone methide (QM) precursors. Homobifunctional compounds contain two equal QM precursors; phenol, naphthol or anthrol subunits, linked by a flexible alkyl chain. Heterobifunctional compounds contain a naphthol moiety as a QM precursor and a 1,8-naphthalimide as a DNA intercalator. Subunits are linked by a flexible alkyl chain. The homobifunctional series were prepared by Grignard reaction from commercially available dibromoalkanes with O-protected phenol, naphthol and anthrol carbaldehydes. Generation of QMs in the phenol subseries was achieved by fluoride addition and in the naphthol and anthrol subseries by photoactivation. Heterobifunctional compounds were prepared by a multi-step, convergent synthesis involving the preparation of O-protected 3-bromo-2-naphthol and ω-formylalkyl-1,8-naphthalimides and ω-formylalkyl-4-diethylamine-1,8-naphthalimides. The key step in the synthesis was Grignard reaction of O-protected 3-bromo-2-naphthol with ω-formylalkyl naphthalimide derivatives. Photochemical reactivity and photophysical properties of homobifunctional and heterobifunctional series were investigated by photo-solvolysis and spectroscopic techniques – UV-vis and fluorescence spectroscopy and laser flash photolysis. The ability of QMs to cross-link DNA, in homobifunctional series was investigated by alkaline gel electrophoresis. Non-covalent binding of heterobifunctional compounds to DNA was investigated by CD and fluorimetric titrations. Furthermore, antiproliferative activity on human cancer cell lines was investigated. Homobifunctional compounds do not react with DNA but they exhibit enhanced antiproliferative activity after irradiation, presumably due to the formation of QMs. Upon excitation of heterobifunctional compounds nonradiative energy transfer (FRET) takes place from naphthol to the naphthalimide moiety, reducing the reactivity in QM formation. Despite that, the studied compounds exhibit enhanced cytotoxicity upon irradiation. 4-Diethylamine-1,8-naphthalimide subseries is particularly interesting since these compounds are selectively cytotoxic to the lung cancer cell line (H460).
Keywords
antiproliferativna aktivnost
antroli
fenoli
fotodehidratacija
kinon-metidi
1
8-naftalimid / naftoli /
Keywords (english)
antiproliferative activity
anthrol
1
8-naphthalimide
naphthol
phenol
photodehydration
quinone-methides
Language croatian URN:NBN urn:nbn:hr:217:228495 Study programme Title: Doctoral study in chemistry Type of resource Text Extent 473 str. ; 30 cm File origin Born digital Access conditions Open access Terms of use Created on 2019-01-08 12:04:09
