Sinteza, mehanizmi fotokemijskih reakcija nastajanja i biološka aktivnost benzenskih, naftalenskih i antracenskih kinon-metida

doctoral thesis

• Title (english): Synthesis, photochemical reaction mechanisms of formation and biological activity of benzene, naphthalene and anthracene quinone methides
• Author: Đani Škalamera
• Mentor: Nikola Basarić (mentor)
• Committee member: Vladislav Tomišić (predsjednik povjerenstva)
• Committee member: Nikola Basarić (član povjerenstva)
• Committee member: Davor Margetić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2015-04-16, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

Sažetak U okviru ovog rada provedena je sinteza tri nove serije spojeva, prekursora kinon-metida (QM), koji su derivati benzena, naftalena i antracena. Istražena je fotoreaktivnost 2-hidroksimetilfenola (1) u cvrstom stanju pri 14 K, a za Mannichove derivate p-krezola, naftalenske i antracenske derivate u otopinama pri sobnoj temperaturi. Utvrđeno je da spoj 1 u čvrstom stanju pri 14 K fotodehidratacijom daje smjesu QM i benzokseta. Mehanizmi fotokemijskih reakcija kod ostalih spojeva studirani su preparativnim fotokemijskim reakcijama, praćenjem ovisnosti učinkovitosti reakcije fotometanolize o udjelu vode u metanolu, UV-vis i fluorescencijskom spektroskopijom te laserskom pulsnom fotolizom (LFP). Predložen je mehanizam fotodeaminacije u Mannichovim derivatima p-krezola, što do sad nije bilo opisano u literaturi. Rezultati dobiveni LFP mjerenjima pokazali su da se napadom nukleofila na bifunkcionalne QM generiraju novi QM, što je od osobitog značaja u biološkim sustavima zbog mogućnosti upotrebe spojeva za križno spajanje DNA. Struktura naftalenskih derivata osmišljena je tako da se ispita optimalan položaj supstitucije na naftalenskom kromoforu za najučinkovitiju reakciju fotodehidratacije. Utvrđeno je da do najučinkovitije reakcije dolazi kod 6-(2-hidroksi-2-adamantil)-2-(4-hidroksifenil)naftalena (12). Antracenski prekursori QM pripravljeni su višestupanjskom sintezom iz 2-aminoantrakinona. Fotogeneriranje QM iz antracenskih derivata zanimljivo je zbog potencijalne primjene u biološkim sustavima, s obzirom da kromofor apsorbira pri valnim duljinama >400 nm. Rezultati istraživanja s LFP su za 3-(difenilhidroksimetil)-2-antrol (16) pokazali da se fotogenerirani QM u prvom stupnju protonira dajući karbokation, koji potom reagira s nukleofilima. Antiproliferativno ispitivanje na humanim staničnim linijama karcinoma pokazalo je da 3-hidroksimetil-2-antrol (14) posjeduje znatno povećanu antiproliferativnu aktivnost uslijed ozracivanja, vjerojatno zbog generiranja reaktivnih QM.

Abstract (english)

The thesis comprises synthesis and investigation of photochemical reactivity of three novel series of quinone methide (QM) precursors, which are derivatives of benzene, naphthalene and anthracene. The photoreactivity of compounds has been studied in solid state at 14 K for 2-hydroxymethylphenol (1), and in solution at room temperature for Mannich derivatives of p-cresol, naphthalene and anthracene derivatives. The photodehydratation of compound 1 in solid state at 14 K gives a mixture of o-QM and benzoxete. Mechanisms of photochemical reactions for other compounds were studied by preparative irradiations, studying the dependence of photomethanolysis efficiency on the water content in methanol, by UV-vis and fluorescence spectroscopy and laser flash photolysis (LFP). The mechanism of photodeamination in Mannich derivatives od p-cresol is proposed, which to date has not been reported. The LFP results have demonstrated that the attack of nucleophiles to bifunctional QM generates new QM species. This observation is of particular importance in the biological systems since it could lead to cross-linking of DNA. Naphthalene derivatives were designed to investigate the optimal substitution pattern on the naphthalene chromophore for the most efficient photodehydratation. It was found that 6-(2-hydroxy-2-adamantyl)-2-(4-hydroxyphenyl)naphthalene (12) underwent the most efficient photodehydration. Antracene derivatives were prepared by the multistep synthetic procedure starting from 2-aminoanthraquinone. Photogeneration of QMs from anthracene derivatives is important due to potential application in biological systems, given that the chromophore absorbs at wavelengths >400 nm. Investigation of 3-(diphenylhydroxymethyl)-2-anthrol (16) with LFP has shown that the photogenerated QM undergoes protonation to give the cation that subsequently reacts with nucleophiles. Antiproliferative investigation on human cancer cell lines showed that 3-hydroxymethyl-2-anthrol (14) had significantly higher antiproliferative activity on irradiation, probably due to the generation of reactive QMs.

• Keywords: kinon-metidi; Mannichovi derivati fenola; naftilfenol; antrol; fotosolvoliza; fotodehidratacija; fotodeaminacija
• Keywords (english): quinone methides; Mannich derivatives of phenols; naphthylphenol; anthrol; photosolvolyses; photodehydration; photodeamination
• Language: croatian
• URN:NBN: urn:nbn:hr:217:228142
• Study programme: Title: Doctoral study in chemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija (doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija)
• Type of resource: Text
• Extent: 296 str. ; 30 cm
• File origin: Born digital
• Access conditions: Open access
• Created on: 2017-02-10 13:35:45