Antiradikalska aktivnost avarola: teorijski i eksperimentalni pristup

Abstract

Avarol je sekundarni metabolit izolovan iz morskog sunđera Dysidea avara. Smatra se da hidrohinonski segment molekula avarola ima ključnu ulogu u njegovoj biološkoj aktivnosti, dok je uloga terpenoidnog dela manje značajna. Avarol ima nisku toksičnost i širok dijapazon bioloških aktivnosti, između ostalog antioksidativnu, antiinflamatornu, antitumorsku, antipsorijatičnu i anti-HIV. Imajući u vidu ove činjenice, kao i to da avarol može proći kroz krvno-moždanu barijeru, on predstavlja dobrog kandidata za razvoj novih terapija za neurodegenerativne bolesti, posebno Alchajmerovu bolest. Međutim, problem primene avarola u terapijske svrhe ogleda se u njegovoj nerastvorljivosti u vodi. Pošto se smatra da su jedan od uzročnika Alchajmerove bolesti slobodni radikali, potrebno je detaljno ispitati prirodu interakcija avarola sa njima. U ovoj doktorskoj disertaciji, interakcije avarola sa slobodnim radikalima proučavane su primenom metoda teorijske hemije i elektronske paramagnetne rezonantne (EPR) spektroskopije. Zbog kompleksnosti sistema, kod teorijskih proračuna upotrebljen je hidrohinon kao model molekul. Osim toga, primenom ciklične voltametrije i ultraljubičaste i vidljive spektroskopije ispitana je interakcija avarola sa L-dopom, prekursorom kateholaminskih neurotransmitera. Teorijskim proračunima zasnovanim na teoriji funkcionala gustine (DFT), odnosno kvantnoj teoriji atoma u molekulima (QTAIM), ispitano je do kakvih interakcija dolazi između hidrohinona i tri radikala: hidroksilnog, hidroperoksilnog i metoksi radikala. Na osnovu rezultata teorijskih proračuna, ustanovljeno je da je energijska barijera za reakciju hidrohinona sa hidroperoksilnim radikalom znatno viša od barijere za reakciju hidrohinona sa hidroksilnim radikalom. Sem toga, reakcija apstrakcije vodonikovog atoma sa hidroksilne grupe hidrohinona od strane sva tri posmatrana radikala odvija se mehanizmom poznatim kao PCET (spregnuti prenos protona i elektrona, od eng. proton-coupled electron transfer). Takođe, primenom modela implicitnog rastvarača, ustanovljeno je i da (u slučaju hidroksilnog i hidroperoksilnog radikala) prisustvo rastvarača ne utiče na mehanizam po kom se apstrakcija atoma vodonika odvija...

avara. The hydroquinone moiety of avarol is supposed to play a key role in its biological activity, while the role of its terpenoid moiety is merely marginal. Avarol is known for its low toxicity and a wide range of biological activities, antioxidative, antiinflamatoric, antitumour, antipsoriatic and anti-HIV being some of the most important ones. Having this in mind, as well as the fact that avarol can cross through the blood-brain barrier, it could serve as a good candidate for the development of the new therapies for neurodegenerative diseases, principally Alzheimer’s disease. However, its poor solubility in water hampers its application in therapeutical purposes. Since free radicals are presumed to be one of the causes of Alzheimer’s disease, the nature of interactions of avarol with these species should be explored more elaborately. In this doctoral dissertation, interactios of avarol with free radicals have been studied by the means of computational chemistry and electron paramagnetic resonance (EPR) spectroscopy. Due to the complexity of the systems, hydroquinone was used as a model molecule for computational studies. The interaction of avarol with L-dopa (precursor for catecholamine neurotransmitters) was studied using cyclic voltammetry and ultraviolet-visible spectroscopy. Theoretical computations based on density functional theory (DFT), and quantum theory of atoms in molecules (QTAIM) were employed in order to study interactions between hydroquinone and three radical species: hydroxyl, hydroperoxyl and metoxy radicals. Based on the results of theoretical computations, it was found that the energy barrier for the reaction of hydroquinone with hydroperoxyl radical is significantly higher compared to its reaction with hydroxyl radical. The reaction of hydrogen atom abstraction from the hydroxyl group of hydroquinone by all three radicals follows PCET (proton coupled electron transfer) mechanism. By using the implicite solvent method, it was determined that (in the reactions with hydroxyl and hydroperoxyl radical), the presence of solvent does not affect the mechanism of hydrogen atom transfer...