20.500.12556/DKUM-98104 Preučevanje antikarcinogenega delovanja polifenola herbacetina z uporabo kvanto-mehanskih simulacij Studying the anticarcinogenic activity of the polyphenol herbacetin using quantum-mechanical simulations Herbacetin je bioaktivni polifenol iz družine flavonoidov, ki ga najdemo v rastlinah, kot so laneno seme in različna zelišča, kot sta Ephedra sinica Staph in Sedum roseum. Že dolgo se uporablja v tradicionalni kitajski medicini za zdravljenje različnih bolezni. Današnje raziskave kažejo, da ima herbacetin pomembne učinke proti raku, saj deluje kot močan antioksidant in lahko upočasni ali prepreči razvoj tumorjev. Poleg tega ima tudi protivnetne, protivirusne, protidiabetične in druge zdravilne lastnosti. V diplomski nalogi smo preučevali vlogo herbacetina kot polifenolnega lovilca devetih končnih kemijskih karcinogenov: aflatoksina B1 ekso-8,9-epoksida, 2-cianoetilen oksida, etilen oksida, glicidamida, kloroetilen oksida, vinilkarbamat epoksida, stiren oksida, propilen oksida in β-propiolaktona. Glavni cilj naloge je bil izračunati aktivacijske proste energije ter bolje razumeti mehanizme reakcij alkilacije med herbacetinom in obravnavanimi karcinogeni. Izračune smo izvedli s kvantnomehansko metodo Hartree-Fock ob uporabi fleksibilnih baznih setov 6-31G(d) in 6-311++G(d,p). Simulacije smo izvajali s programom Gaussian 16 na superračunalniškem sistemu HPC Vega, in sicer v vakuumu ter z uporabo dveh implicitnih modelov topil: polarizabilnega kontinuuma SCRF in Langevinovih dipolov. Dobljene rezultate aktivacijskih prostih energij smo primerjali z eksperimentalnimi podatki za reakcije istih karcinogenov z najbolj reaktivno DNA bazo – gvaninom, da bi ugotovili, ali lahko herbacetin deluje kot učinkovit naravni lovilec kemijskih karcinogenov. Na podlagi rezultatov smo ugotovili, da herbacetin lahko učinkovito zaščiti DNK pred nekaterimi karcinogeni, vendar je njegova uspešnost odvisna od vrste karcinogena. Pri β-propiolaktona, kloroetilen oksidu, etilen oksidu in propilen oksidu so aktivacijske proste energije za reakcije s herbacetinom nižje kot pri gvaninu, kar pomeni, da te karcinogene herbacetin učinkovito ulovi in s tem zmanjšuje tveganje za nastanek poškodb DNA. Nekoliko manjši potencial je herbacetin izkazal tudi kot lovilec vinilkarbamat epoksida in 2-cianoetilen oksida. Po drugi strani pa je herbacetin manj učinkovit lovilec glicidamida, stiren oksida in aflatoksin B1 ekso-8,9-epoksida, kjer so izračunane vrednosti višje kot referencčne vrednosti za gvanin, zato je v teh primeih njegov zaščitni učinek omejen. Iz grafičnih prikazov optimiziranih struktur prehodnih stanj je tudi razvidno, da alkilacija med herbacetinom in devetimi karcinogeni poteka po mehanizmu nukleofilne substitucije SN2. Herbacetin se je v raziskavi izkazal kot potencialna antikarcinogena spojina, ki lahko zmanjša genotoksičnost kemijskih karcinogenov v telesu. Verjamemo, da bo naše delo dobra podlaga za prihodnje klinične študije in bo pripomoglo k oblikovanju novih strategij za preprečevanje rakavih obolenj. Herbacetin is a bioactive polyphenol from the flavonoid family, found in plants such as flaxseed and various herbs, such as Ephedra sinica Staph and Sedum roseum . It has long been used in traditional Chinese medicine to treat various diseases. Current research shows that it has significant anticancer effects, as it acts as a powerful antioxidant and can slow or prevent the development of tumors. In addition, it also has anti-inflammatory, antiviral, antidiabetic, and other medicinal properties. In this thesis, we studied herbacetin as a polyphenol scavenger of nine selected ultimate chemical carcinogens: aflatoxin B1 exo-8,9-epoxide, 2-cyanoethylene oxide, ethylene oxide, glycidamide, chloroethylene oxide, vinylcarbamate epoxide, styrene oxide, propylene oxide, and β-propiolactone. The main goal of the thesis was to calculate the activation free energies and better understand the mechanisms of alkylation reactions between herbacetin and the studied genotoxic carcinogens. The calculations were performed using the quantum mechanical Hartree-Fock method in combination with 6-31G(d) and 6-311++G(d,p) flexible basis sets. The simulations were performed using the Gaussian 16 program on the supercomputer cluster HPC Vega, in vacuum and using two implicit solvent models: polarizable continuum model SCRF and Langevin dipoles. The obtained activation free energies were compared with experimental data for the reactions of the same carcinogens with the most reactive DNA base – guanine, to determine whether herbacetin can act as an effective natural scavenger of chemical carcinogens. Based on the obtained results, herbacetin can effectively protect DNA from certain chemical carcinogens, however, its efficiency depends on the specific carcinogen. For the reactions of herbacetin with β-propiolactone, chloroethylene oxide, ethylene oxide, and propylene oxide, the activation free energies are lower than those for guanine, indicating that herbacetin is an excellent scavenger of these carcinogens and thereby reduces the risk of DNA damage. A slightly lower potential was observed for the reaction of herbacetin with vinyl carbamate epoxide and 2-cyanoethylene oxide. On the other hand, herbacetin is less effective scavenger of glycidamide, styrene oxide, and aflatoxin B1 exo-8,9-epoxide, where the calculated activation free energies were higher than reference values for guanine, leading to limited protective effect. The graphical representations of optimized transition state structures revealed that the alkylation reactions between herbacetin and nine carcinogens proceed via the nucleophilic substitution mechanism SN2. Our research demonstrated that herbacetin is a promising anti-carcinogenic agent capable of mitigating the genotoxic effects of chemical carcinogens within the organism. We are confident that our findings will serve as a firm basis for future experimental research and contribute significantly to development of novel cancer prevention strategies. polifenoli herbacetin kemijski karcinogeni antikarcinogeni učinki aktivacijska prosta energija kvantnomehanske simulacije polyphenols herbacetin chemical carcinogens anticarcinogenic effects activation free energy quantum-mechanical simulations true true false Slovenski jezik Angleški jezik Diplomsko delo/naloga 2026-05-16 09:46:47 2026-09-08 12:57:27 2026-09-09 03:06:31 0000-00-00 00:00:00 2026 0 Maribor 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 UN_Mestnik_Klara_2026.pdf UN_Mestnik_Klara_2026.pdf 1 BB8F0F65BCFA8CCF0E8F20B1FBBD7500 4fafd79fe09c803a9d52b04acf6c1ac32a42f60132cb305be3302a0a51061908 f7060d27-7094-11f1-9d76-00155d580e34 https://dk.um.si/Dokument.php?lang=slv&id=207581 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0