Új bioaktív, anellált nitrogén heterociklusos vegyületek kutatása = Research of new, bioactive anellated nitrogen heterocycles

A palyazat kereteben szamos uj, stabilis nitroxid szabad gyokkel vagy annak redukalt formajaval modositott vegyuletet allitottunk elő. Az előallitott vegyuletek kemiai sokfelesege harom fő teruletre oszpontosul: uj spinjelző vegyuletek, ROS es RNS okozta karosodasok kivedesere alkalmas vegyuletek es szenzorvegyuletek. Lipidek, nukleinbazisok feherjekbe epithető paramagneses aminosavak spinjelolesere dolgoztunk ki jelolő molekulakat, uj, click-reakcioban is alkalmazhato spinjelző vegyuleteket szintetizaltunk. A hidroxilamin reagalo csoporttal rendelkező uj spinjrelző vegyuletek alkalmasak karbonilcsoportot tartalmazo feherje oldallancok modositasara. Uj, kinazolinon es benzimidazol alpu PARP-gatlo es antioxidans kettőshatasu vegyuleteket fejlesztettunk ki, tovabba az Ebselen, Verapamil es Amiodaron gyogyszermolekulakat modositottuk nitroxidokkal. A modositott vegyuletek megtartottak eredeti hatasukat, de extra antioxidans hatassal/kisebb toxicitassal rendelkeztek mint az alapmolekulak. Tovabb folytattuk a danzil fluorofor csoportot tartamazo kettős (fluoreszcens es spin) redox szenzorok vizsgalatat. Uj, pH erzekeny benzimidazol szarmazekokat szintetizaltunk. Modszert dolgoztunk ki izoindolin nitroxidok szintezisere es heterociklusokkal anellalt nitroxidok előallitasara. A projekt soran ill. az előző palyazatok soran elert eredmenyeinket ket osszegző cikkben ( Journal of Hetreocyclic Chemistry es Journal of Cardiovascular Toxicology) foglaltuk ossze. | In the frame of this project several new compounds were synthesized containing nitroxide or its precursor. The main emphases were on: new spin labels, ROS and RNS radical scavengers capable of decreasing pathological processes and sensor compounds. New spin labels were incorporated into lipids, nucleic acids and proteins. Paramagnetic click chemistry partners were developed which can be incorporated by 1,3-dipolar cycloaddition reactions. New O-alkylated hydroxylamines were synthesized to modify proteins containing carbonyl group (may be formed during oxidative stress). New dual active (PARP inhibitor and antioxidant) benzimidazole and quinazoline compounds were synthesized and tested. This phenomenon was extended on Ebselen and Amiodarone drugs with paramagnetic function keeping in mind that modified compound need to treasure the original activity with extra antioxidant activity without reducing therapeutic index. Sensor compounds: fluorescent/spin ROS and EPR active pH sensors were obtained. New synthetic procedures were introduced for synthesis of isoindolines and nitroxides condensed with heterocycles. We published a new nitroxide chemistry review. A short review article was also published on the importance of dual activity in reducing the toxic side effects of anthracycline antitumor drugs (such as Doxorubicin).