enoviti magistrski študijski program Farmacija
Sara Bavcon (Avtor), Marija Sollner Dolenc (Mentor), Andrej Perdih (Komentor)

Povzetek

Rakava obolenja so eden izmed najpogostejših vzrokov smrti ter hkrati kompleksna bolezen z mnogimi faktorji, ki pogojujejo njen nastanek. Zato vseskozi poteka intenzivno raziskovanje novih zdravilnih učinkovin, ki bi učinkoviteje zdravila raznolika rakava obolenja. Uveljavljene tarče za zdravljenje raka so encimi iz družine topoizomeraz, ki sodelujejo pri sproščanju in uvajanju topoloških sprememb v molekulo DNA, ter so ključni za uspešno celično delitev in preživetje celic. Človeška DNA topoizomeraza IIα s svojim kompleksnim katalitičnim ciklom omogoča različne pristope k zaviranju tega encima in posledično zaustavitvi rasti rakavih celic. Zaradi neželenih učinkov, predvsem kardiotoksičnosti nekaterih že znanih topoizomeraznih strupov v terapiji, so nove raziskave usmerjene v razvoj zaviralcev, ki bi delovali na druga, alternativna mesta v katalitičnem ciklu encima.V nalogi smo na podlagi predhodno izvedenega strukturno podprtega načrtovanja sintetizirali novo serijo zaviralcev človeške DNA topoizomeraze IIα (topo IIα), derivate 3,5-disubstituiranega 1,2,4-oksodiazola, za katero smo predpostavili interakcijo z vezavnim mestom za ATP na N-terminalni domeni encima. Kot izhodni spojini smo izbrali 3-aminobenzonitril ter 4-aminobenzonitril. Vse sintetizirane spojine smo ustrezno ovrednotili s pomočjo spektroskopskih metod in jim določili fizikalno-kemijske lastnosti. Pridobili smo tudi 7 komercialno dostopnih spojin, ki so strukturno podobne načrtovanim. 8 sintetiziranih spojin iz tega kemijskega razreda ter komercialno dostopne disubstituirane 1,2,4-oksadiazole smo preizkusili z uporabo in vitro topo IIα relaksacijskega encimskega testa, da smo ovrednotili njihovo zaviralno delovanje in dobili prve informacije o odnosu med strukturo in delovanjem, ki so pomembne za nadaljnji razvoj. 5 spojin iz razreda 1,2,4-oksadiazolov je izkazalo zaviralno aktivnost z določenim IC50 pod 1000 μM, pri tem je najboljše rezultate pokazala spojina 4, ki je imela IC50 140,2 μM. To so tudi prve spojine iz tega kemijskega razreda, ki izkazujejo zaviralni učinek na človeško topoizomerazo IIα. Na podlagi rezultatov sintetiziranih spojin ter komercialno dostopnih derivatov smo tako ugotovili, da je za zaviralni učinek najbolj ugodna meta-meta substitucija fenilnih obročev na mestih 3 in 5 1,2,4-oksadiazola, ter da končne spojine v obliki estrov izkazujejo boljšo zaviralo aktivnost kot kisline. Ovrednotili smo tudi, kateri substituenti niso ugodni za interakcijo s predpostavljenim vezavnim mestom. Rezultati te naloge bodo uporabni pri nadaljnji optimizaciji disubstituiranih 1,2,4-oksodiazolov kot novega razreda zaviralcev človeške topoizomeraze IIα s protirakavim delovanjem.

Ključne besede

topoizomeraza II alfa;zaviralci topoizomeraze II alfa;sinteze učinkovin;protirakave učinkovine;1,2,4-oksadiazol;načrtovanje učinkovin;

Podatki

Jezik: Slovenski jezik
Leto izida:
Tipologija: 2.09 - Magistrsko delo
Organizacija: UL FFA - Fakulteta za farmacijo
Založnik: [S. Bavcon]
UDK: 543.057:616-006(043.3)
COBISS: 4541297 Povezava se bo odprla v novem oknu
Št. ogledov: 833
Št. prenosov: 144
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Angleški jezik
Sekundarni naslov: Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles as potential inhibitors of human DNA topoisomerase II[alpha]
Sekundarni povzetek: Cancer is one of the most common causes of death which is also a complex mutilfunctional illness with many factors that determine its occurrence. Therefore intensive research of new active substances is taking place, which could prove to be an effective drug for a variety of cancerous diseases present. Established targets used in the cancer treatment are enzymes from the family of the human DNA topoisomerases which are involved in the introduction of topological changes of the DNA molecule and are crucial for a successful cell division and cell survival. Human DNA topoisomerase IIα with its complex catalytic cycle provides various approaches to enzyme inhibition and consequently stop the growth of cancer cells. Due to serious adverse effects, especially cardiotoxicity, of some of the established topo IIα poisons used in therapy, new research is focused on the development of novel inhibitors that would act through alternative inhibition mechanisms in the complex catalytic cycle of this enzyme.In this work based on the previously performed structure-based design a new series of 3,5-disubstituted 1,2,4-oxodiazole was synthesized to target the ATP binding site on the topo IIα N- terminal domain and act as the human DNA topoisomerase IIα inhibitors. 3-aminobenzonitrile and 4-aminobenzonitrile were selected as starting materials. All synthesized compounds were evaluated using spectroscopic methods and their physicochemical properties were determined. Additionally, 7 commercially available derivatives structurally similar to the designed compounds were obtained. 8 synthesized compounds from this chemical class and commercially available disubstituted 1,2,4-oxadiazoles were tested in the in vitro topo IIα relaxation enzyme test to evaluate their inhibitory activity and obtain first information about the structure-activity relationship that would be important for further development. 5 compounds from the class 1,2,4-oxadiazoles showed initial inhibitory activity with a determined IC50 values below 1000 μM. Compound 4 proved to be the most promising having an IC50 of 140.2 μM. These compounds represent the first described compounds of this chemical class to exhibit an inhibitory effect on topoisomerase IIα. After analysis of the structure–activity relationship (SAR) data it has been found that for the inhibitory effect the most favorable position of the phenyl rings relative to the 1,2,4-oxadiazole skeleton is the meta-meta and that esters exhibited better inhibitory activity than corresponding acids. It was also evaluated which substituents are not favorable for the topo IIα inhibitory activity. The results of our work will be useful in further optimization of the disubstituted 1,2,4-oxodiazoles as a new class of the human topoisomerase IIα inhibitors with potential anticancer activity.
Sekundarne ključne besede: Rak (medicina);Klinične raziskave;
Vrsta dela (COBISS): Magistrsko delo/naloga
Komentar na gradivo: Univ. Ljubljana, Fak. za farmacijo
Strani: XX, 790 f., [2] f. pril.
ID: 12025779