Универзитет у Новом Саду, Природно-математички факултет
Abstract
Doktorska disertacija je usmerena ka dizajnu i sintezi novih Dmodifikovanih steroidnih derivata sa ciljem razvoja potencijalnih antitumorskih agenasa. Ukupno su sintetizovana 36 nova jedinjenja, uključujudi N-supstituisane triazolske, O-supstituisane oksimino, D-seko hidrazonske i heterociklične derivate. Strukture dobijenih jedinjenja potvrđene su primenom savremenih spektroskopskih metoda (NMR i HRMS). In silico analize apsorpcije, distribucije, metabolizma, izlučivanja i toksičnosti, sprovedene pomodu softverskih alata SwissADME i ProTox-3.0, pokazale su da vedina jedinjenja poseduje povoljne fizičko-hemijske osobine, dobru prediktivnu oralnu bioraspoloživost i nizak toksični potencijal. Za odabrana jedinjenja dalje su in vitro ispitani afiniteti vezivanja za steroidne receptore (ERα, ERβ, AR, GR), kao i inhibitorni potencijal prema enzimima uključenim u metabolizam steroidnih hormona, AKR1C3 i AKR1C4. Takođe je izvršena procena citotoksičnosti na panelu humanih delijskih linija kancera. Dobijeni rezultati ukazuju na potencijal pojedinih derivata kao perspektivnih antitumorskih agenasa.The doctoral dissertation is centered on the rational design and synthesis of novel D-ring-modified steroidal derivatives with the aim of developing potential antitumor agents. A total of 36 new compounds were synthesized, including N-substituted triazole, Osubstituted oxime, D-seco hydrazone, and various heterocyclic derivatives. The structures of the synthesized compounds were unambiguously elucidated using advanced spectroscopic techniques, (NMR and HRMS). In silico ADME and toxicity predictions, performed using SwissADME and ProTox-3.0 platforms, demonstrated that the majority of the compounds exhibit favorable physicochemical properties, predicted oral bioavailability, and low toxicity profiles. Selected compounds were further subjected to in vitro biological evaluation, including receptor-binding affinity assays toward steroid receptors (ERα, ERβ, AR, GR), as well as inhibition studies against key enzymes involved in steroid hormone methabolism, AKR1C3 and AKR1C4. Additionally, cytotoxic potential was assessed on a panel of human cancer cell lines. The obtained results highlight the potential of certain derivatives as promising candidates for further development as antitumor agents
