Viktorija Preitakaitė defended her thesis entitled "Exploration of anticancer compounds and enzyme-prodrug systems" for the degree of Doctor of Science in Biochemistry.
Scientific supervisor: Prof. Dr. Rolandas Meškys (Vilnius University, Natural Sciences, Biochemistry).
Composition of the Dissertation Defense Board: Chairperson - Dr. Vytautas Smirnovas (Vilnius University, Natural Sciences, Biochemistry); Prof. Dr. Daiva Baltriukienė (Vilnius University, Natural Sciences, Biochemistry); Prof. Dr. Saulius Serva (Vilnius University, Natural Sciences, Biochemistry); Dr. Violeta Jonušienė (Vilnius University, Natural Sciences, Biochemistry); Dr. Ilma Tapio (Natural Resources Institute, Finland, Natural Sciences, Biochemistry).
The ever-growing challenges of drug resistance and systemic toxicity in cancer treatment highlight the urgent need for more effective and selective therapeutic strategies. This dissertation explores two closely related and complementary directions: the search for new compounds with anticancer activity and developing enzyme–prodrug systems for targeted cancer therapy. During the studies, the cytotoxicity of water-soluble indirubin derivatives was evaluated, and compounds with promising anticancer activity were identified. In addition, a set of modified 5-fluoropyrimidine nucleosides was proposed as potential prodrugs, activated by specifically selected bacterial enzymes. It was demonstrated that the amidohydrolases YqfB and D8_RL efficiently catalyze the hydrolysis of N4-acylated 5-fluorocytidines, generating the active anticancer compound 5-fluorocytidine. Furthermore, the cytidine deaminases CDA_EH, CDA_F14, and CDA_Lsp were shown to catalyze the conversion of various S4-/N4-/O4-modified 5-fluoropyrimidines into the cytotoxic compounds 5-fluorouridine or 5-fluoro-2′-deoxyuridine. Several novel enzyme–prodrug combinations with high efficiency and strong therapeutic potential were proposed. The obtained results contribute to developing more selective therapeutic tools and encourage further research into enzyme–prodrug systems.
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