| Abstract [eng] |
The ongoing challenges of drug resistance and systemic toxicity in cancer treatment highlight the urgent need for more effective and selective therapeutic strategies. This thesis explores two complementary approaches: developing novel anticancer compounds and investigating enzyme-prodrug systems for targeted cancer therapy. Several water-soluble indirubin derivatives were evaluated for cytotoxicity, identifying compounds with promising anticancer activity. In parallel, a collection of modified 5-fluoropyrimidine nucleosides was proposed as prodrugs suitable for activation by specific bacterial enzymes. Two amidohydrolases, YqfB and D8_RL, were shown to catalyze the hydrolysis of N4-acylated 5-fluorocytidines, yielding the active anticancer agent 5-fluorocytidine. Three cytidine deaminases – CDA_EH, CDA_F14, and CDA_Lsp – efficiently converted various S4-/N4-/O4-modified 5-fluoropyrimidines into cytotoxic 5-fluorouridine or 5-fluoro-2′-deoxyuridine. Several novel enzyme-prodrug pairs were identified, offering high specificity and potential for clinical application. These findings contribute to developing more selective cancer therapies and support ongoing research into enzyme-prodrug systems. |
