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Title: Design, synthesis and biological evaluation of nucleotide pro-drugs centred on clinically active anticancer nucleosides
Author: Gonczy, Blanka
ISNI:       0000 0004 6349 1353
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2016
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Cancer is one the on the leading causes of mortality in world, causing 8.2 million deaths in 2012. In light of these statistics, the battle against cancer is ongoing. Nucleoside analogues are a major force in cancer chemotherapy. However, one problem accompanying nucleoside-based therapy is drug resistance, due to the abrogation of mechanisms that are crucial to their transformation to their bioactive metabolites (nucleoside phosphates). The ProTide technology was designed to overcome the limitations associated with nucleoside analogues. The technology enables the delivery of the nucleoside monophosphate into the cell by passive diffusion. Work in this thesis details the application of the aryloxyphosphoramidate and phosphorodiamidate pronucleotide approaches on potent anticancer purine and pyrimidine nucleoside analogues. The work presented in this thesis shows that: I. ProTides of 5-fluorouracil- 2’deoxyuridine (FUDR), the deoxyribonucleoside derivative of 5-fluorouracil (5- FU), were able to overcome several important cancer resistance mechanisms, including active transport and nucleoside kinase mediated activation, illustrated by a potent cytotoxic action in different cancer cell lines. Eight potential candidates were synthesised in large-scale and underwent a comprehensive lead selection, identifying NUC3373 for clinical trials, to start in 2015; II. The successful application of ProTide and phosphorodiamidate technologies to 6-thioinosine and 6-thioguanosine did not improve their activity nor did it help in clarifying their mechanism of action. 6-S-Methyl-thioinosine and its ProTides exhibited far greater efficacy compared to 6-thioinosine; III. Application of the ProTide technology on cladribine provided IV proof of the enhanced potencies of 3’-ProTide derivatives over their 5’-counterparts; IV. 2’-deoxy-5-azacytidine (Decitabine) ProTides did not exhibit an improvement in activity compared to the parent nucleoside in different cell models of cancer; V. The bioactivation mechanisms of ProTides using enzymatic assays were successful. Based on these findings, potential avenues to further explore are the cladribine and 6-S-methyl-thioinosine ProTide families, with the hope to identify new clinical candidates.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer) ; RM Therapeutics. Pharmacology