| Summary: | The development of phosphoramidates as a new pronucleotide approach has shown to lead to a significant boost in activity for a series of antiviral nucleoside analogues. Given the importance of nucleoside analogues in anticancer therapy and the need of more potent drugs against what is considered the major cause of death in the developed world, the aim of the present thesis was to investigate phosphoramidates as new potential anticancer prodrugs. A consistent part of the work presented is related to the further SAR investigation of Thymectacin, a BVdU phosphoramidate prodrug that has recently entered clinical trials against colon cancer. Herein, the use of naphthyl as a new phosphate masking group is reported for the first time. The antileukaemic drug Cladribine was a new target for the application of our approach and two series of related phosphoramidates represent the second major contribution to this thesis. Synthesis and cytostatic evaluation were also carried out for novel phosphoramidate derivatives of a different anticancer agent Zebularine, a natural nucleoside Adenosine and an inactive nucleoside analogue IsoCladribine. Through the combination of computational and NMR studies, the absolute stereochemistry of the phosphorus center of separated phosphoramidate diastereoisomers was suggested for the first time. Eventually, a preliminary molecular modelling study was performed on the human Hintl enzyme to investigate its possible role in the activation of phosphoramidates.
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