Nucleoside analogues are an important class of antimetabolites, used both as anticancer and antiviral agents for their resemblance to endogenous nucleosides, and their capacity to inhibit metabolic pathways in which these substrates are involved, leading to therapeutic potential. The need for both new anticancer and antiviral cures is significant, and often caused by the emergence of resistance to the available therapies. In the case of therapies with nucleoside analogues, the delivery of a nucleoside monophosphate prodrug inside the cell has potential to overcome resistance to treatment, and proved successful especially with the application of the ProTide approach. This strategy led to the progression into clinical trials of numerous antiviral and anticancer agents. This work focused on the synthesis of novel ProTide prodrugs to different nucleoside analogues that are involved in clinical trials, such as purine and pyrimidine nucleosides with modifications in the base and sugar regions. This strategy was also applied to nucleoside analogues where in vitro evaluation has never been reported. The synthetic strategies to prepare each nucleoside analogue are also reported. The in vitro evaluation of novel nucleotide prodrugs as anticancer and antiviral agents is described and discussed. Moreover the mechanism of activation of the ProTides is supported by studying their bioactivation to the corresponding monophosphate forms, through enzymatic NMR studies and molecular modeling simulations. Modifications on the scaffold of the two most promising families of ProTides were also performed, leading to the introduction of groups on the nucleobase or alteration of the sugar moiety. Moreover, the phosphosphate group was also modified, with the application of alternative phosphorodiamidate and phosphonoamidate prodrug approaches, with the aim of improving the biological profile. Selected analogues from two families were submitted to numerous preclinical assessments, retaining better potency compared to the parent nucleosides. Moreover these analogues were stable in human plasma, serum and liver microsomes. Further investigations on these potential new drugs are currently ongoing.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:678972 |
| Date | January 2015 |
| Creators | Ferrari, Valentina |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/85091/ |
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