Design, synthesis and biological evaluation of new anti-VZV agents.

An introduction to this work presented in this thesis involves an overview of nucleic acids and the use of nucleoside analogues in antiviral therapy. Bicyclic furano pyrimidine nucleosides (BCNA)s were discovered by the McGuigan group as potent and selective inhibitors of Varicella-Zoster Virus. A brief description of Structure Activity Relationships of this class of compounds is presented, identifying a long lipophilic chain as a specific requirements for antiviral activity. We herein report the synthesis and biological evaluation of a new series aimed to further investigate the specific requirement for biological acitivity. Two sites of BCNAs were modified on the lead compound, the side chain and the sugar moiety. A series bearing electron-donating and electron-withdrawing aryl groups was synthesised in order to investigate the role of the position of the substitutent. Then, the phosphoramidate approach was applied to the lead compound in order to broaden the spectrum of activity, which was limited only to VZV. Modifications of the sugar moiety include the inversion of all the stereo-centres of the lead compound, obtaining the L-enantiomer, and the inversion of the stereochemistry at the C-1' obtaining thus the a-derivative. Furthermore the replacement of the furano ring of the sugar with a cyclopentane was thought as a good strategy in order to increase the resistance to enzymatic cleavage. Given the poor bioavailability of the lead compound, the valyl ester was synthesised making also the hydrochloric and succinate salts to increase the chemical stability and water solubility. Finally, using the intrinsic fluorescence of these derivatives, a cell study was carried out in order to investigate the distribution of the compound inside the cell