Affiliation: Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.
CycloSal-BVDUMP triesters 32-34 5-[(E)-2-bromovinyl]-2-deoxyuridine (BVDU 2) have been studied with regard to their potential anti-EBV activity. In addition to the 3-unmodified cycloSal-BVDUMP triesters 32a-f, the 3- hydroxyl function has been esterified with different aliphatic carboxylic acids (33a-g) and α-amino acids having natural and non-natural Cα-configuration (34a-m). In addition to the synthesis of these compounds, different physicochemical properties will be reported, i.e. lipophilicity and hydrolysis behaviour. It could be shown that BVDUMP and not 3,5- cyclic BVDUMP was delivered from most of the compounds by chemical hydrolysis in phosphate buffers at pH 6.8 and 7.3 as well as P3HR-1 cell extracts. Finally, the compounds were tested for their anti-EBV activity. As a result, the prototype compounds and particularly triesters 32c,d exhibited pronounced anti-EBV activity making these compounds promising candidates for further development. However, the 3-ester derivatives were devoid of any antiviral activity, while the 3-aminoacyl derivatives showed an antiviral activity, in dependence of the amino acid and the Cα- configuration. In addition, all cycloSal-BVDU phosphotriesters proved to be potent and selective inhibitors of herpes simplex virus type 1 replication. Several pronucleotide concepts will be briefly summarised but the cycloSal-pronucleotide system described in more detail is the only approach that showed an improvement in antiviral activity of the nucleoside analogue BVDU.