CycloSal-Pronucleotides of Brivudine Monophosphate - Highly Active Antiviral Agents

ISSN: 2211-3533 (Online)
ISSN: 2211-3525 (Print)


Volume 14, 2 Issues, 2016


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Anti-Infective Agents

Formerly: Anti-Infective Agents in Medicinal Chemistry

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CycloSal-Pronucleotides of Brivudine Monophosphate - Highly Active Antiviral Agents



Anti-Infective Agents, 4(4): 317-335.

Author(s): Chris Meier, Astrid Meerbach and Peter Wutzler.

Affiliation: Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.

Abstract

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.

Keywords:

pronucleotides, cyclosal-prodrugs, ebv, hsv, anti-herpes virus drugs.



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Article Details

Volume: 4
Issue Number: 4
First Page: 317
Last Page: 335
Page Count: 19
DOI: 10.2174/156801205774322232
Price: $58
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