Synthesis and antiviral evaluation of C5-substituted-(1,3-diyne)-2'-deoxyuridines.

Abstract

Starting from acetylated 5-ethynyl-2'-deoxyuridine (3), 14 hitherto unknown C5-substituted-(1,3-diyne)-2'-deoxyuridines (with cyclopropyl, hydroxymethyl, methylcyclopentane, p-(substituted)phenyl and disubstituted-phenyl substituents) have been synthesized via a nickel-copper catalyzed C-H activation between two terminal alkynes, in yields ranging from 19% to 67%. Their antiviral activities were measured against a large number of DNA and RNA viruses including herpes simplex virus type 1 and type 2, varicella-zoster virus, human cytomegalovirus and vaccinia virus. The 5-[4-(4-trifluoromethoxyphenyl)buta-1,3-diynyl]-2'-deoxyuridine (26) is the most potent inhibitor of this series against VZV with an EC(50) of ~1 μM and a CC(50) of 55 μM. Their cytostatic activities were determined against murine leukemia cells, human T-lymphocyte cells and cervix carcinoma cells. Compounds were also evaluated on a wide panel of RNA viruses, including influenza virus A (H1N1 and H3N2) and B in MDCK cell cultures, parainfluenza-3 virus, reovirus-1, Sindbis virus and Punta Toro virus in Vero cell cultures and vesicular stomatitis, coxsackie B4 and respiratory syncytial virus in HeLa cell cultures and against human immunodeficiency virus type 1 and 2 in CEM cell cultures, with no specific antiviral effect. This class of compounds could be of further interest for lead optimization as anti-infectious (i.e. herpetic) agents.

• Authors: Ozkan Sari, Vincent Roy, Jan Balzarini, Robert Snoeck, Graciela Andrei, Luigi A Agrofoglio
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 53 Pg. 220-8 (Jul 2012) ISSN: 1768-3254 [Electronic] France
• PMID: 22578783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012. Published by Elsevier Masson SAS.

Chemical References

• Antiviral Agents
• Deoxyuridine

Topics

• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line
• Chemistry Techniques, Synthetic
• Deoxyuridine (chemical synthesis, chemistry, pharmacology)
• Humans
• Inhibitory Concentration 50
• Virus Replication (drug effects)
• Viruses (drug effects)