title: 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.affiliation: Institut de Chimie Organique et Analytique, UMR 7311 CNRS, Université d'Orléans, UFR Science-rue de chartres, 45067 Orléans, France.
authors.forename: Ozkan
authors.initials: O
authors.lastname: Sari
authors.forename: Vincent
authors.initials: V
authors.lastname: Roy
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Luigi A
authors.initials: LA
authors.lastname: Agrofoglio
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D003857:Deoxyuridine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D014779:Virus Replication / Q000187:drug effects; D014780:Viruses / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D003857:Deoxyuridine