title: Synthesis and antiviral evaluation of 6-(alkyl-heteroaryl)furo[2,3-d]pyrimidin-2(3H)-one nucleosides and analogues with ethynyl, ethenyl, and ethyl spacers at C6 of the furopyrimidine core.
abstract: Sonogashira coupling strategies were employed to synthesize new furo[2,3-d]pyrimidin-2(3H)-one (FuPyrm) 2'-deoxynucleoside analogues. Partial or complete reduction of ethyne-linked compounds afforded ethenyl- and ethyl-linked derivatives. Levels of inhibition of varicella-zoster virus (VZV), human cytomegalovirus (HCMV), a broad range of other DNA and RNA viruses, and several cancer cell lines were evaluated in cell cultures. The anti-VZV potency decreased with increasing rigidity of the side chain at C6 of the FuPyrm ring in the order dec-1-yn-1-yl < dec-1-en-1-yl < decan-1-yl. In contrast, compounds with a rigid ethynyl spacer between C6 of the FuPyrm ring and a 4-alkylphenyl moiety were more potent inhibitors of VZV than the corresponding derivatives with an ethyl spacer. Replacement of the phenyl moiety in 6-(4-alkylphenyl) derivatives with a pyridine ring (in either regioisomeric orientation) gave analogues with increased solubility in methanol but reduced anti-VZV potency, and replacement with a pyrimidine ring reduced the anti-VZV activity even further. The pyridine-ring-containing analogues were approximately 20-fold more potent inhibitors of VZV than acyclovir but were approximately 6-fold less potent than BVDU and approximately 60-fold weaker than the most active 6-(4-pentylphenyl)-substituted prototype.
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602-5700, USA. morris_robins@byu.edu
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Robins
authors.forename: Ireneusz
authors.initials: I
authors.lastname: Nowak
authors.forename: Vivek K
authors.initials: VK
authors.lastname: Rajwanshi
authors.forename: Karl
authors.initials: K
authors.lastname: Miranda
authors.forename: John F
authors.initials: JF
authors.lastname: Cannon
authors.forename: Matt A
authors.initials: MA
authors.lastname: Peterson
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D003587:Cytomegalovirus / Q000187:drug effects / Q000235:genetics; D004267:DNA Viruses / Q000187:drug effects; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012328:RNA Viruses / Q000187:drug effects; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000235:genetics
chemical_list: D000475:Alkenes; D000480:Alkynes; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D005663:Furans; D011741:Pyrimidine Nucleosides; D013937:Thymidine Kinase