title: Synthesis and biological evaluation of 2',4'- and 3',4'-bridged nucleoside analogues.
abstract: Most nucleosides in solution typically exist in equilibrium between two major sugar pucker forms, N-type and S-type, but bridged nucleosides can be locked into one of these conformations depending on their specific structure. While many groups have researched these bridged nucleosides for the purpose of determining their binding affinity for antisense applications, we opted to look into the potential for biological activity within these conformationally-locked structures. A small library of 2',4'- and 3',4'-bridged nucleoside analogues was synthesized, including a novel 3',4'-carbocyclic bridged system. The synthesized compounds were tested for antibacterial, antitumor, and antiviral activities, leading to the identification of nucleosides possessing such biological activities. To the best of our knowledge, these biologically active compounds represent the first example of 2',4'-bridged nucleosides to demonstrate such properties. The most potent compound, nucleoside 33, exhibited significant antiviral activity against pseudoviruses SF162 (IC(50)=7.0 μM) and HxB2 (IC(50)=2.4 μM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. kcn@scripps.edu
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: Shelby P
authors.initials: SP
authors.lastname: Ellery
authors.forename: Fatima
authors.initials: F
authors.lastname: Rivas
authors.forename: Karen
authors.initials: K
authors.lastname: Saye
authors.forename: Eric
authors.initials: E
authors.lastname: Rogers
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Workinger
authors.forename: Mark
authors.initials: M
authors.lastname: Schallenberger
authors.forename: Rommel
authors.initials: R
authors.lastname: Tawatao
authors.forename: Ana
authors.initials: A
authors.lastname: Montero
authors.forename: Ann
authors.initials: A
authors.lastname: Hessell
authors.forename: Floyd
authors.initials: F
authors.lastname: Romesberg
authors.forename: Dennis
authors.initials: D
authors.lastname: Carson
authors.forename: Dennis
authors.initials: D
authors.lastname: Burton
mesh_terms: D000900:Anti-Bacterial Agents / 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*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004926:Escherichia coli / Q000187:drug effects; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D009705:Nucleosides