title: North- and south-bicyclo[3.1.0]hexene nucleosides: the effect of ring planarity on anti-HIV activity.
abstract: The syntheses of new conformationally locked North- and South-bicyclo[3.1.0]hexene nucleosides is reported. The North analogues were synthesized by a convergent approach from the known (1S,2R,5R)-5-[(tert-butyldiphenylsilyloxy)methyl]bicyclo[3.1.0]hex-3-en-2-ol by Mitsunobu coupling with the nucleobases. The South analogues were synthesized from their bicyclo[3.1.0]hexane nucleoside precursors by the selective protection of the primary hydroxy group, conversion of the secondary alcohol into a good leaving group, and base-catalyzed elimination to generate the olefin. The transformation of a bicyclo[3.1.0]hexane nucleoside into a bicyclo[3.1.0]hexene nucleoside flattens the five-membered ring of the bicyclic system and rescues anti-HIV activity for North-D4T, North-D4A, and South-D4C. The relationship between planarity and the anti/syn disposition of the nucleobase that is favored by a particular pseudosugar platform are proposed as key parameters in controlling biological activity.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Russ
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Gonzalez-Moa
authors.forename: B Christie
authors.initials: BC
authors.lastname: Vu
authors.forename: Dina M
authors.initials: DM
authors.lastname: Sigano
authors.forename: James A
authors.initials: JA
authors.lastname: Kelley
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Lai
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D006801:Humans; D008968:Molecular Conformation; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D001643:Bridged Bicyclo Compounds; D009705:Nucleosides; C046059:bicyclo(3.1.0)hexane; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase