title: A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude.
abstract: The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N(3)-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70 degrees away from a perfect N (P = 0 degrees ) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (nu(max)) of N-MCD4T to 6.81 degrees, and the superposition of both structures showed a RMS deviation of only 0.039 A. The combined structural analysis of P and nu(max) shows that while the value of P may differ substantially, the low nu(max) resolves the differences and becomes the dominant pseudorotational parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC(50) than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.
authors.affiliation: Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Choi
authors.forename: Clifford
authors.initials: C
authors.lastname: George
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Comin
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Barchi
authors.forename: Hak Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.forename: Paul L
authors.initials: PL
authors.lastname: Boyer
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000821:virology; D008968:Molecular Conformation; D018716:Molecular Mimicry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C476440:1-(5-(hydroxymethyl)bicyclo(3.1.0)hex-3-en-2-yl)-5-methyl-1,3-dihydropyrimidine-2,4-dione; D019380:Anti-HIV Agents; D001643:Bridged Bicyclo Compounds; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D054303:HIV Reverse Transcriptase; D013936:Thymidine