title: Conformationally locked nucleoside analogues. Synthesis of dideoxycarbocyclic nucleoside analogues structurally related to neplanocin C.
abstract: The glycon moiety of nucleosides in solution is known to exist in a rapid dynamic equilibrium between extreme northern and southern conformations as defined by the pseudorotation cycle. The concept of preparing rigid nucleoside analogues with the glycon conformation locked in one of these two extremes was tested with the synthesis of some cyclopropane-fused dideoxycarbocyclic nucleosides, similar to the well-known class of anti-HIV active dideoxynucleosides. The new compounds described here are dideoxynucleoside analogues of the fermentation product neplanocin C (6) which exhibits a typical northern geometry for its 6-oxabicyclo[3.1.0]hexane pseudosugar moiety. However, in view of the lability of the epoxide ring in this system, the equivalent cyclopropane-fused bicyclo[3.1.0]hexane system was used instead to prepare the corresponding dideoxynucleoside analogues bearing all the common bases [(+/-)-9-13]. Due to the well-documented preference of unrestricted bicyclo[3.1.0]hexane systems to exist exclusively in a boat conformation, the resulting nucleosides are structurally locked in a typical northern conformation similar to that of neplanocin C. The locked northern conformation in these nucleosides remained unchanged in solution in the 20-80 degrees C temperature range according to variable temperature 1H NMR studies. For the synthesis of these compounds, racemic trans-1-[(benzyloxy)methyl]-4-hydroxybicyclo[3.1.0]hexane [(+/-)-18] was prepared by a samarium-promoted cyclopropanation reaction with the antecedent cyclopentenol. All of the bases were incorporated under Mitsunobu conditions and converted to the desired final products following a standard methodology. Anti-HIV evaluation revealed that only the adenosine analogue (+/-)-9 possessed enough activity to warrant resolution into its optical antipodes. This was realized by chiral HPLC chromatography to give the individual enantiomers (-)-32 and (+)-33. Adenosine deaminase was used to identify isomer (+)-33 as the enantiomer with the "natural" configuration which was solely responsible for the observed biological activity and toxicity of (+/-)-9. It is possible that the exclusive northern conformation adopted by these nucleosides reduces their substrate affinity for the various activating kinases, except in the case of the adenosine analogue.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute, NIH, Bethesda, Maryland 20892.
authors.forename: J B
authors.initials: JB
authors.lastname: Rodriguez
authors.forename: V E
authors.initials: VE
authors.lastname: Marquez
authors.forename: M C
authors.initials: MC
authors.lastname: Nicklaus
authors.forename: H
authors.initials: H
authors.lastname: Mitsuya
authors.forename: J J
authors.initials: JJ
authors.lastname: Barchi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry; D000243:Adenosine Deaminase / Q000378:metabolism; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D006678:HIV / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009705:Nucleosides / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: C089723:1-(hydroxymethyl)-4-(6-amino-9-purinyl)bicyclo(3.1.0)hexane; D000998:Antiviral Agents; D001643:Bridged Bicyclo Compounds; D009705:Nucleosides; C031098:neplanocin C; D000243:Adenosine Deaminase; D000225:Adenine; D000241:Adenosine