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North- and South-Bicyclo[3.1.0]Hexene Nucleosides: The Effect of Ring Planarity on Anti-HIV Activity

  1. Pamela L. Russ1,
  2. Maria J. Gonzalez-Moa Dr.1,4,
  3. B. Christie Vu Dr.2,
  4. Dina M. Sigano Dr.1,
  5. James A. Kelley Dr.1,
  6. Christopher C. Lai Dr.1,
  7. Jeffrey R. Deschamps Dr.3,
  8. Stephen H. Hughes Dr.2,
  9. Victor E. Marquez Dr.1

Article first published online: 16 JUN 2009

DOI: 10.1002/cmdc.200900153

Issue

ChemMedChem

ChemMedChem

Volume 4, Issue 8, pages 1354–1363, August 3, 2009

Additional Information

How to Cite

Russ, Pamela L., Gonzalez-Moa, Maria J., Vu, B. Christie., Sigano, Dina M., Kelley, James A., Lai, Christopher C., Deschamps, Jeffrey R., Hughes, Stephen H. and Marquez, Victor E. (2009), North- and South-Bicyclo[3.1.0]Hexene Nucleosides: The Effect of Ring Planarity on Anti-HIV Activity. ChemMedChem, 4: 1354–1363. doi: 10.1002/cmdc.200900153

Author Information

  1. 1

    Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, 376 Boyles St., Frederick, MD 21702 (USA), Fax: (+1) 301-846-6033

  2. 2

    HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, P.O. Box B, Bldg. 539, Frederick, MD 21702-1201 (USA)

  3. 3

    Naval Research Laboratory, 4555 Overlook Avenue, Code 6030, Washington DC 20375 (USA)

  4. 4

    current address: Arizona State University, 1001 S. McAllister Ave., Code 5901, Tempe, AZ 85287 (USA)

Publication History

  1. Issue published online: 30 JUL 2009
  2. Article first published online: 16 JUN 2009
  3. Manuscript Revised: 5 MAY 2009
  4. Manuscript Received: 16 APR 2009

Funded by

  • NIH
  • National Cancer Institute

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Keywords:

  • antiviral agents;
  • carbocycles;
  • conformationally locked;
  • nucleosides;
  • pseudorotational cycles

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.

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