North‐ and South‐Bicyclo[3.1.0]Hexene Nucleosides: The Effect of Ring Planarity on Anti‐HIV Activity |
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| Authors: | Pamela L Russ Maria J Gonzalez‐Moa Dr B Christie Vu Dr Dina M Sigano Dr James A Kelley Dr Christopher C Lai Dr Jeffrey R Deschamps Dr Stephen H Hughes Dr Victor E Marquez Dr |
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| Affiliation: | 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. current address: Arizona State University, 1001 S. McAllister Ave., Code 5901, Tempe, AZ 85287 (USA);3. HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, P.O. Box?B, Bldg. 539, Frederick, MD 21702‐1201 (USA);4. Naval Research Laboratory, 4555 Overlook Avenue, Code 6030, Washington?DC 20375 (USA) |
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| Abstract: | The syntheses of new conformationally locked North‐ and South‐bicyclo3.1.0]hexene nucleosides is reported. The North analogues were synthesized by a convergent approach from the known (1S,2R,5R)‐5‐(tert‐butyldiphenylsilyloxy)methyl]bicyclo3.1.0]hex‐3‐en‐2‐ol by Mitsunobu coupling with the nucleobases. The South analogues were synthesized from their bicyclo3.1.0]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 bicyclo3.1.0]hexane nucleoside into a bicyclo3.1.0]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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| Keywords: | antiviral agents carbocycles conformationally locked nucleosides pseudorotational cycles |
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