Sculpting the Bicyclo[3.1.0]hexane Template of Carbocyclic Nucleosides to Improve Recognition by Herpes Thymidine Kinase

Maria J. Comin,† Riad Agbaria,‡ Tsipi Ben-Kasus,‡ Mahmoud Huleihel,§ Chenzhong Liao,† Guangyu Sun,† Marc C. Nicklaus,† Jeffrey R. Deschamps, Damon A. Parrish, and Victor E. Marquez*†
Contribution from the Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, 376 Boyles Street, Frederick, Maryland 21702, Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, The National Institute for Biotechnology and Department of Virology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, and Naval Research Laboratory, Washington, DC 20375
J. Am. Chem. Soc., 2007, 129 (19), pp 6216–6222
DOI: 10.1021/ja0688732
Publication Date (Web): April 24, 2007
Copyright © 2007 American Chemical Society
†

 National Cancer Institute at Frederick.

,
‡

 Department of Clinical Pharmacology, Ben-Gurion University of the Negev.

,
§

 The National Institute for Biotechnology and Department of Virology, Ben-Gurion University of the Negev.

,

 Naval Research Laboratory.

,
*

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, marquezv@dc37a.nci.nih.gov

Abstract

Abstract Image

The replacement of the furanose ring by a cyclopentane in nucleosides generates a group of analogues known generically as carbocyclic nucleosides. These compounds have increased chemical and enzymatic stability due to the absence of a true glycosyl bond that characterizes conventional nucleosides. The additional fusion of a cyclopropane ring to the cyclopentane produces a bicyclo[3.1.0]hexane system that depending on its location relative to the nucleobase is able to lock the embedded cyclopentane ring into conformations that mimic the typical north and south conformations of the furanose ring in conventional nucleosides. These bicyclo[3.1.0]hexane templates have already provided important clues to differentiate the contrasting conformational preferences between kinases and polymerases. Herein, we describe the design, synthesis, and phosphorylation pattern of a new bicyclo[3.1.0]hexane thymidine analogue that seems to possess an ideal spatial distribution of pharmacophores for an optimal interaction with herpes simplex 1 thymidine kinase. The bicyclo[3.1.0]hexane template represents a privileged rigid template for sculpting other carbocyclic nucleosides to meet the demands of specific receptors.

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  • Published In Issue May 16, 2007
  • Received December 12, 2006

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