Structure‐Based Design,Synthesis, and Evaluation of 2′‐(2‐Hydroxyethyl)‐2′‐deoxyadenosine and the 5′‐Diphosphate Derivative as Ribonucleotide Reductase Inhibitors |
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Authors: | Dianqing Sun Dr. Hai Xu Dr. Sanath R. Wijerathna Chris Dealwis Dr. Richard E. Lee Dr. |
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Affiliation: | 1. Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163 (USA), Fax. (+1)?901‐448‐6828;2. ;3. Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106 (USA), Fax: (+1)?216‐368‐1300;4. C.D. is affiliated with the Center for Proteomics at Case Western Reserve University. |
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Abstract: | Analysis of the recently solved X‐ray crystal structures of Saccharomyces cerevisiae ribonucleotide reductase I (ScRnr1) in complex with effectors and substrates led to the discovery of a conserved water molecule located at the active site that interacted with the 2′‐hydroxy group of the nucleoside ribose. In this study 2′‐(2‐hydroxyethyl)‐2′‐deoxyadenosine 1 and the 5′‐diphosphate derivative 2 were designed and synthesized to see if the conserved water molecule could be displaced by a hydroxymethylene group, to generate novel RNR inhibitors as potential antitumor agents. Herein we report the synthesis of analogues 1 and 2 , and the co‐crystal structure of adenosine diphosphate analogue 2 bound to ScRnr1, which shows the conserved water molecule is displaced as hypothesized. |
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Keywords: | crystallography nucleosides nucleotides ribonucleotide reductase structure‐based drug design |
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