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Structure‐Based Design, Synthesis, and Evaluation of 2′‐(2‐Hydroxyethyl)‐2′‐deoxyadenosine and the 5′‐Diphosphate Derivative as Ribonucleotide Reductase Inhibitors
Author(s) -
Sun Dianqing,
Xu Hai,
Wijerathna Sanath R.,
Dealwis Chris,
Lee Richard E.
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900236
Subject(s) - ribonucleotide reductase , stereochemistry , chemistry , nucleoside , ribose , ribonucleotide , deoxyadenosine , nucleoside triphosphate , derivative (finance) , adenosine , adenosine diphosphate , saccharomyces cerevisiae , cofactor , enzyme , biochemistry , nucleotide , biology , protein subunit , financial economics , economics , gene , platelet , platelet aggregation , immunology
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.