title: Structure-Based Design, Synthesis, and Evaluation of 2'-(2-Hydroxyethyl)-2'-deoxyadenosine and the 5'-Diphosphate Derivative as Ribonucleotide Reductase Inhibitors.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163 (USA).
authors.forename: Dianqing
authors.initials: D
authors.lastname: Sun
authors.forename: Hai
authors.initials: H
authors.lastname: Xu
authors.forename: Sanath R
authors.initials: SR
authors.lastname: Wijerathna
authors.forename: Chris
authors.initials: C
authors.lastname: Dealwis
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003839:Deoxyadenosines / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000201:enzymology
chemical_list: C545677:2'-(2-hydroxyethyl)-2'-deoxyadenosine; C545678:2'-(2-hydroxyethyl)-2'-deoxyadenosine 5'-phosphate; D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D012264:Ribonucleotide Reductases
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