Structure-Based Design, Synthesis, and Evaluation of 2'-(2-Hydroxyethyl)-2'-deoxyadenosine and the 5'-Diphosphate Derivative as Ribonucleotide Reductase Inhibitors.
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.
Sun
Dianqing
D
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163 (USA).
Xu
Hai
H
Wijerathna
Sanath R
SR
Dealwis
Chris
C
Lee
Richard E
RE
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
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
J Med Chem. 2008 Aug 14;51(15):4653-9
18610997
FEBS Lett. 1990 Oct 15;272(1-2):61-4
2226836
Crit Rev Clin Lab Sci. 1997;34(6):503-28
9439883
Structure. 2000 May 15;8(5):R105-10
10801499
Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4022-7
16537479
Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9
2025413
Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4028-33
16537480
Curr Med Chem. 2005;12(11):1283-94
15974997
Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12339-44
10535923
Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21
9757107
J Biol Chem. 1998 Dec 18;273(51):34098-104
9852067
J Biomol NMR. 1996 Dec;8(4):477-86
9008363