Work

Structure‐Based Design, Synthesis, and Evaluation of 2′‐(2‐Hydroxyethyl)‐2′‐deoxyadenosine and the 5′‐Diphosphate Derivative as Ribonucleotide Reductase Inhibitors

Year: 2009

Type: article

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.

Source: ChemMedChem

DOI: 10.1002/cmdc.200900236

Authors: Dianqing Sun, Hai Xu, Sanath R. Wijerathna, Chris Dealwis, Richard E. Lee

Institutions: University of Tennessee Health Science Center, Case Western Reserve University

Language: English

Topic: Biochemical and Molecular Research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: U.S. Public Health Service, National Cancer Institute, National Institute of Allergy and Infectious Diseases

Awards: G1101494886, Structure-Function and Inhibition of Rnr1, Multi-Drug Resistant Tuberculosis Drugs: Targeting Cell Wall Synthetic Enzymes, G953877658