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 yeast ribonucleotide reductase I (RnrI) 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 of the nucleoside ribose. In this study 2′-(2-hydroxyethyl)-2′-deoxy-adenosine 1 and its 5′-diphosphate 2 were designed and synthesized to see if the conserved water molecule could be displaced by a hydroxylmethylene group, to generate a novel of inhibitors of this enzyme towards the development of potential anti-neoplastic agents. In this paper, we report the synthesis of these two adenosine analogs 1 and 2, and the cocrystal structure of adenosine diphosphate analog 2 bound with RnrI enzyme which displaces the conserved water as hypothesized.

The Structural Basis for the Allosteric Regulation of Ribonucleotide Reductase

“…32,41,65–72 Drug/molecule that targets the P-site will interfere with the quaternary structure of RR via a specific protein–protein interaction. Exploiting this particular characteristic will enable us to develop the highly specific inhibitors that do not lack the specificity associated with nucleoside analogs that target the A-, S-, and C-site of RR.…”

Targeting the Large Subunit of Human Ribonucleotide Reductase for Cancer Chemotherapy

“…There are other examples of C-site inhibitors. In a rational drug design effort, we were able to modify the 2′ hydroxyl of the ribose ring with a hydroxyethylene moiety [ 87 ]. The rationale behind the design involved the observation of a water molecule bound at the active site of the yeast enzyme [ 84 ].…”