6-(Hetero)Arylpurine nucleotides as inhibitors of the oncogenic target DNPH1: synthesis, structural studies and cytotoxic activities

Eur J Med Chem. 2014 Oct 6;85:418-37. doi: 10.1016/j.ejmech.2014.07.110. Epub 2014 Aug 1.


The 2'-deoxynucleoside 5'-phosphate N-hydrolase 1 (DNPH1) has been proposed as a new molecular target for cancer treatment. Here, we describe the synthesis of a series of novel 6-aryl- and 6-heteroarylpurine riboside 5'-monophosphates via Suzuki-Miyaura cross-coupling reactions, and their ability to inhibit recombinant rat and human DNPH1. Enzymatic inhibition studies revealed competitive inhibitors in the low micromolar range. Crystal structures of human and rat DNPH1 in complex with one nucleotide from this series, the 6-naphthylpurine derivative, provided detailed structural information, in particular regarding the possible conformations of a long and flexible loop wrapping around the large hydrophobic substituent. Taking advantage of these high-resolution structures, we performed virtual docking studies in order to evaluate enzyme-inhibitor interactions for the whole compound series. Among the synthesized compounds, several molecules exhibited significant in vitro cytotoxicity against human colon cancer (HCT15, HCT116) and human promyelocytic leukemia (HL60) cell lines with IC50 values in the low micromolar range, which correlated with in vitro DNPH1 inhibitory potency.

Keywords: Cancer; Cross-coupling reaction; Crystal structure; DNPH1; Inhibitor; Nucleoside analogues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Molecular Docking Simulation
  • Molecular Targeted Therapy*
  • N-Glycosyl Hydrolases / antagonists & inhibitors*
  • N-Glycosyl Hydrolases / chemistry
  • N-Glycosyl Hydrolases / metabolism
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism
  • Protein Conformation
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism
  • Purine Nucleotides / chemical synthesis*
  • Purine Nucleotides / chemistry
  • Purine Nucleotides / metabolism
  • Purine Nucleotides / pharmacology*
  • Rats
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Purine Nucleotides
  • DNPH1 protein, human
  • N-Glycosyl Hydrolases