Synthesis and biochemical evaluation of δ(2)-isoxazoline derivatives as DNA methyltransferase 1 inhibitors

J Med Chem. 2011 Nov 10;54(21):7663-77. doi: 10.1021/jm2010404. Epub 2011 Oct 7.


A series of Δ(2)-isoxazoline constrained analogues of procaine/procainamide (7a-k and 8a-k) were prepared and their inhibitory activity against DNA methyltransferase 1 (DNMT1) was tested. Among them, derivative 7b is far more potent in vitro (IC(50) = 150 μM) than other non-nucleoside inhibitors and also exhibits a strong and dose-dependent antiproliferative effect against HCT116 human colon carcinoma cells. The binding mode of 7b with the enzyme was also investigated by means of a simple competition assay as well as of docking simulations conducted using the recently published crystallographic structure of human DNMT1. On the basis of the findings, we assessed that the mode of inhibition of 7b is consistent with a competition with the cofactor and propose it as a novel lead compound for the development of non-nucleoside DNMT inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Binding, Competitive
  • Cell Proliferation / drug effects
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors*
  • DNA (Cytosine-5-)-Methyltransferases / chemistry
  • Drug Screening Assays, Antitumor
  • HCT116 Cells
  • Humans
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology
  • Models, Molecular
  • Protein Binding
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / chemistry
  • S-Adenosylmethionine / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship


  • 5-(N,N-dimethylaminomethyl)-3-(4-nitrophenyl)-4,5-dihydroisoxazole
  • Antineoplastic Agents
  • Isoxazoles
  • Recombinant Proteins
  • S-Adenosylmethionine
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human