Design, synthesis and evaluation of novel metalloproteinase inhibitors based on L-tyrosine scaffold

Bioorg Med Chem. 2012 Oct 1;20(19):5738-44. doi: 10.1016/j.bmc.2012.08.014. Epub 2012 Aug 22.

Abstract

A series of novel L-tyrosine derivatives were designed, synthesized and assayed for their inhibitory activities on matrix metalloproteinase 2 (MMP-2) and histone deacetylase 8 (HDAC-8). The results showed that these L-tyrosine derivatives exhibited inhibitory profiles against MMP-2 and HDAC-8. The compounds 6h (IC(50)=0.013 ± 0.001 μM) and 6j (IC(50)=0.017 ± 0.001 μM) were equal potent MMP-2 inhibitors to the positive control NNGH (IC(50)=0.014 ± 0.001 μM). As for HDAC-8 inhibition, some of the hydroxamate compounds, such as 6d (IC(50)=3.6 ± 0.2 μM) and 6c (IC(50)=5.8 ± 0.5 μM), were equal potent to the positive control SAHA (IC(50)=1.6 ± 0.1 μM). Structure-activity relationships were also briefly discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design
  • Histone Deacetylases / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / chemistry*
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Models, Molecular
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / metabolism
  • Tyrosine / analogs & derivatives*
  • Tyrosine / chemical synthesis
  • Tyrosine / pharmacology*

Substances

  • Matrix Metalloproteinase Inhibitors
  • Repressor Proteins
  • Tyrosine
  • Matrix Metalloproteinase 2
  • HDAC8 protein, human
  • Histone Deacetylases