Phenoxypropanolamine derivatives as selective inhibitors of the 20S proteasome β1 and β5 subunits

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5172-5178. doi: 10.1016/j.bmcl.2017.10.055. Epub 2017 Oct 23.

Abstract

New series of thiophene-containing phenoxypropanolamines were synthesized and evaluated for their potency to inhibit the three proteolytic activities of the mammalian 20S proteasome. Noticeable inhibition of both ChT-L and PA activities was obtained with three compounds: one with unsubstituted phenoxypropanolamine group (7) and the two others with a p-Cl-substituted group (4 and 9). For three other compounds (3, 8 and 10), ChT-L activity alone was significantly inhibited. In silico docking performed on the β5 and β1 subunits bearing the respective ChT-L and PA catalytic sites showed features common to poses associated with active compounds. These features may constitute a selectivity criterion for structure-guided inhibitor design.

Keywords: 20S proteasome; ChT-L, T-L and PA activities; In silico structure-based docking; Phenoxypropanolamine; Selective inhibition; Thiophene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Catalytic Domain
  • Cattle
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Mycobacterium tuberculosis / enzymology
  • Phenoxypropanolamines / chemical synthesis
  • Phenoxypropanolamines / chemistry*
  • Phenoxypropanolamines / metabolism
  • Proteasome Endopeptidase Complex / chemistry*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / chemical synthesis
  • Proteasome Inhibitors / chemistry*
  • Proteasome Inhibitors / metabolism
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / metabolism
  • Structure-Activity Relationship

Substances

  • Phenoxypropanolamines
  • Proteasome Inhibitors
  • Protein Subunits
  • Proteasome Endopeptidase Complex