1,4-Thienodiazepine-2,5-diones via MCR (I): synthesis, virtual space and p53-Mdm2 activity

Chem Biol Drug Des. 2010 Aug;76(2):116-29. doi: 10.1111/j.1747-0285.2010.00989.x. Epub 2010 May 18.


1,4-Thienodiazepine-2,5-diones have been synthesized via the Ugi-Deprotection-Cyclization (UDC) approach starting from Gewald 2-aminothiophenes in a convergent and versatile manner. The resulting scaffold is unprecedented, cyclic, and peptidomimetic with four points of diversity introduced from readily available starting materials. In addition to eighteen synthesized and characterized compounds, a virtual compound library was generated and evaluated for chemical space distribution and drug-like properties. A small focused compound library of 1,4-thienodiazepine-2,5-diones has been screened for the activity against p53-Mdm2 interaction. Biological evaluations demonstrated that some compounds exhibited promising antagonistic activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azepines / chemical synthesis
  • Azepines / chemistry*
  • Azepines / pharmacology
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Humans
  • Magnetic Resonance Spectroscopy
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Thiophenes / chemistry
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / metabolism*


  • Azepines
  • Thiophenes
  • Tumor Suppressor Protein p53
  • thieno-1,4-diazepine
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2