Diaryl- and triaryl-pyrrole derivatives: inhibitors of the MDM2–p53 and MDMX–p53 protein–protein interactions† †Electronic supplementary information (ESI) available: Experimental details for compound synthesis, analytical data for all compounds and intermediates. Details for the biological evaluation. Further details for the modeling. Table of combustion analysis data. See DOI: 10.1039/c3md00161jClick here for additional data file.

نویسندگان

  • Tim J. Blackburn
  • Shafiq Ahmed
  • Christopher R. Coxon
  • Junfeng Liu
  • Xiaohong Lu
  • Bernard T. Golding
  • Roger J. Griffin
  • Claire Hutton
  • David R. Newell
  • Stephen Ojo
  • Anna F. Watson
  • Andrey Zaytzev
  • Yan Zhao
  • John Lunec
  • Ian R. Hardcastle
چکیده

Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-ylidene)methyl)-2,5-dimethyl-1H-pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile as an MDM2-p53 inhibitor (IC50 = 12.3 μM). MDM2-p53 and MDMX-p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (MDM2 IC50 = 0.11 μM; MDMX IC50 = 4.2 μM) and 5-((1-(4-nitrophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (MDM2 IC50 = 0.15 μM; MDMX IC50 = 4.2 μM), and cellular activity consistent with p53 activation in MDM2 amplified cells. Further SAR studies demonstrated the requirement for the triarylpyrrole moiety for MDMX-p53 activity but not for MDM2-p53 inhibition.

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منابع مشابه

Novel octavalent cross-linker displays efficient trapping of protein–protein interactions† †Electronic supplementary information (ESI) available: General experimental details and characterisation data for compounds 1–3. See DOI: 10.1039/b701542a Click here for additional data file. Click here for additional data file.

A novel octavalent, resorcin[4]arene derived, cross-linker designed to overcome some of the limitations of commercially available reagents is significantly more efficient for covalent stabilisation of protein-protein interactions.

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عنوان ژورنال:

دوره 4  شماره 

صفحات  -

تاریخ انتشار 2013