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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.

ABSTRACT: 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 ?M). 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 ?M; MDMX IC50 = 4.2 ?M) 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 ?M; MDMX IC50 = 4.2 ?M), 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.

SUBMITTER: Blackburn TJ 

PROVIDER: S-EPMC3777193 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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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.

Blackburn Tim J TJ   Ahmed Shafiq S   Coxon Christopher R CR   Liu Junfeng J   Lu Xiaohong X   Golding Bernard T BT   Griffin Roger J RJ   Hutton Claire C   Newell David R DR   Ojo Stephen S   Watson Anna F AF   Zaytzev Andrey A   Zhao Yan Y   Lunec John J   Hardcastle Ian R IR  

MedChemComm 20130729 9

Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2<i>H</i>)-ylidene)methyl)-2,5-dimethyl-1<i>H</i>-pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[<i>b</i>]thiophene-3-carbonitrile as an MDM2-p53 inhibitor (IC<sub>50</sub> = 12.3 μM). MDM2-p53 and MDMX-p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5-diphenyl-1<i>H</i>-pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1<i>H</i>,5<i>H</i>)-dione (MDM2 IC<sub>50</sub> = 0.11 μM; MDMX IC<sub>50</sub> = 4.2 μM) and 5-((1-(4-nitropheny  ...[more]

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