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.
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.
Newcastle Cancer Centre , Northern Institute for Cancer Research and School of Chemistry , Newcastle University , Bedson Building , Newcastle , NE1 7RU , UK . Email: Ian.Hardcastle@ncl.ac.uk ; ; Tel: +44 (0)191 222 6645.
Tim J
TJ
Blackburn
Shafiq
S
Ahmed
Christopher R
CR
Coxon
Junfeng
J
Liu
Xiaohong
X
Lu
Bernard T
BT
Golding
Roger J
RJ
Griffin
Claire
C
Hutton
David R
DR
Newell
Stephen
S
Ojo
Anna F
AF
Watson
Andrey
A
Zaytzev
Yan
Y
Zhao
John
J
Lunec
Ian R
IR
Hardcastle