Small molecule inhibitors of the p53-MDM2 protein-protein interaction
Fitzgerald, Ross Patrick (2011) Small molecule inhibitors of the p53-MDM2 protein-protein interaction. PhD thesis, University of Nottingham.
In Chapter 2, bis- and tris- arylsulfonamides, were investigated as possible inhibitors of the p53-MDM2 protein-protein interaction (PPI). The lead compound, 19, inhibited the PPI, in a fluorescence polarisation (FP) based competitive binding assay with ICso 26.4 pM and the most potent analogue, 66, with ICso 3 μM. The active compounds in this series, possess a 5-chloro-4-nitro-2-sulfonamoyl substituted thiophene ring that is very susceptible to SNAr reactions at the 5-position. Analogues of 19 and 66 were prepared to investigate the SAR of these inhibitors. No improvements in activity or structural activity relationship (SAR) consistent with MDM2 binding were observed and no active analogues without the reactive functionality were found. These compound are no longer being investigated.
Actions (Archive Staff Only)