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Title: Design and synthesis of small-molecule inhibitors of the p53-MDM2 interaction
Author: Zhang, Bian
ISNI:       0000 0004 7960 9985
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2016
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The p53 tumour suppressor protein is a regulator of cell growth and proliferation and responds to different types of cellular stress, resulting in cell cycle arrest or apoptosis. In unstressed cells, p53 is modulated by a p53-MDM2 auto-regulatory feedback loop. In tumour cells which overexpress MDM2, inhibition of the MDM2-p53 interaction may release p53 potentially resulting in an anti-cancer effect. Several small-molecule inhibitors of the MDM2-p53 interaction have been reported, and a number have entered clinical trials. Lead identification of the isoindolinone series was conducted previously at Newcastle University to afford isoindolinone 1a (IC50 = 44 nM). Owing to potential toxicity relating to the 4-nitro substituent, replacement by a 4-chloro group led to isoindolinone 2a, which was accessed by a simpler synthesis and gave a similar result on biological evaluation (IC50 = 32 nM). The aims of the project were to improve drug-like properties of the isoindolinone series, resolve stereochemical issues and identify a clinical candidate. The X-ray crystal structure of 1a bound to MDM2 indicated an open space near the benzylic methylene group of the isoindolinone, when bound to MDM2. A methyl group was introduced on the benzylic methylene group of 2a to afford four diastereoisomers. The most active diastereoisomer 3b (IC50 = 40 nM) was isolated by normal phase chromatography, greatly simplifying the process of enantiomer separation, which for 1a required chiral HPLC separation. Potency and selectivity were maintained for 3b compared with 2a. To enhance potency further, diastereoisomer 4b, bearing a shortened C-3 substituent, was synthesized and showed excellent cell-free potency (IC50 = 9 nM) and cellular potency against MDM2 (GI50 = 360 nM). This compound was selected for pharmacokinetic and pharmacodynamic studies. IV The X-ray crystal structure of 1a bound to MDM2 also indicated that the ortho-position of the benzyl group of the isoindolinone points towards the solvent. A carboxyl group was introduced at the ortho-benzyl position to give isoindolinone 5a, which showed good water solubility and excellent cell-free potency (IC50 = 3 nM). Combining these observations with the results for 4a led to compound 6a. However, the cell-free potency of 6a was in the same range (IC50 = 2 nM) as for 5a and cellular potency was very poor. The methylsulfonyl group (as in 7a) was found to be a good replacement for the carboxyl group of 6a. Isoindolinone 7a showed the same cell-free potency as for 6a and improved cellular potency (GI50 = 82 nM). Selective deuteration of 7a (as in 8a) improved mouse pharmacokinetic data, for example, oral bioavailability (F% = 50), presumably due to the suppression of metabolism of the primary hydroxymethyl group.
Supervisor: Not available Sponsor: Newcastle University ; Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available