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Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction.

Pettersson M, Quant M, Min J, Iconaru L, Kriwacki RW, Waddell MB, Guy RK, Luthman K, Grøtli M - PLoS ONE (2015)

Bottom Line: The key step of the synthesis involved the cyclisation of substituted dipeptides.The other set of tetrasubstituted 2,5-diketopiperazines were designed based on structure-based docking studies and the Ugi multicomponent reaction was used for the synthesis.This latter set comprised the most potent inhibitors which displayed micromolar IC50-values in a biochemical fluorescence polarisation assay.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96, Gothenburg, Sweden.

ABSTRACT
The transcription factor p53 is the main tumour suppressor in cells and many cancer types have p53 mutations resulting in a loss of its function. In tumours that retain wild-type p53 function, p53 activity is down-regulated by MDM2 (human murine double minute 2) via a direct protein-protein interaction. We have designed and synthesised two series of 2,5-diketopiperazines as inhibitors of the MDM2-p53 interaction. The first set was designed to directly mimic the α-helical region of the p53 peptide, containing key residues in the i, i+4 and i+7 positions of a natural α-helix. Conformational analysis indicated that 1,3,6-trisubstituted 2,5-diketopiperazines were able to place substituents in the same spatial orientation as an α-helix template. The key step of the synthesis involved the cyclisation of substituted dipeptides. The other set of tetrasubstituted 2,5-diketopiperazines were designed based on structure-based docking studies and the Ugi multicomponent reaction was used for the synthesis. This latter set comprised the most potent inhibitors which displayed micromolar IC50-values in a biochemical fluorescence polarisation assay.

No MeSH data available.


Related in: MedlinePlus

Examples of type II and III inhibitors previously reported.
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pone.0137867.g001: Examples of type II and III inhibitors previously reported.

Mentions: Several inhibitors which target the MDM2-p53 interaction have been published [12]. These inhibitors can be divided into three groups: type I, II and III [13]. Type I inhibitors are peptide oligomers designed to mimic the α-helical topography. Type II inhibitors are based on scaffolds that place substituents in the same spatial orientation as that of the parent helix, but the scaffolds themselves are not designed to mimic the α-helix topography. These scaffolds vary widely in structure, but all can arrange the substituents in an analogous manner with the i, i+4 and i+7 amino acid side chains of an α-helical structure. Representative examples of type II inhibitors targeting the MDM2-p53 interaction include the nutlins [14], piperidinones [15] (Fig 1) and spiroindolines [16]


Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction.

Pettersson M, Quant M, Min J, Iconaru L, Kriwacki RW, Waddell MB, Guy RK, Luthman K, Grøtli M - PLoS ONE (2015)

Examples of type II and III inhibitors previously reported.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591261&req=5

pone.0137867.g001: Examples of type II and III inhibitors previously reported.
Mentions: Several inhibitors which target the MDM2-p53 interaction have been published [12]. These inhibitors can be divided into three groups: type I, II and III [13]. Type I inhibitors are peptide oligomers designed to mimic the α-helical topography. Type II inhibitors are based on scaffolds that place substituents in the same spatial orientation as that of the parent helix, but the scaffolds themselves are not designed to mimic the α-helix topography. These scaffolds vary widely in structure, but all can arrange the substituents in an analogous manner with the i, i+4 and i+7 amino acid side chains of an α-helical structure. Representative examples of type II inhibitors targeting the MDM2-p53 interaction include the nutlins [14], piperidinones [15] (Fig 1) and spiroindolines [16]

Bottom Line: The key step of the synthesis involved the cyclisation of substituted dipeptides.The other set of tetrasubstituted 2,5-diketopiperazines were designed based on structure-based docking studies and the Ugi multicomponent reaction was used for the synthesis.This latter set comprised the most potent inhibitors which displayed micromolar IC50-values in a biochemical fluorescence polarisation assay.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96, Gothenburg, Sweden.

ABSTRACT
The transcription factor p53 is the main tumour suppressor in cells and many cancer types have p53 mutations resulting in a loss of its function. In tumours that retain wild-type p53 function, p53 activity is down-regulated by MDM2 (human murine double minute 2) via a direct protein-protein interaction. We have designed and synthesised two series of 2,5-diketopiperazines as inhibitors of the MDM2-p53 interaction. The first set was designed to directly mimic the α-helical region of the p53 peptide, containing key residues in the i, i+4 and i+7 positions of a natural α-helix. Conformational analysis indicated that 1,3,6-trisubstituted 2,5-diketopiperazines were able to place substituents in the same spatial orientation as an α-helix template. The key step of the synthesis involved the cyclisation of substituted dipeptides. The other set of tetrasubstituted 2,5-diketopiperazines were designed based on structure-based docking studies and the Ugi multicomponent reaction was used for the synthesis. This latter set comprised the most potent inhibitors which displayed micromolar IC50-values in a biochemical fluorescence polarisation assay.

No MeSH data available.


Related in: MedlinePlus