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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

General structures of spiro-2-DKPs and non-spiro-DKPs.Hydrophobic substituents are indicated by light grey, while hydrophilic substituents are shown in dark grey.
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pone.0137867.g007: General structures of spiro-2-DKPs and non-spiro-DKPs.Hydrophobic substituents are indicated by light grey, while hydrophilic substituents are shown in dark grey.

Mentions: Furthermore, docking results showed that derivatives with the hydrophilic substituent in the C3-position and one of the interacting hydrophobic substituents in the N4-position were also accommodated in the MDM2-pockets. The model indicated that at the C3-position, the S-configuration was preferred for the new series of spiro-DKPs (spiro-2-DKPs), while the R-configuration was preferred for the derivatives having phenyl substituents at the C6-position (non-spiro-DKPs). Two series of 2,5-DKPs, spiro-2-DKPs and non-spiro-DKP derivatives were selected for synthesis and evaluation as type II inhibitors. The general structures are shown in Fig 7.


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)

General structures of spiro-2-DKPs and non-spiro-DKPs.Hydrophobic substituents are indicated by light grey, while hydrophilic substituents are shown in dark grey.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137867.g007: General structures of spiro-2-DKPs and non-spiro-DKPs.Hydrophobic substituents are indicated by light grey, while hydrophilic substituents are shown in dark grey.
Mentions: Furthermore, docking results showed that derivatives with the hydrophilic substituent in the C3-position and one of the interacting hydrophobic substituents in the N4-position were also accommodated in the MDM2-pockets. The model indicated that at the C3-position, the S-configuration was preferred for the new series of spiro-DKPs (spiro-2-DKPs), while the R-configuration was preferred for the derivatives having phenyl substituents at the C6-position (non-spiro-DKPs). Two series of 2,5-DKPs, spiro-2-DKPs and non-spiro-DKP derivatives were selected for synthesis and evaluation as type II inhibitors. The general structures are shown in Fig 7.

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