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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

Spiro-DKPs as potential α-helix mimetics.(A) General structure of the target spiro-DKPs with numbering. (B) The side chains of Leu26, Trp23, and Phe19 in the p53 helix.(C) Spiro-DKPs. (D) Superimposition of an Ala-helix (black), with a low energy conformation of a spiro-DKP B (green).
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pone.0137867.g002: Spiro-DKPs as potential α-helix mimetics.(A) General structure of the target spiro-DKPs with numbering. (B) The side chains of Leu26, Trp23, and Phe19 in the p53 helix.(C) Spiro-DKPs. (D) Superimposition of an Ala-helix (black), with a low energy conformation of a spiro-DKP B (green).

Mentions: It was anticipated that spiro-DKPs (Fig 2A) would be a suitable starting point for the development of novel type III inhibitors, as these shape-programmable scaffolds can project functional groups into defined three-dimensional constellations to mimic the positioning of the relevant side chains of p53 (Phe19, Trp23, and Leu26) (Fig 2B).


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)

Spiro-DKPs as potential α-helix mimetics.(A) General structure of the target spiro-DKPs with numbering. (B) The side chains of Leu26, Trp23, and Phe19 in the p53 helix.(C) Spiro-DKPs. (D) Superimposition of an Ala-helix (black), with a low energy conformation of a spiro-DKP B (green).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137867.g002: Spiro-DKPs as potential α-helix mimetics.(A) General structure of the target spiro-DKPs with numbering. (B) The side chains of Leu26, Trp23, and Phe19 in the p53 helix.(C) Spiro-DKPs. (D) Superimposition of an Ala-helix (black), with a low energy conformation of a spiro-DKP B (green).
Mentions: It was anticipated that spiro-DKPs (Fig 2A) would be a suitable starting point for the development of novel type III inhibitors, as these shape-programmable scaffolds can project functional groups into defined three-dimensional constellations to mimic the positioning of the relevant side chains of p53 (Phe19, Trp23, and Leu26) (Fig 2B).

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