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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

Conformational analysis of 57RS.(A) Model of two low energy conformations of 57RS; (B) Chemical structure of 57RS with atom numbers; (C) 1H NMR signals from H7 and H6 of 57RS at 25°C and 55°C.
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pone.0137867.g017: Conformational analysis of 57RS.(A) Model of two low energy conformations of 57RS; (B) Chemical structure of 57RS with atom numbers; (C) 1H NMR signals from H7 and H6 of 57RS at 25°C and 55°C.

Mentions: Interestingly, double peaks were observed for several signals in both 1H and 13C NMR spectra for 57RS. Hindered rotation around the N4-C9 bond resulting in two different low energy conformations of 57RS at room temperature in solution could be responsible for the double peaks observed. Conformational analysis of 57RS indicated two major conformations, with the 2-oxopiperazine moiety pointing in opposite directions (Fig 17A).


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)

Conformational analysis of 57RS.(A) Model of two low energy conformations of 57RS; (B) Chemical structure of 57RS with atom numbers; (C) 1H NMR signals from H7 and H6 of 57RS at 25°C and 55°C.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137867.g017: Conformational analysis of 57RS.(A) Model of two low energy conformations of 57RS; (B) Chemical structure of 57RS with atom numbers; (C) 1H NMR signals from H7 and H6 of 57RS at 25°C and 55°C.
Mentions: Interestingly, double peaks were observed for several signals in both 1H and 13C NMR spectra for 57RS. Hindered rotation around the N4-C9 bond resulting in two different low energy conformations of 57RS at room temperature in solution could be responsible for the double peaks observed. Conformational analysis of 57RS indicated two major conformations, with the 2-oxopiperazine moiety pointing in opposite directions (Fig 17A).

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