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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

Ester hydrolysis of non-spiro-DKPs afforded acids 46-53.a
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pone.0137867.g014: Ester hydrolysis of non-spiro-DKPs afforded acids 46-53.a

Mentions: A selection of 2,5-DKP esters were then further reacted to introduce other functionalities at the N4-positon. The esters were first hydrolysed to the corresponding carboxylic acids (Figs 14 and 15). The hydrolysis was initially tested on 36RR using LiOH in THF/water (1:1). However, this reaction resulted in epimerisation at the C6-position. Acid-catalysed hydrolysis of the ethyl ester using HCl at room temperature gave the desired product without epimerisation, but the reaction was rather slow and full conversion was not achieved. Instead, the reaction was performed in aqueous concentrated HCl at 70°C. However, for the tert-butyl ester, the hydrolysis could be run at room temperature. All products were obtained in very good to excellent yields (Figs 14 and 15).


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)

Ester hydrolysis of non-spiro-DKPs afforded acids 46-53.a
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137867.g014: Ester hydrolysis of non-spiro-DKPs afforded acids 46-53.a
Mentions: A selection of 2,5-DKP esters were then further reacted to introduce other functionalities at the N4-positon. The esters were first hydrolysed to the corresponding carboxylic acids (Figs 14 and 15). The hydrolysis was initially tested on 36RR using LiOH in THF/water (1:1). However, this reaction resulted in epimerisation at the C6-position. Acid-catalysed hydrolysis of the ethyl ester using HCl at room temperature gave the desired product without epimerisation, but the reaction was rather slow and full conversion was not achieved. Instead, the reaction was performed in aqueous concentrated HCl at 70°C. However, for the tert-butyl ester, the hydrolysis could be run at room temperature. All products were obtained in very good to excellent yields (Figs 14 and 15).

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