Limits...
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

2,5-DKP derivatives docked into the α-helix binding site of MDM2 (PDB code: 4HBM).(A) and (B) N1 = 4-chlorobenzyl, C3 = Benzyl, N4 = CH2CO2H, C6 = cyclohexyl. (C) N1 = C6 = Phenyl, C3 = benzyl, N4 = CH2CO2H.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4591261&req=5

pone.0137867.g006: 2,5-DKP derivatives docked into the α-helix binding site of MDM2 (PDB code: 4HBM).(A) and (B) N1 = 4-chlorobenzyl, C3 = Benzyl, N4 = CH2CO2H, C6 = cyclohexyl. (C) N1 = C6 = Phenyl, C3 = benzyl, N4 = CH2CO2H.

Mentions: A series of structurally varied 2,5-DKP derivatives was docked into the α-helix binding site of MDM2 (PDB code: 4HBM), using the Schrödinger package (Glide, XP mode), to find a suitable substitution pattern on the 2,5-DKP scaffold (Fig 6). The docking results indicated that the spiro-cyclohexyl group was well accommodated in the Phe-binding pocket (Fig 6A and 6B) and could work as one of the interacting hydrophobic substituents. Likewise, exchanging the cyclohexyl group for a phenyl group (Fig 6C), gave compounds that docked equally well in the Trp-pocket compared to the spiro-cyclohexyl derivatives. The model did however show that the DKP ring is rotated 90°, switching the places of the C3 and C6 substituents, so that they now interact with the Phe- and Leu-pocket, respectively. Replacing the N1 benzyl group with a phenyl group resulted in compounds which had similar binding modes. The docking results also suggested the introduction of a CH2X group at the N4-position, where X = methyl ester, carboxylic acid, amide, or alcohol could provide additional interactions via hydrogen bonding and/or ionic interactions with the His96 and Lys94 residues of MDM2 (Fig 6A and 6C).


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)

2,5-DKP derivatives docked into the α-helix binding site of MDM2 (PDB code: 4HBM).(A) and (B) N1 = 4-chlorobenzyl, C3 = Benzyl, N4 = CH2CO2H, C6 = cyclohexyl. (C) N1 = C6 = Phenyl, C3 = benzyl, N4 = CH2CO2H.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137867.g006: 2,5-DKP derivatives docked into the α-helix binding site of MDM2 (PDB code: 4HBM).(A) and (B) N1 = 4-chlorobenzyl, C3 = Benzyl, N4 = CH2CO2H, C6 = cyclohexyl. (C) N1 = C6 = Phenyl, C3 = benzyl, N4 = CH2CO2H.
Mentions: A series of structurally varied 2,5-DKP derivatives was docked into the α-helix binding site of MDM2 (PDB code: 4HBM), using the Schrödinger package (Glide, XP mode), to find a suitable substitution pattern on the 2,5-DKP scaffold (Fig 6). The docking results indicated that the spiro-cyclohexyl group was well accommodated in the Phe-binding pocket (Fig 6A and 6B) and could work as one of the interacting hydrophobic substituents. Likewise, exchanging the cyclohexyl group for a phenyl group (Fig 6C), gave compounds that docked equally well in the Trp-pocket compared to the spiro-cyclohexyl derivatives. The model did however show that the DKP ring is rotated 90°, switching the places of the C3 and C6 substituents, so that they now interact with the Phe- and Leu-pocket, respectively. Replacing the N1 benzyl group with a phenyl group resulted in compounds which had similar binding modes. The docking results also suggested the introduction of a CH2X group at the N4-position, where X = methyl ester, carboxylic acid, amide, or alcohol could provide additional interactions via hydrogen bonding and/or ionic interactions with the His96 and Lys94 residues of MDM2 (Fig 6A and 6C).

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