Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction
| العنوان: | Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction |
|---|---|
| المؤلفون: | Jaeki Min, M. Brett Waddell, Maria Quant, R. Kiplin Guy, Richard W. Kriwacki, Mariell Pettersson, Kristina Luthman, Luigi I. Iconaru, Morten Grøtli |
| المصدر: | PLoS ONE PLoS ONE, Vol 10, Iss 10, p e0137867 (2015) |
| بيانات النشر: | Public Library of Science, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Models, Molecular, Stereochemistry, lcsh:Medicine, Peptide, Chemistry Techniques, Synthetic, Diketopiperazines, Protein Structure, Secondary, Protein–protein interaction, chemistry.chemical_compound, Protein structure, Peptide synthesis, Humans, Binding site, lcsh:Science, chemistry.chemical_classification, Multidisciplinary, Binding Sites, lcsh:R, Rational design, Proto-Oncogene Proteins c-mdm2, Biochemistry, chemistry, Docking (molecular), Drug Design, lcsh:Q, Tumor Suppressor Protein p53, Research Article, Protein Binding |
| الوصف: | 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 alpha-helical region of the p53 peptide, containing key residues in the i, i+4 and i+7 positions of a natural alpha-helix. Conformational analysis indicated that 1,3,6-trisubstituted 2,5-diketopiperazines were able to place substituents in the same spatial orientation as an alpha-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. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c1a46a51102ac919b0bd01d94c09075aTest http://europepmc.org/articles/PMC4591261Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c1a46a51102ac919b0bd01d94c09075a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
|---|