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Design, Synthesis a...
Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction
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- Pettersson, Mariell, 1984 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,University of Gothenburg
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- Quant, Maria, 1985 (författare)
- Göteborgs universitet,University of Gothenburg
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- Min, J. (författare)
- St. Jude Children Research Hospital
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- Iconaru, L. (författare)
- St. Jude Children Research Hospital
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- Kriwacki, R. W. (författare)
- St. Jude Children Research Hospital
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- Waddell, M. B. (författare)
- St. Jude Children Research Hospital
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- Guy, R. K. (författare)
- St. Jude Children Research Hospital
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- Luthman, Kristina, 1953 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,University of Gothenburg
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- Grøtli, Morten, 1966 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,University of Gothenburg
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(creator_code:org_t)
- 2015-10-01
- 2015
- Engelska.
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:10
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
Nyckelord
- protein-protein interactions
- alpha-helix
- rational design
- cancer-therapy
- p53 pathway
- oncoprotein
- derivatives
- modulators
- mutations
- chemistry
- cancer-therapy
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
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PLoS ONE
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Till lärosätets databas
- Av författaren/redakt...
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Pettersson, Mari ...
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Quant, Maria, 19 ...
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Min, J.
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Iconaru, L.
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Kriwacki, R. W.
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Waddell, M. B.
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visa fler...
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Guy, R. K.
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Luthman, Kristin ...
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Grøtli, Morten, ...
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- Om ämnet
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- NATURVETENSKAP
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NATURVETENSKAP
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och Kemi
- Artiklar i publikationen
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PLoS ONE
- Av lärosätet
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Göteborgs universitet
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Chalmers tekniska högskola