Artificial Macrocycles as Potent p53–MDM2 Inhibitors

[Image: see text] Based on a combination of an Ugi four component reaction and a ring closing metathesis, a library of novel artificial macrocyclic inhibitors of the p53–MDM2 interaction was designed and synthesized. These macrocycles, alternatively to stapled peptides, target for the first time the...

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Autores principales: Estrada-Ortiz, Natalia, Neochoritis, Constantinos G., Twarda-Clapa, Aleksandra, Musielak, Bogdan, Holak, Tad A., Dömling, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2017
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641952/
https://www.ncbi.nlm.nih.gov/pubmed/29057045
http://dx.doi.org/10.1021/acsmedchemlett.7b00219
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author Estrada-Ortiz, Natalia
Neochoritis, Constantinos G.
Twarda-Clapa, Aleksandra
Musielak, Bogdan
Holak, Tad A.
Dömling, Alexander
author_facet Estrada-Ortiz, Natalia
Neochoritis, Constantinos G.
Twarda-Clapa, Aleksandra
Musielak, Bogdan
Holak, Tad A.
Dömling, Alexander
author_sort Estrada-Ortiz, Natalia
collection PubMed
description [Image: see text] Based on a combination of an Ugi four component reaction and a ring closing metathesis, a library of novel artificial macrocyclic inhibitors of the p53–MDM2 interaction was designed and synthesized. These macrocycles, alternatively to stapled peptides, target for the first time the large hydrophobic surface area formed by Tyr67, Gln72, His73, Val93, and Lys94 yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using fluorescence polarization (FP) assay and (1)H–(15)N two-dimensional HSQC nuclear magnetic resonance experiments.
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spelling pubmed-56419522017-10-22 Artificial Macrocycles as Potent p53–MDM2 Inhibitors Estrada-Ortiz, Natalia Neochoritis, Constantinos G. Twarda-Clapa, Aleksandra Musielak, Bogdan Holak, Tad A. Dömling, Alexander ACS Med Chem Lett [Image: see text] Based on a combination of an Ugi four component reaction and a ring closing metathesis, a library of novel artificial macrocyclic inhibitors of the p53–MDM2 interaction was designed and synthesized. These macrocycles, alternatively to stapled peptides, target for the first time the large hydrophobic surface area formed by Tyr67, Gln72, His73, Val93, and Lys94 yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using fluorescence polarization (FP) assay and (1)H–(15)N two-dimensional HSQC nuclear magnetic resonance experiments. American Chemical Society 2017-09-20 /pmc/articles/PMC5641952/ /pubmed/29057045 http://dx.doi.org/10.1021/acsmedchemlett.7b00219 Text en Copyright © 2017 American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes.
spellingShingle Estrada-Ortiz, Natalia
Neochoritis, Constantinos G.
Twarda-Clapa, Aleksandra
Musielak, Bogdan
Holak, Tad A.
Dömling, Alexander
Artificial Macrocycles as Potent p53–MDM2 Inhibitors
title Artificial Macrocycles as Potent p53–MDM2 Inhibitors
title_full Artificial Macrocycles as Potent p53–MDM2 Inhibitors
title_fullStr Artificial Macrocycles as Potent p53–MDM2 Inhibitors
title_full_unstemmed Artificial Macrocycles as Potent p53–MDM2 Inhibitors
title_short Artificial Macrocycles as Potent p53–MDM2 Inhibitors
title_sort artificial macrocycles as potent p53–mdm2 inhibitors
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641952/
https://www.ncbi.nlm.nih.gov/pubmed/29057045
http://dx.doi.org/10.1021/acsmedchemlett.7b00219
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