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Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors
Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small‐molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild‐type tumors; however,...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590160/ https://www.ncbi.nlm.nih.gov/pubmed/30458062 http://dx.doi.org/10.1002/cmdc.201800617 |
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author | Gollner, Andreas Weinstabl, Harald Fuchs, Julian E. Rudolph, Dorothea Garavel, Geraldine Hofbauer, Karin S. Karolyi‐Oezguer, Jale Gmaschitz, Gerhard Hela, Wolfgang Kerres, Nina Grondal, Elisabeth Werni, Patrick Ramharter, Juergen Broeker, Joachim McConnell, Darryl B. |
author_facet | Gollner, Andreas Weinstabl, Harald Fuchs, Julian E. Rudolph, Dorothea Garavel, Geraldine Hofbauer, Karin S. Karolyi‐Oezguer, Jale Gmaschitz, Gerhard Hela, Wolfgang Kerres, Nina Grondal, Elisabeth Werni, Patrick Ramharter, Juergen Broeker, Joachim McConnell, Darryl B. |
author_sort | Gollner, Andreas |
collection | PubMed |
description | Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small‐molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild‐type tumors; however, it also revealed dose‐limiting hematological toxicities and drug‐induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less‐frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro‐oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96(MDM2). The designed molecules required the targeted synthesis of structurally complex spiro[indole‐3,2′‐pyrrolo[2,3‐c]pyrrole]‐2,4′‐diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI‐0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on‐target adverse effects. |
format | Online Article Text |
id | pubmed-6590160 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-65901602019-07-08 Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors Gollner, Andreas Weinstabl, Harald Fuchs, Julian E. Rudolph, Dorothea Garavel, Geraldine Hofbauer, Karin S. Karolyi‐Oezguer, Jale Gmaschitz, Gerhard Hela, Wolfgang Kerres, Nina Grondal, Elisabeth Werni, Patrick Ramharter, Juergen Broeker, Joachim McConnell, Darryl B. ChemMedChem Communications Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small‐molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild‐type tumors; however, it also revealed dose‐limiting hematological toxicities and drug‐induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less‐frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro‐oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96(MDM2). The designed molecules required the targeted synthesis of structurally complex spiro[indole‐3,2′‐pyrrolo[2,3‐c]pyrrole]‐2,4′‐diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI‐0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on‐target adverse effects. John Wiley and Sons Inc. 2018-12-11 2019-01-08 /pmc/articles/PMC6590160/ /pubmed/30458062 http://dx.doi.org/10.1002/cmdc.201800617 Text en © 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Communications Gollner, Andreas Weinstabl, Harald Fuchs, Julian E. Rudolph, Dorothea Garavel, Geraldine Hofbauer, Karin S. Karolyi‐Oezguer, Jale Gmaschitz, Gerhard Hela, Wolfgang Kerres, Nina Grondal, Elisabeth Werni, Patrick Ramharter, Juergen Broeker, Joachim McConnell, Darryl B. Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors |
title | Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors |
title_full | Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors |
title_fullStr | Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors |
title_full_unstemmed | Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors |
title_short | Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors |
title_sort | targeted synthesis of complex spiro[3h‐indole‐3,2′‐pyrrolidin]‐2(1h)‐ones by intramolecular cyclization of azomethine ylides: highly potent mdm2–p53 inhibitors |
topic | Communications |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590160/ https://www.ncbi.nlm.nih.gov/pubmed/30458062 http://dx.doi.org/10.1002/cmdc.201800617 |
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