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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,...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
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.
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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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