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Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines

A number of new substituted morpholinopyrimidines were prepared utilizing sequential nucleophilic aromatic substitution and cross-coupling reactions. One of the disubstituted pyrimidines was converted into two trisubstituted compounds which were screened as PI3K inhibitors relative to the well-chara...

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Autores principales: Wright, Emily W., Nelson, Ronald A., Karpova, Yelena, Kulik, George, Welker, Mark E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100461/
https://www.ncbi.nlm.nih.gov/pubmed/29996482
http://dx.doi.org/10.3390/molecules23071675
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author Wright, Emily W.
Nelson, Ronald A.
Karpova, Yelena
Kulik, George
Welker, Mark E.
author_facet Wright, Emily W.
Nelson, Ronald A.
Karpova, Yelena
Kulik, George
Welker, Mark E.
author_sort Wright, Emily W.
collection PubMed
description A number of new substituted morpholinopyrimidines were prepared utilizing sequential nucleophilic aromatic substitution and cross-coupling reactions. One of the disubstituted pyrimidines was converted into two trisubstituted compounds which were screened as PI3K inhibitors relative to the well-characterized PI3K inhibitor ZSTK474, and were found to be 1.5–3-times more potent. A leucine linker was attached to the most active inhibitor since it would remain on any peptide-containing prodrug after cleavage by prostate-specific antigen, and it did not prevent inhibition of AKT phosphorylation and hence the inhibition of PI3K by the modified inhibitor.
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spelling pubmed-61004612018-11-13 Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines Wright, Emily W. Nelson, Ronald A. Karpova, Yelena Kulik, George Welker, Mark E. Molecules Article A number of new substituted morpholinopyrimidines were prepared utilizing sequential nucleophilic aromatic substitution and cross-coupling reactions. One of the disubstituted pyrimidines was converted into two trisubstituted compounds which were screened as PI3K inhibitors relative to the well-characterized PI3K inhibitor ZSTK474, and were found to be 1.5–3-times more potent. A leucine linker was attached to the most active inhibitor since it would remain on any peptide-containing prodrug after cleavage by prostate-specific antigen, and it did not prevent inhibition of AKT phosphorylation and hence the inhibition of PI3K by the modified inhibitor. MDPI 2018-07-10 /pmc/articles/PMC6100461/ /pubmed/29996482 http://dx.doi.org/10.3390/molecules23071675 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wright, Emily W.
Nelson, Ronald A.
Karpova, Yelena
Kulik, George
Welker, Mark E.
Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines
title Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines
title_full Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines
title_fullStr Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines
title_full_unstemmed Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines
title_short Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines
title_sort synthesis and pi3 kinase inhibition activity of some novel trisubstituted morpholinopyrimidines
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100461/
https://www.ncbi.nlm.nih.gov/pubmed/29996482
http://dx.doi.org/10.3390/molecules23071675
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