Structure–Activity Relationship Studies of Tetracyclic Pyrrolocarbazoles Inhibiting Heterotetrameric Protein Kinase CK2
The serine/threonine kinase CK2 (formerly known as casein kinase II) plays a crucial role in various CNS disorders and is highly expressed in various types of cancer. Therefore, inhibiting this key kinase could be promising for the treatment of these diseases. The CK2 holoenzyme is formed by the rec...
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2024-12-01
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| author | Lukas Kröger Sebastian Borgert Miriam Lauwers Michaela Steinkrüger Joachim Jose Markus Pietsch Bernhard Wünsch |
| author_facet | Lukas Kröger Sebastian Borgert Miriam Lauwers Michaela Steinkrüger Joachim Jose Markus Pietsch Bernhard Wünsch |
| author_sort | Lukas Kröger |
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| description | The serine/threonine kinase CK2 (formerly known as casein kinase II) plays a crucial role in various CNS disorders and is highly expressed in various types of cancer. Therefore, inhibiting this key kinase could be promising for the treatment of these diseases. The CK2 holoenzyme is formed by the recruitment of two catalytically active CK2α and/or CK2α′ subunits by a regulatory CK2β dimer. Starting with the lead furocarbazole W16 (<b>4</b>) inhibiting the CK2α/CK2β interaction, analogous pyrrolocarbazoles were prepared and tested for their protein–protein interaction inhibition (PPII). The key step of the synthesis was a multicomponent Levy reaction of 2-(indolyl)acetate <b>6</b>, benzaldehydes <b>7</b>, and <i>N</i>-substituted maleimides <b>8</b>. Targeted modifications were performed by the saponification of the tetracyclic ester <b>9a</b>, followed by the coupling of the resulting acid <b>10</b> with diverse amines. The replacement of the O-atom of the lead furocarbazole <b>4</b> by an N-atom in pyrrolocarbazoles retained or even increased the inhibition of the CK2α/CK2β interaction. The large benzyloxazolidinyl moiety of <b>4</b> could be replaced by smaller <i>N</i>-substituents without the loss of the PPII. The introduction of larger substituents at the 2-position and/or at <i>p</i>-position of the phenyl moiety at the 10-position to increase the surface for the inhibition of the PPI did not enhance the inhibition of the CK2α/CK2β association. The strong inhibition of the CK2α/CK2β association by the histidine derivative (+)-<b>20a</b> (<i>K</i><sub>i</sub> = 6.1 µM) translated into a high inhibition of the kinase activity of the CK2 holoenzyme (CK2α<sub>2</sub>β<sub>2</sub>, IC<sub>50</sub> = 2.5 µM). Thus, <b>20a</b> represents a novel lead compound inhibiting CK2 via the inhibition of the association of the CK2α and Ck2β subunits. |
| format | Article |
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| spelling | doaj-art-e0a3481a90a04aafbc3dc9615970e8a42025-01-10T13:18:46ZengMDPI AGMolecules1420-30492024-12-013016310.3390/molecules30010063Structure–Activity Relationship Studies of Tetracyclic Pyrrolocarbazoles Inhibiting Heterotetrameric Protein Kinase CK2Lukas Kröger0Sebastian Borgert1Miriam Lauwers2Michaela Steinkrüger3Joachim Jose4Markus Pietsch5Bernhard Wünsch6Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, D-48149 Münster, GermanyInstitut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, D-48149 Münster, GermanyInstitutes I & II of Pharmacology, Center of Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Straße 24, D-50931 Cologne, GermanyInstitutes I & II of Pharmacology, Center of Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Straße 24, D-50931 Cologne, GermanyInstitut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, D-48149 Münster, GermanyInstitutes I & II of Pharmacology, Center of Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Straße 24, D-50931 Cologne, GermanyInstitut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, D-48149 Münster, GermanyThe serine/threonine kinase CK2 (formerly known as casein kinase II) plays a crucial role in various CNS disorders and is highly expressed in various types of cancer. Therefore, inhibiting this key kinase could be promising for the treatment of these diseases. The CK2 holoenzyme is formed by the recruitment of two catalytically active CK2α and/or CK2α′ subunits by a regulatory CK2β dimer. Starting with the lead furocarbazole W16 (<b>4</b>) inhibiting the CK2α/CK2β interaction, analogous pyrrolocarbazoles were prepared and tested for their protein–protein interaction inhibition (PPII). The key step of the synthesis was a multicomponent Levy reaction of 2-(indolyl)acetate <b>6</b>, benzaldehydes <b>7</b>, and <i>N</i>-substituted maleimides <b>8</b>. Targeted modifications were performed by the saponification of the tetracyclic ester <b>9a</b>, followed by the coupling of the resulting acid <b>10</b> with diverse amines. The replacement of the O-atom of the lead furocarbazole <b>4</b> by an N-atom in pyrrolocarbazoles retained or even increased the inhibition of the CK2α/CK2β interaction. The large benzyloxazolidinyl moiety of <b>4</b> could be replaced by smaller <i>N</i>-substituents without the loss of the PPII. The introduction of larger substituents at the 2-position and/or at <i>p</i>-position of the phenyl moiety at the 10-position to increase the surface for the inhibition of the PPI did not enhance the inhibition of the CK2α/CK2β association. The strong inhibition of the CK2α/CK2β association by the histidine derivative (+)-<b>20a</b> (<i>K</i><sub>i</sub> = 6.1 µM) translated into a high inhibition of the kinase activity of the CK2 holoenzyme (CK2α<sub>2</sub>β<sub>2</sub>, IC<sub>50</sub> = 2.5 µM). Thus, <b>20a</b> represents a novel lead compound inhibiting CK2 via the inhibition of the association of the CK2α and Ck2β subunits.https://www.mdpi.com/1420-3049/30/1/63CK2protein kinaseheterotetrameric enzymeprotein–protein interactionenzyme inhibitionLevy reaction |
| spellingShingle | Lukas Kröger Sebastian Borgert Miriam Lauwers Michaela Steinkrüger Joachim Jose Markus Pietsch Bernhard Wünsch Structure–Activity Relationship Studies of Tetracyclic Pyrrolocarbazoles Inhibiting Heterotetrameric Protein Kinase CK2 Molecules CK2 protein kinase heterotetrameric enzyme protein–protein interaction enzyme inhibition Levy reaction |
| title | Structure–Activity Relationship Studies of Tetracyclic Pyrrolocarbazoles Inhibiting Heterotetrameric Protein Kinase CK2 |
| title_full | Structure–Activity Relationship Studies of Tetracyclic Pyrrolocarbazoles Inhibiting Heterotetrameric Protein Kinase CK2 |
| title_fullStr | Structure–Activity Relationship Studies of Tetracyclic Pyrrolocarbazoles Inhibiting Heterotetrameric Protein Kinase CK2 |
| title_full_unstemmed | Structure–Activity Relationship Studies of Tetracyclic Pyrrolocarbazoles Inhibiting Heterotetrameric Protein Kinase CK2 |
| title_short | Structure–Activity Relationship Studies of Tetracyclic Pyrrolocarbazoles Inhibiting Heterotetrameric Protein Kinase CK2 |
| title_sort | structure activity relationship studies of tetracyclic pyrrolocarbazoles inhibiting heterotetrameric protein kinase ck2 |
| topic | CK2 protein kinase heterotetrameric enzyme protein–protein interaction enzyme inhibition Levy reaction |
| url | https://www.mdpi.com/1420-3049/30/1/63 |
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