Kroeger, Lukas, Daniliuc, Constantin G. ORCID: 0000-0002-6709-3673, Ensan, Deeba, Borgert, Sebastian, Nienberg, Christian, Lauwers, Miriam, Steinkrueger, Michaela, Jose, Joachim, Pietsch, Markus and Wuensch, Bernhard (2020). Synthesis and SAR of Tetracyclic Inhibitors of Protein Kinase CK2 Derived from Furocarbazole W16. ChemMedChem, 15 (10). S. 871 - 882. WEINHEIM: WILEY-V C H VERLAG GMBH. ISSN 1860-7187

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Abstract

The serine/threonine kinase CK2 modulates the activity of more than 300 proteins and thus plays a crucial role in various physiological and pathophysiological processes including neurodegenerative disorders of the central nervous system and cancer. The enzymatic activity of CK2 is controlled by the equilibrium between the heterotetrameric holoenzyme CK2 alpha(2)beta(2) and its monomeric subunits CK2 alpha and CK2 beta. A series of analogues of W16 ((3aR,4S,10S,10aS)-4-{[(S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-10-(3,4,5-trimethoxyphenyl)-4,5,10,10a-tetrahydrofuro[3,4-b]carbazole-1,3(3aH)-dione ((+)-3 a)) was prepared in an one-pot, three-component Levy reaction. The stereochemistry of the tetracyclic compounds was analyzed. Additionally, the chemically labile anhydride structure of the furocarbazoles 3 was replaced by a more stable imide (9) and N-methylimide (10) substructure. The enantiomer (-)-3 a (K-i=4.9 mu M) of the lead compound (+)-3 a (K-i=31 mu M) showed a more than sixfold increased inhibition of the CK2 alpha/CK2 beta interaction (protein-protein interaction inhibition, PPII) in a microscale thermophoresis (MST) assay. However, (-)-3 a did not show an increased enzyme inhibition of the CK2 alpha(2)beta(2) holoenzyme, the CK2 alpha subunit or the mutated CK2 alpha ' (C336S) subunit in the capillary electrophoresis assay. In the pyrrolocarbazole series, the imide (-)-9 a (K-i=3.6 mu M) and the N-methylimide (+)-10 a (K-i=2.8 mu M) represent the most promising inhibitors of the CK2 alpha/CK2 beta interaction. However, neither compound could inhibit enzymatic activity. Unexpectedly, the racemic tetracyclic pyrrolocarbazole (+/-)-12, with a carboxy moiety in the 4-position, displays the highest CK2 alpha/CK2 beta interaction inhibition (K-i=1.8 mu M) of this series of compounds.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kroeger, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daniliuc, Constantin G.UNSPECIFIEDorcid.org/0000-0002-6709-3673UNSPECIFIED
Ensan, DeebaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borgert, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nienberg, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lauwers, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinkrueger, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jose, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pietsch, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wuensch, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-336426
DOI: 10.1002/cmdc.202000040
Journal or Publication Title: ChemMedChem
Volume: 15
Number: 10
Page Range: S. 871 - 882
Date: 2020
Publisher: WILEY-V C H VERLAG GMBH
Place of Publication: WEINHEIM
ISSN: 1860-7187
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CATALYTIC SUBUNIT; CASEIN KINASE-2; BETA-SUBUNIT; LEWY BODIES; CK2-ALPHA; PHOSPHORYLATION; IDENTIFICATION; CALMODULIN; TYROSINE; CX-4945Multiple languages
Chemistry, Medicinal; Pharmacology & PharmacyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33642

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