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 CK2α 2 β 2 and its monomeric subunits CK2α and CK2β. A series of) 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 (À )-3 a (K i = 4.9 μM) of the lead compound (+)-3 a (K i = 31 μM) showed a more than sixfold increased inhibition of the CK2α/CK2β interaction (protein-protein interaction inhibition, PPII) in a microscale thermophoresis (MST) assay. However, (À )-3 a did not show an increased enzyme inhibition of the CK2α 2 β 2 holoenzyme, the CK2α subunit or the mutated CK2α' C336S subunit in the capillary electrophoresis assay. In the pyrrolocarbazole series, the imide (À )-9 a (K i = 3.6 μM) and the N-methylimide (+)-10 a (K i = 2.8 μM) represent the most promising inhibitors of the CK2α/CK2β 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 CK2α/CK2β interaction inhibition (K i = 1.8 μM) of this series of compounds.
The one‐pot three‐component Levy reaction was used to prepare tetracyclic pyrrolo[3,4‐b]carbazoles 6–8. cis,cis,cis‐Configured products 6b–8b bearing an ester moiety were isolated for the first time. Epimerization studies showed that the cis,cis,cis‐configured diastereomers 6b–8b are the kinetically controlled less stable products, which are formed first. The stereochemistry is nicely explained by the endo‐stereoselectivity of the Diels–Alder reaction. High temperature, prolonged reaction times, polar solvents, bases and high concentration of acids led to epimerization at 4‐position to provide the thermodynamically favored cis,cis,trans‐configured diastereomers 6a–8a. It is postulated that epimerization occurred via the enol 12 or the corresponding enolate.
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