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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.

Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure-activity relationship study of a small library of ω-phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5-bis(trifluoromethyl)phenyl group and the aromatic character of the ω-phthalimide residue were most important for inhibitory activity. In addition, an alkyl chain composed of three or four methylene groups, connecting the urea and phthalimide moieties, was found to be an optimal spacer for inhibitors. The so-optimized compounds 2 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(1,3-dioxoisoindolin-2-yl)propyl)urea] and 21 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(1,3-dioxoisoindolin-2-yl)butyl)urea] exhibited dissociation constants (K ) of 1-19 μm on the two CEases and showed either a competitive (2 on the human enzyme and 21 on the murine enzyme) or a noncompetitive mode of inhibition. Two related serine hydrolases-monoacylglycerol lipase and fatty acid amide hydrolase-were inhibited by ω-phthalimidoalkyl aryl ureas to a lesser extent.

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