Synthesis, Biological Evaluation, and Molecular Modeling of Natural and Unnatural Flavonoidal Alkaloids, Inhibitors of Kinases

The screening of the ICSN chemical library on various disease-relevant protein kinases led to the identification of natural flavonoidal alkaloids of unknown configuration as potent inhibitors of the CDK1 and CDK5 kinases. We thus developed an efficient and modular synthetic strategy for their preparation and that of analogues in order to determine the absolute configuration of the active natural flavonoidal alkaloids and to provide further insights on the structure–activity relationships in this series. The structural determinants of the interaction between some flavonoidal alkaloids with specific kinases were also evaluated using molecular modeling

Acridone Alkaloids from <i>Glycosmis chlorosperma</i> as DYRK1A Inhibitors

Two new acridone alkaloids, chlorospermines A and B (<b>1</b> and <b>2</b>), were isolated from the stem bark of <i>Glycosmis chlorosperma</i>, together with the known atalaphyllidine (<b>3</b>) and acrifoline (<b>4</b>), by means of bioguided isolation using an in vitro enzyme assay against DYRK1A. Acrifoline (<b>4</b>) and to a lesser extent chlorospermine B (<b>2</b>) and atalaphyllidine (<b>3</b>) showed significant inhibiting activity on DYRK1A with IC₅₀’s of 0.075, 5.7, and 2.2 μM, respectively. Their selectivity profile was evaluated against a panel of various kinases, and molecular docking calculations provided structural details for the interaction between these compounds and DYRK1A

10-Iodo-11<i>H</i>‑indolo[3,2‑<i>c</i>]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A

The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11<i>H</i>-indolo­[3,2-<i>c</i>]­quinoline-6-carboxylic acid revealed structure–activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11<i>H</i>-indolo­[3,2-<i>c</i>]­quinoline-6-carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site

Novel Inverse Binding Mode of Indirubin Derivatives Yields Improved Selectivity for DYRK Kinases

DYRK kinases are involved in alternative pre-mRNA splicing as well as in neuropathological states such as Alzheimer's disease and Down syndrome. In this study, we present the design, synthesis, and biological evaluation of indirubins as DYRK inhibitors with enhanced selectivity. Modifications of the bis-indole included polar or acidic functionalities at positions 5′ and 6′ and a bromine or a trifluoromethyl group at position 7, affording analogues that possess high activity and pronounced specificity. Compound <b>6i</b> carrying a 5′-carboxylate moiety demonstrated the best inhibitory profile. A novel inverse binding mode, which forms the basis for the improved selectivity, was suggested by molecular modeling and confirmed by determining the crystal structure of DYRK2 in complex with <b>6i</b>. Structure–activity relationships were further established, including a thermodynamic analysis of binding site water molecules, offering a structural explanation for the selective DYRK inhibition