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