Results of a docking experiment with 8a in CLK1 (PDB-ID: 1Z57).

<p>A: front view; B: top view; dashed lines: H-bonds and edge to face interaction.</p

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

In vitro growth inhibition of cancer cell lines by KuWal151 (8c)^a.

<p>In vitro growth inhibition of cancer cell lines by KuWal151 (8c)<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196761#t002fn001" target="_blank">^a</a>.</p

Structures of and CMGC kinase inhibition by 3-phenyl-6,7-dihydropyrrolo[3,4-<i>g</i>]indol-8(1<i>H</i>)-ones (IC₅₀-values [μM])^a.

<p>Structures of and CMGC kinase inhibition by 3-phenyl-6,7-dihydropyrrolo[3,4-<i>g</i>]indol-8(1<i>H</i>)-ones (IC₅₀-values [μM])<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196761#t001fn001" target="_blank">^a</a>.</p

Data collection and refinement statistics of CLK/ligand complexes.

<p>Data collection and refinement statistics of CLK/ligand complexes.</p

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

3-Aryl-6,7-dihydropyrrolo[3,4-<i>g</i>]indol-8(1<i>H</i>)-ones listed in Table 1.

<p>3-Aryl-6,7-dihydropyrrolo[3,4-<i>g</i>]indol-8(1<i>H</i>)-ones listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196761#pone.0196761.t001" target="_blank">Table 1</a>.</p

Comparison of co-crystal structures of 8g (PDB-ID: 6FT8; upper row) and 16 (PDB-ID: 6FT9; lower row) in complex with CLK1, respectively; red spheres: water molecules; black dashed lines: hydrogen bonds.

<p>A: Top view of <b>8g.</b> B: Side view of <b>8g</b>. C: Top view of <b>16</b>. D: Side view of <b>16</b>. A, C: While the lactam motives of the ligands perform the canonical hydrogen bonds to the hinge region, the indole nitrogen atoms are connected to a conserved water molecule. B, D: An area near the Lys191 and Glu206 side chains, unoccupied by both <b>7g</b> and <b>16</b>, is filled by three water molecules. The opening to the entrance of the binding pocket is delimited by Asp250. Compared to the shape of the pocket with bound <b>8g</b> (B), the entrance of the binding pocket is widened to accommodate the 2-bromo substituent of <b>16</b> (D).</p

CLK1 inhibitors described in the literature.

<p>TG003 (<b>1</b>); NCGC00185963 (<b>2</b>), KH-CB19 (<b>3</b>); benzo[<i>b</i>]thiophen-2-carboxamide <b>4</b>; T3 (<b>5</b>); TG693 (<b>6</b>); [1,2,3]triazolo[4,5-<i>c</i>]quinoline <b>7</b>.</p

Synthesis procedures for 3-aryl-6,7-dihydropyrrolo[3,4-<i>g</i>]indol-8(1<i>H</i>)-ones.

<p>For residues R^<b>1</b>-R^<b>5</b> refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196761#pone.0196761.t001" target="_blank">Table 1</a>. Reagents and conditions: (reagents and conditions a, for synthesis of <b>10b</b>) NBS, CH_<b>2</b>Cl_<b>2</b>, - 8°C, 1 h, 78%; (reagents and conditions b, for synthesis of <b>10c</b>) NCS, acetonitrile, 60°C → reflux, 2 h, 81%; (reagents and conditions c, for synthesis of <b>10d</b>) CH_<b>3</b>I, KO<i>t</i>Bu, THF, RT, N_<b>2</b>, 24 h, 54%; (d) 1. 37% HCl, NaNO_<b>2</b>, < 0°C; 2. 37% HCl, SnCl_<b>2</b> x 2 H_<b>2</b>O, 30 min; (e) aldehyde or ketone or acetal, acetic acid, 95°C, 3.5 h, 10%-31%; (f) PdCl_<b>2</b>(MeCN)_<b>2</b>, <i>p</i>-benzoquinone, <i>tert</i>-butanol, water, 80°C; (g) <b>11a</b>, ethanol, H_<b>2</b>SO_<b>4</b>, H_<b>2</b>O, 50°C, 2.5 h, 23%; (h) BBr_<b>3</b>, CH_<b>2</b>Cl_<b>2</b>, RT, N_<b>2</b>, 1 h, 33%; (i) acetic anhydride, pyridine, 4-DMAP, RT, 3 h, 29%; (j) alkyl halide, KO<i>t</i>Bu, acetone, RT, N_<b>2</b>, 24 h, 15%-48%; (k) NBS, CH_<b>2</b>Cl_<b>2</b>/acetic acid, < 10°C, N_<b>2</b>, 1.5 h, 29%; (l) appropriate arylboronic acid, Cs_<b>2</b>CO_<b>3</b>, toluene/ethanol, mircowaves, 150°C, 20 min, 5.4%-31%.</p