11 research outputs found
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
Structures of and CMGC kinase inhibition by 3-phenyl-6,7-dihydropyrrolo[3,4-<i>g</i>]indol-8(1<i>H</i>)-ones (IC<sub>50</sub>-values [μM])<sup>a</sup>.
<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 (IC<sub>50</sub>-values [μM])<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196761#t001fn001" target="_blank"><sup>a</sup></a>.</p
In vitro growth inhibition of cancer cell lines by KuWal151 (8c)<sup>a</sup>.
<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"><sup>a</sup></a>.</p
Data collection and refinement statistics of CLK/ligand complexes.
<p>Data collection and refinement statistics of CLK/ligand complexes.</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
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
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
Synthesis procedures for 3-aryl-6,7-dihydropyrrolo[3,4-<i>g</i>]indol-8(1<i>H</i>)-ones.
<p>For residues R<sup><b>1</b></sup>-R<sup><b>5</b></sup> 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<sub><b>2</b></sub>Cl<sub><b>2</b></sub>, - 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<sub><b>3</b></sub>I, KO<i>t</i>Bu, THF, RT, N<sub><b>2</b></sub>, 24 h, 54%; (d) 1. 37% HCl, NaNO<sub><b>2</b></sub>, < 0°C; 2. 37% HCl, SnCl<sub><b>2</b></sub> x 2 H<sub><b>2</b></sub>O, 30 min; (e) aldehyde or ketone or acetal, acetic acid, 95°C, 3.5 h, 10%-31%; (f) PdCl<sub><b>2</b></sub>(MeCN)<sub><b>2</b></sub>, <i>p</i>-benzoquinone, <i>tert</i>-butanol, water, 80°C; (g) <b>11a</b>, ethanol, H<sub><b>2</b></sub>SO<sub><b>4</b></sub>, H<sub><b>2</b></sub>O, 50°C, 2.5 h, 23%; (h) BBr<sub><b>3</b></sub>, CH<sub><b>2</b></sub>Cl<sub><b>2</b></sub>, RT, N<sub><b>2</b></sub>, 1 h, 33%; (i) acetic anhydride, pyridine, 4-DMAP, RT, 3 h, 29%; (j) alkyl halide, KO<i>t</i>Bu, acetone, RT, N<sub><b>2</b></sub>, 24 h, 15%-48%; (k) NBS, CH<sub><b>2</b></sub>Cl<sub><b>2</b></sub>/acetic acid, < 10°C, N<sub><b>2</b></sub>, 1.5 h, 29%; (l) appropriate arylboronic acid, Cs<sub><b>2</b></sub>CO<sub><b>3</b></sub>, toluene/ethanol, mircowaves, 150°C, 20 min, 5.4%-31%.</p
Hit compound 8a identified as CLK1 inhibitor in a library screening and the structurally related dye indirubin (9a).
<p>Both compounds comprise a pyrrole unit connected to a γ-butyrolactam ring via a double bond.</p
Cocrystal structure of 8a with CLK3 (PDB-ID: 6FT7); red spheres: water molecules; EG: Ethylene glycol; black dashed lines: hydrogen bonds.
<p>A: The lactam motif of the ligand forms the canonical hydrogen bonds to the amino acids gk+1 (Glu237) and gk+3 (Leu239); the indole nitrogen is connected to the amino acid gk+4 (Gly240). B: Side view. An ethylene glycol molecule fills a space at the back of the pocket near the αC-helix which is left unoccupied by <b>8a</b>.</p