Figure 1
Molecular structure of indirubin (1).
Figure 2
Hydrophilic groups linked to fused triazole-indirubin skeleton.
Figure 3
Chemical structure of tryptanthrin (2).
Scheme 1
Strategies for preparation of triazole derivatives linked to hydrophilic moieties.
Scheme 2
Synthesis of triazole derivatives through pathway A. (i) Propargyl bromide (1.5 eq) K2CO3 (1.5 eq), dimethyl sulfoxide (DMSO), room temperature (rt), 1 h (88%); (ii) R-N3 (1.2 eq), DMSO/H2O, CuSO4.5H2O (20 mol%) and sodium ascorbate (20 mol%), rt, 1 h. (iii) K2CO3 (4.0 eq), MeOH, N2 atmosphere, rt, 30 min.
Scheme 3
Hydrolysis of indirubin-triazole derivatives TFA/H2O 9:1 v/v, 2 drops H2SO4, tetrahydrofuran (THF), 60 °C, 24 h.
Scheme 4
Partial reductive coupling of triazole-isatin derivative (15).
Scheme 5
Pathway B reactions. (i) NaBH4, MeOH, 40 min, rt (73%). (ii) K2CO3 (3.0 eq), propargyl bromide (3.0 eq), KI (cat), DMSO, 72 h.
Figure 4
Comparison of 1H NMR spectra of reaction mixture (500 MHz, CDCl3), isolated product (500 MHz, CDCl3) and indirubin (500 MHz, DMSO-d6).
Figure 5
UV-Vis spectra of solution of indirubin with different moieties of K2CO3.
Figure 6
UV-Vis spectra of solution of indirubin with different moieties of t-BuOK.
Scheme 6
Different possible isomers towards propargylation reaction: N1-propargyl (blue), O-propargyl (red), C3-propargyl (pink) and N2-propargyl (green).
Figure 7
Free energy profile (∆G) of indirubin monopropargylation reaction through anionic pathway. Units in kcal mol-1, the standard state of 1 mol L-1 for all species, 298 K. The imaginary frequencies for transition states (TS) were 380i, 390i, 377i and 332i cm-1 for 19, 20, 21 and 28, respectively.
Figure 8
Free energy profile (∆G) of indirubin monopropargylation reaction through neutral pathway. Units in kcal mol-1, the standard state of 1 mol L-1 for all species, 298 K. The imaginary frequencies for TS were 412i, 410i, 349i and 405i cm-1 for N1, O, C and N2, respectively.
Figure 9
Free energy profile (∆G) of anionic pathway for a second propargylation reaction involving N1-propargyl-indirubin. Units in kcal mol-1, standard state of 1 mol L-1 for all species, 298 K. The imaginary frequencies for TS were 339i and 382i cm-1 i for N2 and C propargylation, respectively.
Figure 10
Expansion area of the 1H NMR spectra of methylene and methine hydrogen atoms of reaction mixture and isolated product.
Figure 11
Free energy profile (∆G) of neutral pathway for dipropargylation reaction of N1-propargyl-indirubin. Units in kcal mol-1, the standard state of 1 mol L-1 for all species, 298 K. The imaginary frequencies for TS were 391i and 410i cm-1 i for N2 and C propargylation, respectively.
Figure 12
(a) Representation of GSK-β colored from C-terminal to N-terminal (from blue to red), (b) solid representation of the protein highlighting the active site cavity which is zoomed in (c) and (d) the complex between the protein and compound 9 having the lowest binding energy obtained from the docking analysis. Non-polar hydrogens are omitted for clarity. In the ligand, atoms are colored by element: white polar hydrogen, blue: nitrogen, red oxygen and brown carbon.
Figure 13
Ligand interactions in the active site of the protein GSK-3β.
Figure 14
(a) RMSD analysis for the compounds 9, 10 and 11 complexes with ligand (GSK-3) and (b) SASA analysis with respect to the same systems.