Indole-Based Tubulin Inhibitors: Binding Modes and SARs Investigations

Abstract

Tubulin inhibitors can interfere with normal cell mitosis and inhibit cell proliferation through interfering with the normal structure and function of microtubules, forming spindle filaments. Indole, as a privileged pharmacological skeleton, has been widely used in anti-cancer inhibitors. A variety of alkaloids containing an indole core obtained from natural sources have been proven to inhibit tubulin polymerization, and an ever-increasing number of synthetic indole-based tubulin inhibitors have been reported. Among these, several kinds of indole-based derivatives, such as TMP analogues, aroylindoles, arylthioindoles, fused indole, carbazoles, azacarbolines, alkaloid nortopsentin analogues and bis-indole derivatives, have shown good inhibition activities towards tubulin polymerization. The binding modes and SARs investigations of synthetic indole derivatives, along with a brief mechanism on their anti-tubulin activity, are presented in this review.

Keywords: SARs investigations; binding modes; cancer; indole; tubulin inhibitors.

Figure 1

The model of vincristine and colchicine bound to tubulin (PDB code: 1Z2B).

Figure 2

Combretastatin A-4 (CA-4)-based TMP analogues.

Figure 3

Indole-based TMP analogues.

Figure 4

(A) Indole-based TMP analogues; (B) binding mode for compound 6v with tubulin (PDB code: 5LYJ).

Figure 5

(A) Indole-based TMP analogues; (B) binding mode for compound 9 with tubulin (PDB code: 1SA0).

Figure 6

Arythioindole derivatives.

Figure 7

(A) Arythioindole derivatives; (B) binding mode for compound 14e with tubulin (PDB code: 1SA0).

Figure 8

(A) Aroyindole derivatives; (B) binding mode for compound 15k with tubulin (PDB code: 4O2B); (C) binding mode for compound 16e with tubulin (PDB code: 4O2B).

Figure 9

(A) Arythioindole derivatives; (B) surface model for residues of tubulin and the binding site of compound 20 (PDB code: 1SA0).

Figure 10

Design strategies for fused indole analogues. Docked structure of compound 22. (Topoisomerase 1-DNA complex: PDB code: 1T8I, tubulin: PDB code: 1SA0).

Figure 11

Carbazole derivatives.

Figure 12

Azacarboline derivatives (tubulin: PDB code: 1SA0, KSP: PDB code: 1Q08).

Figure 13

(A)Alkaloid nortopsentin analogue derivatives; (B) the molecular docking models for compounds 27q, 28s and 29x. (PDB code: 1SA0).

Figure 14

(A) Left: In the surface view of tubulin, colchicine (white) bound at the interface of the α₁-β₁ (blue and green) tubulin heterodimer. The binding site of indirubin was close to that of colchicine. Right: Three residues on the α₁ subunit (orange) had hydrogen bond interactions with indirubin (30), and the hydrophobic pocket formed by several residues is shown in violet; (B) binding mode for indirubin (30) with tubulin (PDB code: 1SA0).

Figure 15

(A) Structure of 2-anilinopyridine-arylpropenone analogues; (B) binding mode for compound 31 with tubulin (PDB code: 1Z2B).

Figure 16

(A) Design strategy of novel indole–quinoline derivatives inspired by the structure of known phenstatin and isoCA-4. Docked structure of compound 32b; (B) binding mode for compound 32b with tubulin (PDB code: 5LYJ).

Figure 17

(A) Design of novel indole-based compound 33a-33k from the skeleton of reported tubulin inhibitors JAI-51 and crolibulin. Docked structure of compound 33b; (B) binding mode for compound 33b with tubulin (PDB code: 1SA0).

Figure 18

(A) Strategy design of novel 2-anilinopyridine-arylpropenone analogues 35a-35p. Docked structure of compound 35a; (B) binding mode for compound 35a with tubulin (PDB code: 3UT5).

Figure 19

(A) All residues that had hydrogen bond interactions with 22 ligands described above (colchicine binding site); (B) tubulin proteins used for docking with 22 ligands.

Figure 20

(A) In the surface view of tubulin, CYS241 and ALA250 (red) are located in the hydrophobic pocket extended by the TMP group of colchicine. LYS352 (violet) is on the other side of the colchicine “L-shaped” cavity; (B) Figure A is shown as cartoon (PDB code: 1SA0); (C) THR179 (vol) is adjacent to the “B-ring” side of CA-4 (PDB code: 4LYJ); (D) THR179 and ASP251 are close to the seven-member aromatic ring and TMP group of colchicine, respectively (PDB code: 4O2B). (E) GLN247 is adjacent to CYS241 and slightly beyond the TMP group (PDB code: 4O2B).