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. 2021 Dec;36(1):640-658.
doi: 10.1080/14756366.2021.1883598.

Discovery of new quinolines as potent colchicine binding site inhibitors: design, synthesis, docking studies, and anti-proliferative evaluation

Mohamed Hagras  1 , Moshira A El Deeb  2 , Heba S A Elzahabi  3 , Eslam B Elkaeed  1   4 , Ahmed B M Mehany  5 , Ibrahim H Eissa  6
Affiliations

Discovery of new quinolines as potent colchicine binding site inhibitors: design, synthesis, docking studies, and anti-proliferative evaluation

Mohamed Hagras et al. J Enzyme Inhib Med Chem. 2021 Dec.

Abstract

Discovering of new anticancer agents with potential activity against tubulin polymerisation is still a promising approach. Colchicine binding site inhibitors are the most relevant anti-tubulin polymerisation agents. Thus, new quinoline derivatives have been designed and synthesised to possess the same essential pharmacophoric features of colchicine binding site inhibitors. The synthesised compounds were tested in vitro against a panel of three human cancer cell lines (HepG-2, HCT-116, and MCF-7) using colchicine as a positive control. Comparing to colchicine (IC50 = 7.40, 9.32, and 10.41 µM against HepG-2, HCT-116, and MCF-7, respectively), compounds 20, 21, 22, 23, 24, 25, 26, and 28 exhibited superior cytotoxic activities with IC50 values ranging from 1.78 to 9.19 µM. In order to sightsee the proposed mechanism of anti-proliferative activity, the most active members were further evaluated in vitro for their inhibitory activities against tubulin polymerisation. Compounds 21 and 32 exhibited the highest tubulin polymerisation inhibitory effect with IC50 values of 9.11 and 10.5 nM, respectively. Such members showed activities higher than that of colchicine (IC50 = 10.6 nM) and CA-4 (IC50 = 13.2 nM). The impact of the most promising compound 25 on cell cycle distribution was assessed. The results revealed that compound 25 can arrest the cell cycle at G2/M phase. Annexin V and PI double staining assay was carried out to explore the apoptotic effect of the synthesised compounds. Compound 25 induced apoptotic effect on HepG-2 thirteen times more than the control cells. To examine the binding pattern of the target compounds against the tubulin heterodimers active site, molecular docking studies were carried out.

Keywords: Cancer; colchicine binding site inhibitors; docking; quinoline; tubulin polymerisation.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Reported colchicine binding site inhibitors.
Figure 2.
Figure 2.
The colchicine binding site having a funnel shape.
Figure 3.
Figure 3.
(A) Seven pharmacophoric features of colchicine binding site inhibitors: three hydrogen bond acceptors (A1, A2 & A3), one hydrogen bond donor (D1), two hydrophobic centres (H1 & H2), and one planar group (R1) (based on Ref.14,44). (B) The pharmacophoric model with two planes: plane A (green) points A1, D1, H1 and R1, Plane B (turquoise) consists of points A2, A3, and H2, and (based on Ref.39,44).
Figure 4.
Figure 4.
Pharmacophoric points of colchicine and podophyllotoxin as CBSIs.
Figure 5.
Figure 5.
Representative examples of the newly synthesised compounds having the same essential pharmacophoric features of the CBSIs.
Figure 6.
Figure 6.
Summary for all chemical modifications.
Figure 7.
Figure 7.
Rational of molecular design of the new proposed CBSIs.
Scheme 1. Synthesis of the target compounds 5–7.
Scheme 1. Synthesis of the target compounds 5–7.
Scheme 2. Synthesis of the target compounds 8–25.
Scheme 2. Synthesis of the target compounds 8–25.
Scheme 3. Synthesis of the target compounds 26–34.
Scheme 3. Synthesis of the target compounds 26–34.
Figure 8.
Figure 8.
HepG-2 cells distribution upon treatment with compound 25.
Figure 9.
Figure 9.
Induced apoptosis on HepG-2 cells by compound 25.
Figure 10.
Figure 10.
(A) 3D structure of co-crystallised ligand, DAMA-colchicine, docked into the colchicine binding site (B) 2D structure of co-crystallised ligand, DAMA-colchicine, docked into the colchicine binding site.
Figure 11.
Figure 11.
(A) 3D structure of compound 19 docked into the colchicine binding site (B) 2D structure of compound 19 docked into the colchicine binding site.
Figure 12.
Figure 12.
(A) 3D structure of compound 25 docked into the colchicine binding site (B) 2D structure of compound 25 docked into the colchicine binding site.
Figure 13.
Figure 13.
(A) 3D structure of compound 28 docked into the colchicine binding site (B) 2D structure of compound 28 docked into the colchicine binding site.
Figure 14.
Figure 14.
Structure-activity relationship of the synthesised compounds as anti-proliferative agents.
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