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. 2022 Sep 3;27(17):5688.
doi: 10.3390/molecules27175688.

New 1,2,3-Triazole-Coumarin-Glycoside Hybrids and Their 1,2,4-Triazolyl Thioglycoside Analogs Targeting Mitochondria Apoptotic Pathway: Synthesis, Anticancer Activity and Docking Simulation

Wael A El-Sayed  1   2 , Fahad M Alminderej  1 , Marwa M Mounier  3 , Eman S Nossier  4 , Sayed M Saleh  1   5 , Asmaa F Kassem  6
Affiliations

New 1,2,3-Triazole-Coumarin-Glycoside Hybrids and Their 1,2,4-Triazolyl Thioglycoside Analogs Targeting Mitochondria Apoptotic Pathway: Synthesis, Anticancer Activity and Docking Simulation

Wael A El-Sayed et al. Molecules. .

Abstract

Toxicity and resistance to newly synthesized anticancer drugs represent a challenging phenomenon of intensified concern arising from variation in drug targets and consequently the prevalence of the latter concern requires further research. The current research reports the design, synthesis, and anticancer activity of new 1,2,3-triazole-coumarin-glycosyl hybrids and their 1,2,4-triazole thioglycosides as well as acyclic analogs. The cytotoxic activity of the synthesized products was studied against a panel of human cancer cell lines. Compounds 8, 10, 16 and 21 resulted in higher activities against different human cancer cells. The impact of the hybrid derivative 10 upon different apoptotic protein markers, including cytochrome c, Bcl-2, Bax, and caspase-7 along with its effect on the cell cycle was investigated. It revealed a mitochondria-apoptotic effect on MCF-7 cells and had the ability to upregulate pro-apoptotic Bax protein and downregulate anti-apoptotic Bcl-2 protein and thus implies the apoptotic fate of the cells. Furthermore, the inhibitory activities against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases for 8, 10 and 21 were studied to detect the mechanism of their high potency. The coumarin-triazole-glycosyl hybrids 8 and 10 illustrated excellent broad inhibitory activity (IC50= 0.22 ± 0.01, 0.93 ± 0.42 and 0.24 ± 0.20 μM, respectively, for compound 8), (IC50 = 0.12 ± 0.50, 0.79 ± 0.14 and 0.15± 0. 60 μM, respectively, for compound 10), in comparison with the reference drugs, erlotinib, sorafenib and roscovitine (IC50 = 0.18 ± 0.05, 1.58 ± 0.11 and 0.46 ± 0.30 μM, respectively). In addition, the docking study was simulated to afford better rationalization and put insight into the binding affinity between the promising derivatives and their targeted enzymes and that might be used as an optimum lead for further modification in the anticancer field.

Keywords: 1,2,3-triazoles; 1,2,4-triazoles; CDK-2; EGFR; anticancer; coumarin; glycosides; molecular docking.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Some reported anticancer agents bearing coumarin, triazole and/or glycoside moieties with various mechanisms.
Figure 2
Figure 2
Design of new coumarin-triazole hybrids expected to possess potent antiproliferative activity through inhibition of EGFR, VEGFR-2 and CDK-2 kinases.
Scheme 1
Scheme 1
Synthesis of 1,2,4-triazole-coumarin hybrid thioglycosides.
Scheme 2
Scheme 2
Synthesis of 1,2,3-triazol-coumarin hybrid glycosides.
Figure 3
Figure 3
In vitro cytotoxic screening (%) of the newly synthesized coumarin derivatives upon normal human cell lines (BJ-1) at 100 µM; each result is a mean of three replicate samples, and values are represented as % inhibition.
Figure 4
Figure 4
Levels of Bax, Bcl-2, Bax/Bcl-2 ratio, cytochrome c and caspase-7 protein in MCF-7 cells after treatment with compound 10 and the standard drug for 24 h compared with the untreated one, 5-flu: 5-fluorouracil as a reference drug.
Figure 4
Figure 4
Levels of Bax, Bcl-2, Bax/Bcl-2 ratio, cytochrome c and caspase-7 protein in MCF-7 cells after treatment with compound 10 and the standard drug for 24 h compared with the untreated one, 5-flu: 5-fluorouracil as a reference drug.
Figure 5
Figure 5
Cell cycle analysis and the effect of the target 10 on the percentage of V-FITC-positive annexin staining in MCF-7 cells in comparison with the control.
Figure 5
Figure 5
Cell cycle analysis and the effect of the target 10 on the percentage of V-FITC-positive annexin staining in MCF-7 cells in comparison with the control.
Figure 6
Figure 6
(A,B) views illustrate the 2D binding features of the coumarin targets, 8 and 10, while (C) view illustrates the 3D superimposition between original ligand erlotinib (red), 8 (green) and 10 (yellow) within the active site of EGFR (PDB code: 1M17), respectively.
Figure 6
Figure 6
(A,B) views illustrate the 2D binding features of the coumarin targets, 8 and 10, while (C) view illustrates the 3D superimposition between original ligand erlotinib (red), 8 (green) and 10 (yellow) within the active site of EGFR (PDB code: 1M17), respectively.
Figure 7
Figure 7
(A,B) views illustrate the 2D binding features of the coumarin targets, 8 and 10, while (C) view illustrates the 3D superimposition between the original ligand sorafenib (red), 8 (green) and 10 (yellow) within the active site of VEGFR-2 (PDB code: 4ASD), respectively.
Figure 7
Figure 7
(A,B) views illustrate the 2D binding features of the coumarin targets, 8 and 10, while (C) view illustrates the 3D superimposition between the original ligand sorafenib (red), 8 (green) and 10 (yellow) within the active site of VEGFR-2 (PDB code: 4ASD), respectively.
Figure 8
Figure 8
(A,B) views illustrate the 2D binding features of the coumarin targets, 8 and 10, while (C) view illustrates the 3D superimposition between the original ligand roscovitine (red), 8 (green) and 10 (yellow) within the active site of CDK-2/cyclin A2 (PDB code: 3DDQ), respectively.
Figure 8
Figure 8
(A,B) views illustrate the 2D binding features of the coumarin targets, 8 and 10, while (C) view illustrates the 3D superimposition between the original ligand roscovitine (red), 8 (green) and 10 (yellow) within the active site of CDK-2/cyclin A2 (PDB code: 3DDQ), respectively.
Figure 8
Figure 8
(A,B) views illustrate the 2D binding features of the coumarin targets, 8 and 10, while (C) view illustrates the 3D superimposition between the original ligand roscovitine (red), 8 (green) and 10 (yellow) within the active site of CDK-2/cyclin A2 (PDB code: 3DDQ), respectively.
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References

    1. An W., Lai H., Zhang Y., Liu M., Lin X., Cao S. Apoptotic pathway as the therapeutic target for anticancer traditional Chinese medicines. Front. Pharmacol. 2019;10:758. doi: 10.3389/fphar.2019.00758. - DOI - PMC - PubMed
    1. Xie L.L., Shi F., Tan Z., Li Y., Bode A.M., Cao Y. Mitochondrial network structure homeostasis and cell death. Cancer Sci. 2018;109:3686–3694. doi: 10.1111/cas.13830. - DOI - PMC - PubMed
    1. Yao X., Cao Y., Lu L., Xu Y., Chen H., Liu C., Tao Z. Plasmodium infection suppresses colon cancer growth by inhibiting proliferation and promoting apoptosis associated with disrupting mitochondrial biogenesis and mitophagy in mice. Parasit. Vectors. 2022;15:192. doi: 10.1186/s13071-022-05291-x. - DOI - PMC - PubMed
    1. Ferlay J., Colombet M., Soerjomataram I., Parkin D.M., Piñeros M., Znaor A., Bray F. Cancer statistics for the year 2020: An overview. Int. J. Cancer. 2021;149:778–789. doi: 10.1002/ijc.33588. - DOI - PubMed
    1. Gerber D.E. Targeted therapies: A new generation of cancer treatments. Am. Fam. Physician. 2008;77:311–319. - PubMed