Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jan 8;17(1):81.
doi: 10.3390/ph17010081.

1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking

Ahmed E Elsawi  1 , Mai I Shahin  2 , Hager A Elbendary  3 , Tarfah Al-Warhi  4 , Fatma E Hassan  5   6 , Wagdy M Eldehna  1
Affiliations

1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking

Ahmed E Elsawi et al. Pharmaceuticals (Basel). .

Abstract

Targeting the VEGFR-2 signaling pathway is an inveterate approach toward combating pancreatic and hepatocellular cancers. Based on Sunitinib, the FDA-approved VEGFR-2 inhibitor, novel indolin-2-one-triazole hybrids were designed and synthesized as anti-hepatocellular and anti-pancreatic cancer agents with VEGFR-2 inhibitory activity. All the targeted compounds were assessed for their anti-cancer activity, revealing IC50 values extending from 0.17 to 4.29 µM for PANC1 and 0.58 to 4.49 µM for HepG2 cell lines. An extensive SAR study was conducted to explore the effect of different substituents along with N-alkylation. The potent anti-cancer analogs 11d, 11e, 11g, 11k and 14c were evaluated for their VEGFR-2 inhibitory actions, where their IC50 values ranged from 16.3 to 119.6 nM compared to Sorafenib, which revealed an IC50 of 29.7 nM, having compound 11d as the most active analog. An in silico ADME study was performed to confirm the drug-likeness of the synthesized compounds. Finally, molecular docking simulation was conducted for the most potent VEGFR-2 inhibitor (11d), demonstrating the strong binding with the vital amino acid residues of the VEGFR-2 ATP binding site.

Keywords: angiogenesis; anti-cancer agents; molecular modeling; synthesis; tail approach.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of potent chemotherapeutic agents with significant VEGFR-2 inhibitory activity encompassing indolin-2-one (in red) or 1,2,4 triazole heterocycles (in blue).
Figure 2
Figure 2
Rational design of the targeted molecules based on Sunitinib interactions with VEGFR-2 receptor.
Scheme 1
Scheme 1
Synthesis of key hydrazide intermediates 9a–b. Reagents and conditions: (i) aq. NaOH, stirring, room temperature, 1 h. (ii) Methanol, Pd/C, room temperature, 3 h. (iii) Acetic anhydride, heating 75 °C, 40 min. (iv) HCl, NaNO2, stirring, 0–5 °C, 20 min. (v) Sodium acetate, stirring, 0–10 °C, 3 h. (vi) Ethanol, NH2NH2·H2O 90%, reflux, 1 h.
Scheme 2
Scheme 2
Synthesis of target 1,5-diaryl substituted triazole-indolin-2-one hybrids 11a–l. Reagents and conditions: (i) ethanol, acetic acid, reflux, 2 h.
Scheme 3
Scheme 3
Synthesis of target 1,5-diaryl substituted triazole-indolin-2-one hybrids 14a–d. Reagents and conditions: (i) acetonitrile, potassium carbonate, stirring, room temperature, 18 h. (ii) Ethanol, acetic acid, reflux, 2 h.
Figure 3
Figure 3
BOILED-Egg plot of the synthesized compounds.
Figure 4
Figure 4
Superimposition of the co-crystallized ligand. Sorafenib (orange) and the docked pose (violet) of VEGFR-2.
Figure 5
Figure 5
Binding of 11d with VEGFR-2, showing the whole protein and 11d located in the active site.
Figure 6
Figure 6
Docking representation of 11d within the active site of VEGFR-2 (A) 2D schematic presentation and (B) active site display.
Figure 7
Figure 7
RMSD analysis for the MDSs against VEGFR-2 enzyme for 100 ns.
Figure 8
Figure 8
RMSF analysis for the MDSs against VEGFR-2 enzyme for 100 ns.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Risau W. Mechanisms of angiogenesis. Nature. 1997;386:671–674. doi: 10.1038/386671a0. - DOI - PubMed
    1. Liu Z.-L., Chen H.-H., Zheng L.-L., Sun L.-P., Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct. Target. Ther. 2023;8:198. doi: 10.1038/s41392-023-01460-1. - DOI - PMC - PubMed
    1. Nishida N., Yano H., Nishida T., Kamura T., Kojiro M. Angiogenesis in Cancer. Vasc. Health Risk Manag. 2006;2:213–219. doi: 10.2147/vhrm.2006.2.3.213. - DOI - PMC - PubMed
    1. Ansari M., Bokov D., Markov A., Jalil A., Shalaby M., Suksatan W., Chupradit S., Al-Ghamdi H., Shomali N., Zamani A., et al. Cancer combination therapies by angiogenesis inhibitors; a comprehensive review. Cell Commun. Signal. 2022;20:49. doi: 10.1186/s12964-022-00838-y. - DOI - PMC - PubMed
    1. Patel S.A., Nilsson M.B., Le X., Cascone T., Jain R.K., Heymach J.V. Molecular Mechanisms and Future Implications of VEGF/VEGFR in Cancer Therapy. Clin. Cancer Res. 2023;29:30–39. doi: 10.1158/1078-0432.CCR-22-1366. - DOI - PMC - PubMed

LinkOut - more resources