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Published on: February 9, 2021
1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological
Ahmed E Elsawi1, Mai I Shahin2, Hager A Elbendary3
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
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.
Insights
Novel indolin-2-one-triazole hybrids were synthesized to target vascular endothelial growth factor receptor 2 (VEGFR-2) for pancreatic and hepatocellular cancers. Compound 11d showed potent VEGFR-2 inhibition and promising anti-cancer activity.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) signaling is crucial in pancreatic and hepatocellular cancers.
- Sunitinib, an FDA-approved drug, targets VEGFR-2, highlighting its therapeutic potential.
Purpose of the Study:
- Design and synthesize novel indolin-2-one-triazole hybrids as potential anti-cancer agents.
- Evaluate the VEGFR-2 inhibitory activity and anti-cancer efficacy of these novel compounds.
- Conduct structure-activity relationship (SAR) studies to optimize anti-cancer properties.
Main Methods:
- Synthesis of indolin-2-one-triazole hybrids.
- In vitro anti-cancer activity assessment against PANC1 and HepG2 cell lines (IC50 determination).
- VEGFR-2 inhibitory activity evaluation (IC50 determination) for potent analogs.
- In silico ADME studies and molecular docking simulations.
Main Results:
- Synthesized compounds exhibited anti-cancer activity with IC50 values ranging from 0.17 to 4.49 µM.
- Potent analogs (11d, 11e, 11g, 11k, 14c) demonstrated significant VEGFR-2 inhibition (IC50: 16.3–119.6 nM), with compound 11d being the most active.
- In silico studies confirmed drug-likeness and strong binding of compound 11d to the VEGFR-2 ATP binding site.
Conclusions:
- Novel indolin-2-one-triazole hybrids show promising anti-cancer potential against pancreatic and hepatocellular cancers by inhibiting VEGFR-2.
- Compound 11d emerged as a potent VEGFR-2 inhibitor with favorable drug-like properties, warranting further investigation.
