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

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 agent...

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Published inPharmaceuticals (Basel, Switzerland) Vol. 17; no. 1; p. 81
Main Authors Elsawi, Ahmed E, Shahin, Mai I, Elbendary, Hager A, Al-Warhi, Tarfah, Hassan, Fatma E, Eldehna, Wagdy M
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 01.01.2024
MDPI
Subjects
Amino acids
Angiogenesis
anti-cancer agents
Binding sites
Blood vessels
Cancer
Cells
Clinical trials
Hybridization
Liver cancer
molecular modeling
Pancreatic cancer
Pharmacokinetics
synthesis
tail approach
Triazoles
Tropical diseases
Tumors
Vascular endothelial growth factor
Saudi Arabia
synthesis
tail approach
molecular modeling
angiogenesis
anti-cancer agents
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Summary: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 IC 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 -alkylation. The potent anti-cancer analogs , , , and were evaluated for their VEGFR-2 inhibitory actions, where their IC values ranged from 16.3 to 119.6 nM compared to Sorafenib, which revealed an IC 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 ( ), demonstrating the strong binding with the vital amino acid residues of the VEGFR-2 ATP binding site.
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ISSN:1424-8247
1424-8247
DOI:10.3390/ph17010081