Design and synthesis of antiproliferative 2-oxoindolin-3-ylidenes incorporating urea function with potential VEGFR-2
Dalia R Aboshouk1, M Adel Youssef2, Siva S Panda3
1Department of Pesticide Chemistry, National Research Centre, Dokki, 12622, Giza, Egypt.
Abstract:
Targeted therapy is preferable over other therapeutics due to its limitation of drawbacks and better pharmaceutical outcomes. VEGF and its receptors have been observed to be hyper-activated in many cancer types and are considered promising targets for assigning anticancer agents. The current study is directed towards synthesis of novel antiproliferative 2-oxoindolin-3-ylidenes incorporating urea function with VEGFR-2 properties. The targeted agents were obtained through a two-step reaction. Addition of the appropriate 1-(acetylphenyl)-3-phenylurea 9a,b to the corresponding isatin 10a-f in ethanol containing a quantitative amount of Et2NH followed by acidic dehydration (AcOH/HCl) afforded the targeted agents 12a-j. Promising antiproliferation properties (MTT assay) were observed for most of the synthesized agents against HCT116 (colon), MCF7 (breast) and PaCa2 (pancreatic) cancer cell lines relative to sunitinib. VEGFR-2 inhibitory properties are consistent with the antiproliferation properties exhibited against the tested cell lines. Compound 12b (R = 4-NHCONHPh, R' = H; % inhibition = 87.2) is the most promising/potent anti-VEGFR-2 agent synthesized with activity close to that of sunitinib (% inhibition = 89.4) at 10 μM. Molecular docking studies (PDB: 3WZE and 3AGD) support the antiproliferation effects against cancer cell lines tested with VEGFR-2 inhibitory properties. The results are consistent with collaboration of the pharmacophores considered (2-oxoindolyl heterocycle and urea) in improving the bio-properties.
Insights
Researchers synthesized novel urea-containing compounds targeting vascular endothelial growth factor receptor 2 (VEGFR-2) for cancer therapy. Compound 12b demonstrated potent antiproliferative activity against colon, breast, and pancreatic cancer cells, comparable to sunitinib.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Pharmacology
Background:
- Targeted cancer therapies offer advantages over traditional treatments.
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is a key target in various cancers.
- Novel antiproliferative agents are needed to overcome therapeutic limitations.
Purpose of the Study:
- To synthesize novel 2-oxoindolin-3-ylidenes incorporating a urea moiety.
- To evaluate the antiproliferative and VEGFR-2 inhibitory properties of these novel compounds.
- To explore structure-activity relationships for potential anticancer drug development.
Main Methods:
- Two-step synthesis involving condensation of substituted ureas with isatins.
- Antiproliferative activity assessed using MTT assays against HCT116, MCF7, and PaCa2 cancer cell lines.
- VEGFR-2 inhibition and molecular docking studies were performed to understand mechanism of action.
Main Results:
- Most synthesized compounds exhibited promising antiproliferative activity.
- Compound 12b showed significant inhibition of VEGFR-2 (87.2%), comparable to sunitinib (89.4%).
- Molecular docking supported the observed antiproliferation and VEGFR-2 inhibitory effects.
Conclusions:
- The synthesized urea-containing 2-oxoindolin-3-ylidenes are potent antiproliferative agents.
- Compound 12b is a promising candidate for further development as an anti-VEGFR-2 anticancer drug.
- The combination of 2-oxoindolyl heterocycle and urea pharmacophores enhances bio-properties.
