Design and synthesis of antiproliferative 2-oxoindolin-3-ylidenes incorporating urea function with potential VEGFR-2 inhibitory properties

Dalia R Aboshouk; M Adel Youssef; Siva S Panda; Benson M Kariuki; Mohamed S Bekheit; Ahmed R Hamed; Walid Fayad; Ahmed A F Soliman; Adel S Girgis

doi:10.1038/s41598-024-82005-6

Design and synthesis of antiproliferative 2-oxoindolin-3-ylidenes incorporating urea function with potential VEGFR-2 inhibitory properties

Sci Rep. 2025 Jan 3;15(1):618. doi: 10.1038/s41598-024-82005-6.

Authors

Dalia R Aboshouk¹, M Adel Youssef², Siva S Panda³, Benson M Kariuki⁴, Mohamed S Bekheit¹, Ahmed R Hamed⁵, Walid Fayad⁶, Ahmed A F Soliman⁶, Adel S Girgis⁷

Affiliations

¹ Department of Pesticide Chemistry, National Research Centre, Dokki, 12622, Giza, Egypt.
² Department of Chemistry, Faculty of Science, Helwan University, Helwan, Egypt.
³ Department of Chemistry and Biochemistry & Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912, USA.
⁴ School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK.
⁵ Chemistry of Medicinal Plants Department, National Research Centre, Dokki, 12622, Giza, Egypt.
⁶ Drug Bioassay-Cell Culture Laboratory, Pharmacognosy Department, National Research Centre, Dokki, 12622, Giza, Egypt.
⁷ Department of Pesticide Chemistry, National Research Centre, Dokki, 12622, Giza, Egypt. girgisas10@yahoo.com.

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.

Keywords: 2-Oxoindolin-3-ylidenes; Cancer; Molecular modeling; VEGFR-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation* / drug effects
Drug Design*
HCT116 Cells
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology
MCF-7 Cells
Molecular Docking Simulation*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Structure-Activity Relationship
Urea* / analogs & derivatives
Urea* / chemical synthesis
Urea* / chemistry
Urea* / pharmacology
Vascular Endothelial Growth Factor Receptor-2* / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2* / metabolism

Substances

Vascular Endothelial Growth Factor Receptor-2
Urea
Antineoplastic Agents
Indoles
Protein Kinase Inhibitors
KDR protein, human