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

• Published in: Scientific reports 2025-01, Vol.15 (1), p.618-14, Article 618
• Main Authors: Aboshouk, Dalia R., Youssef, M. Adel, Panda, Siva S., Kariuki, Benson M., Bekheit, Mohamed S., Hamed, Ahmed R., Fayad, Walid, Soliman, Ahmed A. F., Girgis, Adel S.
• Format: Article
• Language: English
• Subjects: 2-Oxoindolin-3-ylidenes; 631/67; 631/67/1347; Antineoplastic drugs; Cancer; Dehydration; Ethanol; Humanities and Social Sciences; Molecular modeling; multidisciplinary; Pancreatic cancer; Pharmacophores; Phenylurea; Receptor mechanisms; Science; Science (multidisciplinary); Tumor cell lines; Urea; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; VEGFR-2
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-82005-6

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 Et 2 NH 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.