Novel VEGFR-2 inhibitors as antiangiogenic and apoptotic agents via paracrine and autocrine cascades: Design, synthesis, and biological evaluation

• Published in: Bioorganic chemistry 2023-10, Vol.139, p.106678-106678, Article 106678
• Main Authors: Abdel Rahman, Doaa E., Fouad, Marwa A., Mohammed, Eman R., El-Zoheiry, Haidy H., Abdelrasheed Allam, Heba
• Format: Article
• Language: English
• Subjects: Angiogenesis; Anticancer; Apoptosis; Autocrine; Paracrine; Pyridazinone; VEGFR-2
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106678

[Display omitted] •VEGFs proof angiogenic and antiapoptotic effects via paracrine and autocrine loops.•Phenylpyridazinone based VEGFR-2 inhibitors were optimized from sorafenib.•Compounds 12c and 13a showed excellent antiproliferative effect against HUVECs.•Compounds 12c and 13a revealed increase in apoptosis and necrosis percentages.•Compounds 12c and 13a distinctly inhibit cells in invasion and migration assays. Appertaining to its paracrine and autocrine signaling loops, VEGFR-2 succeeded in grabbing attention as one of the leading targets in cancer treatment. Based on the foregoing and our comprehensive studies regarding pharmacophoric features and activity of sorafenib, novel phenylpyridazinone based VEGFR-2 inhibitors 4, 6a-e, 7a,b, 9a,b, 12a-c, 13a,b, 14a,b, 15a,b, and 17a-d were optimized. An assortment of biological assays was conducted to assess the antiangiogenic and apoptotic activities of the synthesized derivatives. In vitro VEGFR-2 kinase assay verified the inhibitory activity of the synthesized derivatives with IC50 values from 49.1 to 418.0 nM relative to the reference drug sorafenib (IC50 = 81.8 nM). Antiproliferative activity against HUVECs revealed that compounds 2-{2-[2-(6-oxo-3-phenylpyridazin-1(6H)-yl)acetyl]hydrazineyl}-N-(p-tolyl)acetamide (12c) and 2-[(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-phenylpyridazin-3(2H)-one (13a) possessed superior activity (IC50 values = 11.5 and 12.3 nM, respectively) in comparison to sorafenib (IC50 = 23.2 nM). For the purpose of appraising their antiproliferative effect, derivatives 12c and 13a were exposed to cell cycle analysis, apoptotic, cell invasion and migration assays in addition to determination of VEGFR-2 in protein level. Moreover, cytotoxicity as well as selectivity index against WI-38 cell line was measured to examine safety of derivatives 12c and 13a. After that, molecular docking study was executed on the top five compounds in the in vitro VEGFR-2 kinase assay 6d, 12c, 13a, 14a and 17c to get a deep perception on binding mode of the synthesized compounds and correlate the design strategy with biological results. Finally, physicochemical, pharmacokinetic properties, and drug-likeness studies were performed on the top five derivative in in vitro VEGFR-2 kinase assay.