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

التفاصيل البيبلوغرافية
العنوان: Novel VEGFR-2 inhibitors as antiangiogenic and apoptotic agents via paracrine and autocrine cascades: Design, synthesis, and biological evaluation.
المؤلفون: Abdel Rahman DE; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt., Fouad MA; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt; Pharmaceutical Chemistry Department, School of Pharmacy, New Giza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt., Mohammed ER; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt., El-Zoheiry HH; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt. Electronic address: haidi.abdelhamid@pharma.cu.edu.eg., Abdelrasheed Allam H; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt.
المصدر: Bioorganic chemistry [Bioorg Chem] 2023 Oct; Vol. 139, pp. 106678. Date of Electronic Publication: 2023 Jun 16.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Amsterdam : Elsevier
Original Publication: New York, London, Academic Press.
مواضيع طبية MeSH: Antineoplastic Agents*/chemistry, Cell Proliferation ; Drug Design ; Drug Screening Assays, Antitumor ; Molecular Docking Simulation ; Molecular Structure ; Protein Kinase Inhibitors ; Sorafenib/pharmacology ; Structure-Activity Relationship ; Vascular Endothelial Growth Factor Receptor-2
مستخلص: 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 IC 50 values from 49.1 to 418.0 nM relative to the reference drug sorafenib (IC 50  = 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 (IC 50 values = 11.5 and 12.3 nM, respectively) in comparison to sorafenib (IC 50  = 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
فهرسة مساهمة: Keywords: Angiogenesis; Anticancer; Apoptosis; Autocrine; Paracrine; Pyridazinone; VEGFR-2
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Protein Kinase Inhibitors)
9ZOQ3TZI87 (Sorafenib)
EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
EC 2.7.10.1 (KDR protein, human)
تواريخ الأحداث: Date Created: 20230624 Date Completed: 20230814 Latest Revision: 20230814
رمز التحديث: 20240829
DOI: 10.1016/j.bioorg.2023.106678
PMID: 37354661
قاعدة البيانات: MEDLINE
الوصف
تدمد:1090-2120
DOI:10.1016/j.bioorg.2023.106678