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Design, Synthesis, Molecular Modeling, and Anticancer Evaluation of New VEGFR-2 Inhibitors Based on the Indolin-2-One Scaffold.

التفاصيل البيبلوغرافية
العنوان: Design, Synthesis, Molecular Modeling, and Anticancer Evaluation of New VEGFR-2 Inhibitors Based on the Indolin-2-One Scaffold.
المؤلفون: Abdelgawad MA; Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Aljouf 72341, Saudi Arabia., Hayallah AM; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Sphinx University, New Assiut 71515, Egypt., Bukhari SNA; Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Aljouf 72341, Saudi Arabia., Musa A; Department of Pharmacognosy, College of Pharmacy, Jouf University, Aljouf 72341, Saudi Arabia., Elmowafy M; Department of Pharmaceutics, College of Pharmacy, Jouf University, Aljouf 72341, Saudi Arabia., Abdel-Rahman HM; Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr University, Assiut 2014101, Egypt., Abd El-Gaber MK; Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
المصدر: Pharmaceuticals (Basel, Switzerland) [Pharmaceuticals (Basel)] 2022 Nov 15; Vol. 15 (11). Date of Electronic Publication: 2022 Nov 15.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101238453 Publication Model: Electronic Cited Medium: Print ISSN: 1424-8247 (Print) Linking ISSN: 14248247 NLM ISO Abbreviation: Pharmaceuticals (Basel) Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, c2004-
مستخلص: A new series of indoline-2-one derivatives was designed and synthesized based on the essential pharmacophoric features of VEGFR-2 inhibitors. Anti-proliferative activities were assessed for all derivatives against breast (MCF-7) and liver (HepG2) cancer cell lines, using sunitinib as a reference agent. The most potent anti-proliferative derivatives were evaluated for their VEGFR-2 inhibition activity. The effects of the most potent inhibitor, 17a , on cell cycle, apoptosis, and expression of apoptotic markers (caspase-3&-9, BAX, and Bcl-2) were studied. Molecular modeling studies, such as docking simulations, physicochemical properties prediction, and pharmacokinetic profiling were performed. The results revealed that derivatives 5b , 10e , 10g , 15a , and 17a exhibited potent anticancer activities with IC 50 values from 0.74-4.62 µM against MCF-7 cell line (sunitinib IC 50 = 4.77 µM) and from 1.13-8.81 µM against HepG2 cell line (sunitinib IC 50 = 2.23 µM). Furthermore, these compounds displayed potent VEGFR-2 inhibitory activities with IC 50 values of 0.160, 0.358, 0.087, 0.180, and 0.078 µM, respectively (sunitinib IC 50 = 0.139 µM). Cell cycle analysis demonstrated the ability of 17a to induce a cell cycle arrest of the HepG2 cells at the S phase and increase the total apoptosis by 3.5-fold. Moreover, 17a upregulated the expression levels of apoptotic markers caspase-3 and -9 by 6.9-fold and 3.7-fold, respectively. In addition, 17a increased the expression level of BAX by 2.7-fold while decreasing the expression level of Bcl-2 by 1.9-fold. The molecular docking simulations displayed enhanced binding interactions and similar placement as sunitinib inside the active pocket of VEGFR-2. The molecular modeling calculations showed that all the test compounds were in accordance with Lipinski and Veber rules for oral bioavailability and had promising drug-likeness behavior.
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معلومات مُعتمدة: Research Group (DSR-2022-RG-0147). Al Jouf University
فهرسة مساهمة: Keywords: VEGFR-2 inhibitors; anti-proliferative; apoptosis; docking; indolin-2-one; isatin; sunitinib
تواريخ الأحداث: Date Created: 20221124 Latest Revision: 20221129
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC9698773
DOI: 10.3390/ph15111416
PMID: 36422546
قاعدة البيانات: MEDLINE
الوصف
تدمد:1424-8247
DOI:10.3390/ph15111416