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Tytuł:
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Design, green synthesis, molecular docking and anticancer evaluations of diazepam bearing sulfonamide moieties as VEGFR-2 inhibitors.
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Autorzy:
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Saleh NM; Department of Chemistry, Faculty of Science, Al-Azhar University (Girls Branch), PO Box 11754, Cairo, Egypt. Electronic address: .
El-Gaby MSA; Department of Chemistry, Faculty of Science, Al-Azhar University at Assiut, Assiut 71524, Egypt.
El-Adl K; Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt. Electronic address: .
Abd El-Sattar NEA; Department of Chemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.
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Źródło:
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Bioorganic chemistry [Bioorg Chem] 2020 Nov; Vol. 104, pp. 104350. Date of Electronic Publication: 2020 Oct 08.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: Amsterdam : Elsevier
Original Publication: New York, London, Academic Press.
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MeSH Terms:
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Drug Design*
Antineoplastic Agents/*pharmacology
Diazepam/*pharmacology
Protein Kinase Inhibitors/*pharmacology
Sulfonamides/*pharmacology
Vascular Endothelial Growth Factor Receptor-2/*antagonists & inhibitors
Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Diazepam/chemical synthesis ; Diazepam/chemistry ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Structure-Activity Relationship ; Sulfonamides/chemistry ; Vascular Endothelial Growth Factor Receptor-2/metabolism
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Contributed Indexing:
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Keywords: Anticancer agents; Benzodiazepines; Molecular docking; Sulfonamide; VEGFR-2 inhibitors
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Substance Nomenclature:
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0 (Antineoplastic Agents)
0 (Protein Kinase Inhibitors)
0 (Sulfonamides)
EC 2.7.10.1 (KDR protein, human)
EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
Q3JTX2Q7TU (Diazepam)
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Entry Date(s):
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Date Created: 20201104 Date Completed: 20210330 Latest Revision: 20210330
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Update Code:
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20240105
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DOI:
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10.1016/j.bioorg.2020.104350
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PMID:
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33142416
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Novel series of diazepam bearing sulfonamide moieties 5 a-f and 7 a-c were designed, synthesized and evaluated for anticancer activity against HepG2, HCT-116 and MCF-7 cell lines. MCF-7 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5 d was found to be the most potent derivative overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC 50 = 8.98 ± 0.1, 7.77 ± 0.1 and 6.99 ± 0.1 µM respectively. Compound 5 d exhibited higher activity than sorafenib, (IC 50 = 9.18 ± 0.6, 5.47 ± 0.3 and 7.26 ± 0.3 µM respectively), against HepG2 and MCF-7 but exhibited lower activity against HCT116 cancer cell lines respectively. Also, this compound displayed lower activity than doxorubicin, (IC 50 = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 µM respectively), against HepG2 and MCF-7 but higher activity against HCT116 cell lines respectively. Compounds 5 b , 5 c , 5 d , 5 e , 5 f and 7 c are respectively, 5.77, 8.58, 9.54, 5.71, 4.68 and 2.31 fold times more toxic in breast cancer cell lines (MCF-7, the most sensitive cells) than in VERO normal cells. All the synthesized compounds 5 a-f and 7 a-c were evaluated for their inhibitory activities against VEGFR-2. Among them, compound 5 d was found to be the most potent derivative that inhibited VEGFR-2 at IC 50 value of 0.10 ± 0.01 µM, which is equipotent to sorafenib IC 50 value (0.10 ± 0.02 µM). Compound 5 c exhibited excellent activity with IC 50 value of 0.12 ± 0.01 µM which nearly equipotent to that of sorafenib. Compounds 5 b , 5 e and 5 f exhibited very good activity with the same IC 50 value of 0.14 ± 0.02 µM. Also, compounds 7 c and 7 b possessed good VEGFR-2 inhibition with IC 50 values of 0.16 ± 0.06 and 0.17 ± 0.06 µM respectively which are more than the half activity of that of sorafenib. The data obtained from docking studies were highly correlated with that obtained from the biological screening.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
