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Tytuł:
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Effects of substituent pattern on the intracellular target of antiproliferative benzo[b]thiophenyl chromone derivatives.
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Autorzy:
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Saito Y; School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
Taniguchi Y; School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
Hirazawa S; School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
Miura Y; School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
Tsurimoto H; School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
Nakayoshi T; Graduate School of Pharmacy, Meijo University, Tempaku-ku, Nagoya, 468-8503, Japan.
Oda A; Graduate School of Pharmacy, Meijo University, Tempaku-ku, Nagoya, 468-8503, Japan.
Hamel E; Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, 21702, United States.
Yamashita K; School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
Goto M; Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, United States. Electronic address: .
Nakagawa-Goto K; School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan; Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, United States. Electronic address: .
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Źródło:
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European journal of medicinal chemistry [Eur J Med Chem] 2021 Oct 15; Vol. 222, pp. 113578. Date of Electronic Publication: 2021 May 25.
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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: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
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MeSH Terms:
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Antineoplastic Agents/*pharmacology
Chromones/*pharmacology
Thiophenes/*pharmacology
Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Cell Proliferation/drug effects ; Chromones/chemical synthesis ; Chromones/chemistry ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Models, Molecular ; Molecular Structure ; Structure-Activity Relationship ; Thiophenes/chemical synthesis ; Thiophenes/chemistry ; Tumor Cells, Cultured
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Contributed Indexing:
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Keywords: Antiproliferative activity; Benzothiophene; Flavone; Flavonol; Topoisomerase I; Tubulin
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Substance Nomenclature:
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0 (Antineoplastic Agents)
0 (Chromones)
0 (Thiophenes)
073790YQ2G (benzothiophene)
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Entry Date(s):
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Date Created: 20210625 Date Completed: 20210831 Latest Revision: 20210831
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Update Code:
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20240105
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DOI:
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10.1016/j.ejmech.2021.113578
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PMID:
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34171512
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A new biological scaffold was produced by replacing the 6π-electron phenyl ring-B of a natural flavone skeleton with a 10π-electron benzothiophene (BT). Since aromatic rings are important for ligand protein interactions, this expansion of the π-electron system of ring-B might change the bioactivity profile. One of the resulting novel natural product-inspired compounds, 2-(benzo[b]thiophen-3-yl)-5-hydroxy-7-isopropoxy-6-methoxyflavone (6), effectively arrested the cell cycle at the G2/M phase and displayed significant antiproliferative effects with IC 50 values of 0.05-0.08 μM against multiple human tumor cell lines, including a multidrug resistant line. A structure-activity relationship study revealed that a 10π-electron system with high aromaticity, juxtaposed 4-oxo and 5-hydroxy groups, and 7-alkoxy groups were important for potent antimitotic activity. Interestingly, two BT-flavonols (3-hydroxyflavone), 16 and 20, with 3-hydroxy and 5-alkoxy groups, induced distinct biological profiles affecting the cell cycle at the G1/S phase by inhibition of DNA replication through an interaction with topoisomerase I.
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 © 2021. Published by Elsevier Masson SAS.)
