Discovery of 1,2-diphenylethene derivatives as human DNA topoisomerase II catalytic inhibitors and antitumor agents

Xu, Guangsen; Li, Zhiying; Ding, Yanjiao; Shen, Yuemao

doi:10.1016/j.ejmech.2022.114706

Cited by 6 publications

(2 citation statements)

References 49 publications

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“…In eukaryotic cells and according to its mechanism of action, topoisomerase is classified into topoisomerase I (Topo I) and II (Topo II) 6 , 8 . It has been found that mammalian Topo II worked through two different modes of action and thus categorised into: (a) topo II poisons and (b) topo II catalytic inhibitors; 9 (a) topo II poisons irreversibly bind to DNA-protein complex via covalent bonds and induce DNA double strand breaks (DSBs) which finally results in an apoptotic fate 2 , 10 . The second class is (b) catalytic inhibitors which act by binding non-covalently to the Topo II protein complex, preventing Topo II from binding to DNA or to ATP 11 .…”

Section: Introductionmentioning

confidence: 99%

New imidazole-2-thiones linked to acenaphythylenone as dual DNA intercalators and topoisomerase II inhibitors: structural optimization, docking, and apoptosis studies

Mohamed,

Alshammari,

Aly

et al. 2024

Journal of Enzyme Inhibition and Medicinal Chemistry

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In this article, a new series of 2-((3,5-disubstituted-2-thioxo-imidazol-1-yl)imino)acenaphthylen-1(2 H )-ones were synthesized. Imidazole-2-thione with acenaphthylen-one gave a hybrid scaffold that integrated key structural elements essential for DNA damage via direct DNA intercalation and inhibition of the topoisomerase II enzyme. All the synthesized compounds were screened to detect their DNA damage using a terbium fluorescent probe. Results demonstrated that 4-phenyl-imidazoles 5b and 5e in addition to 4-(4-chlorophenyl)imidazoles 5h and 5j would induce detectable potent damage in ctDNA. The four most potent compounds as DNA intercalators were further evaluated for their antiproliferative activity against HepG2, MCF-7 and HCT-116 utilizing the MTT assay. The highest anticancer activity was recorded with compounds 5b and 5h against the breast cancer cell line MCF-7 which were 1.5- and 3- folds more active than doxorubicin , respectively. Therefore, imidazole-2-thione tethered acenaphthylenone derivatives can be considered as promising scaffold for the development of effective dual DNA intercalators and topoisomerase II inhibitors.

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Section: Introductionmentioning

confidence: 99%

New imidazole-2-thiones linked to acenaphythylenone as dual DNA intercalators and topoisomerase II inhibitors: structural optimization, docking, and apoptosis studies

Mohamed,

Alshammari,

Aly

et al. 2024

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…This process does not induce DNA cleavage, and thus does not trigger the DNA repair system. In principle, these inhibitors have lower toxicity and fewer side effects, and have become a research hotspot in recent years in the field of Topo II inhibitors [ 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

MSN8C: A Promising Candidate for Antitumor Applications as a Novel Catalytic Inhibitor of Topoisomerase II

Huang

Liu

et al. 2023

Molecules

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MSN8C, an analog of mansonone E, has been identified as a novel catalytic inhibitor of human DNA topoisomerase II that induces tumor regression and differs from VP-16(etoposide). Treatment with MSN8C showed significant antiproliferative activity against eleven human tumor cell lines in vitro. It was particularly effective against the HL-60/MX2 cell line, which is resistant to Topo II poisons. The resistance factor (RF) of MSN8C for Topo II in HL-60/MX2 versus HL-60 was 1.7, much lower than that of traditional Topo II poisons. Furthermore, in light of its potent antitumor efficacy and low toxicity, as demonstrated in the A549 tumor xenograft model, MSN8C has been identified as a promising candidate for antitumor applications.

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Synthesis of 2‐phenylnaphthalenoid amide derivatives and their topoisomerase IIα inhibitory and antiproliferative activities

Wu,

Xu,

et al. 2024

Archiv der Pharmazie

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Topoisomerases are highly associated with cell proliferation, becoming an important target for the development of antitumor drugs. 2‐Phenylnaphthalenoids (2PNs) have been identified as human DNA topoisomerase IIα (TopoIIα) inhibitors. In this study, based on the 2PN scaffold, 20 amide derivatives (J1–J10, K1–K10) were synthesized. Among them, K10 showed high TopoIIα inhibitory activity and stronger antiproliferation activity against HepG‐2 and MDA‐MB‐231 cells (IC50 0.33 and 0.63 μM, respectively) than the positive control VP‐16 (IC50 9.19 and 10.86 μM) and the lead F2 (IC50 0.64 and 1.51 μM). Meanwhile, K10 could also inhibit migration and promote apoptosis of HepG‐2 and MDA‐MB‐231 cells. Therefore, K10 can be developed into a potent TopoIIα inhibitor as an antitumor agent. The structure–activity relationship was also discussed.

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Discovery of 1,2-diphenylethene derivatives as human DNA topoisomerase II catalytic inhibitors and antitumor agents

Cited by 6 publications

References 49 publications

New imidazole-2-thiones linked to acenaphythylenone as dual DNA intercalators and topoisomerase II inhibitors: structural optimization, docking, and apoptosis studies

New imidazole-2-thiones linked to acenaphythylenone as dual DNA intercalators and topoisomerase II inhibitors: structural optimization, docking, and apoptosis studies

MSN8C: A Promising Candidate for Antitumor Applications as a Novel Catalytic Inhibitor of Topoisomerase II

Synthesis of 2‐phenylnaphthalenoid amide derivatives and their topoisomerase IIα inhibitory and antiproliferative activities

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