2-Methoxydiol derivatives as new tubulin and HDAC dual-targeting inhibitors, displaying antitumor and antiangiogenic response
Copyright © 2022 Elsevier Inc. All rights reserved..
Multi-target drugs design has become an active research field because of their advantages in cancer treatment. In present study, HDAC inhibitors pharmacophore and 2-methoxyestradiol(2ME2) were combined into a new hybrid molecule for the first time. Forty-seven 2ME2 derivatives were synthesized and evaluated for antiproliferative activity. In particular, compound 4s exhibited a dual inhibition of tubulin polymerization and HDAC (IC50 = 0.06 µM toward HDAC2) activity, as well as the most potent cytotoxicity IC50 values of 0.37-4.84 µM against six cancer cell lines. Compound 4s remarkably disrupted microtubule networks, arrested cell cycle at G2/M phase, induced mitochondrial membrane potential collapse and eventually apoptosis in A549 cells. Notably, 4s was discovered to potently imped the tube-formation of HUVECs and prohibited the proliferation, migration, and invasion of HUVECs, as well as A549 cells. In addition, the anti-angiogenic and anti-metastasis activities were demonstrated via a zebrafish model test. All these beneficial anticancer activities together with its high selectivity toward noncancer cells, suggested 4s may deserves consideration for cancer therapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:120 |
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| Enthalten in: |
Bioorganic chemistry - 120(2022) vom: 15. März, Seite 105625 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sun, Moran [VerfasserIn] |
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| Links: |
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| Themen: |
2-Methoxyestradiol |
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| Anmerkungen: |
Date Completed 13.06.2022 Date Revised 30.06.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bioorg.2022.105625 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM336124961 |
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| 520 | |a Copyright © 2022 Elsevier Inc. All rights reserved. | ||
| 520 | |a Multi-target drugs design has become an active research field because of their advantages in cancer treatment. In present study, HDAC inhibitors pharmacophore and 2-methoxyestradiol(2ME2) were combined into a new hybrid molecule for the first time. Forty-seven 2ME2 derivatives were synthesized and evaluated for antiproliferative activity. In particular, compound 4s exhibited a dual inhibition of tubulin polymerization and HDAC (IC50 = 0.06 µM toward HDAC2) activity, as well as the most potent cytotoxicity IC50 values of 0.37-4.84 µM against six cancer cell lines. Compound 4s remarkably disrupted microtubule networks, arrested cell cycle at G2/M phase, induced mitochondrial membrane potential collapse and eventually apoptosis in A549 cells. Notably, 4s was discovered to potently imped the tube-formation of HUVECs and prohibited the proliferation, migration, and invasion of HUVECs, as well as A549 cells. In addition, the anti-angiogenic and anti-metastasis activities were demonstrated via a zebrafish model test. All these beneficial anticancer activities together with its high selectivity toward noncancer cells, suggested 4s may deserves consideration for cancer therapy | ||
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| 700 | 1 | |a Zhang, Yixin |e verfasserin |4 aut | |
| 700 | 1 | |a Ba, Mengyu |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Duan, Yongtao |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Yongfang |e verfasserin |4 aut | |
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