Structure-based approaches for the design of 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d][1,2,3]triazoles as tubulin polymerization inhibitors
Copyright © 2024 Elsevier Masson SAS. All rights reserved..
The colchicine binding site on tubulin has been widely acknowledged as an attractive target for anticancer drug exploitation. Here, we reported the structural optimization of the lead compound 4, which was proved in our previous work as a colchicine binding site inhibitor (CBSI). Based on docking researches for the active binding conformation of compound 4, a series of novel 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d][1,2,3]triazole derivatives (9a-9x) were developed by replacing a CH group in the 1H-benzo[d]imidazole skeleton of compound 4 with a nitrogen atom as a hydrogen bond acceptor. Among them, compound 9a showed the strongest antiproliferative activity with IC50 values ranging from 14 to 45 nM against three human cancer cell lines (MCF-7, SGC-7901 and A549), lower than that of compound 4. Mechanistic studies indicated that compound 9a could inhibit tubulin polymerization, destroy the microtubule skeleton, block the cell cycle in G2/M phase, induce cancer cell apoptosis, prevent cancer cell migration and colony formation. Moreover, compound 9a significantly inhibited tumor growth in vivo without observable toxicity in the mice 4T1 xenograft tumor model. In conclusion, this report shows a successful case of the structure-based design approach of a potent tubulin polymerization inhibitor for cancer treatment.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:269 |
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| Enthalten in: |
European journal of medicinal chemistry - 269(2024) vom: 05. Apr., Seite 116309 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huang, Mingxin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.04.2024 Date Revised 08.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2024.116309 |
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| Förderinstitution / Projekttitel: |
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| 520 | |a The colchicine binding site on tubulin has been widely acknowledged as an attractive target for anticancer drug exploitation. Here, we reported the structural optimization of the lead compound 4, which was proved in our previous work as a colchicine binding site inhibitor (CBSI). Based on docking researches for the active binding conformation of compound 4, a series of novel 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d][1,2,3]triazole derivatives (9a-9x) were developed by replacing a CH group in the 1H-benzo[d]imidazole skeleton of compound 4 with a nitrogen atom as a hydrogen bond acceptor. Among them, compound 9a showed the strongest antiproliferative activity with IC50 values ranging from 14 to 45 nM against three human cancer cell lines (MCF-7, SGC-7901 and A549), lower than that of compound 4. Mechanistic studies indicated that compound 9a could inhibit tubulin polymerization, destroy the microtubule skeleton, block the cell cycle in G2/M phase, induce cancer cell apoptosis, prevent cancer cell migration and colony formation. Moreover, compound 9a significantly inhibited tumor growth in vivo without observable toxicity in the mice 4T1 xenograft tumor model. In conclusion, this report shows a successful case of the structure-based design approach of a potent tubulin polymerization inhibitor for cancer treatment | ||
| 650 | 4 | |a Case Reports | |
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| 650 | 4 | |a 1H-benzo[d][1,2,3]triazole | |
| 650 | 4 | |a Colchicine binding site | |
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| 650 | 4 | |a Structure-based design approach | |
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| 700 | 1 | |a Liu, Haoyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Runlai |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Mi |e verfasserin |4 aut | |
| 700 | 1 | |a Guan, Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Weige |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Dun |e verfasserin |4 aut | |
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