Tetrahydro-β-carboline derivatives as potent histone deacetylase 6 inhibitors with broad-spectrum antiproliferative activity
Copyright © 2023 Elsevier Masson SAS. All rights reserved..
A series of tetrahydro-β-carboline (THβC)-based hydroxamic acids were rationally designed and synthesized as novel selective HDAC6 inhibitors (sHDAC6is) by the application of scaffold hopping strategy. Several THβC analogues were highly potent (IC50 < 5 nM) and selective against HDAC6 enzyme and exhibited good antiproliferative activity against human multiple myeloma (MM) cell. Molecular docking interpreted the structure activity relationship (SAR). Target engagement of HDAC6 was confirmed in RPMI-8226 cells using the WB assay. In vitro, (1S, 3R)-1-(4-chlorophenyl)-N-(4-(hydroxycarbamoyl)benzyl)-2,3,4,9-tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxamide (14g) showed potent broad antiproliferative activity against various tumors including leukemia, colon cancer, melanoma, and breast cancer cell lines, better than ACY-1215. Moreover, 14g also showed good pharmacokinetics properties in mice via oral administration.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:260 |
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| Enthalten in: |
European journal of medicinal chemistry - 260(2023) vom: 15. Nov., Seite 115776 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Xin [VerfasserIn] |
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| Links: |
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| Themen: |
65027TMI0H |
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| Anmerkungen: |
Date Completed 18.09.2023 Date Revised 18.09.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2023.115776 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM361582056 |
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| 245 | 1 | 0 | |a Tetrahydro-β-carboline derivatives as potent histone deacetylase 6 inhibitors with broad-spectrum antiproliferative activity |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a A series of tetrahydro-β-carboline (THβC)-based hydroxamic acids were rationally designed and synthesized as novel selective HDAC6 inhibitors (sHDAC6is) by the application of scaffold hopping strategy. Several THβC analogues were highly potent (IC50 < 5 nM) and selective against HDAC6 enzyme and exhibited good antiproliferative activity against human multiple myeloma (MM) cell. Molecular docking interpreted the structure activity relationship (SAR). Target engagement of HDAC6 was confirmed in RPMI-8226 cells using the WB assay. In vitro, (1S, 3R)-1-(4-chlorophenyl)-N-(4-(hydroxycarbamoyl)benzyl)-2,3,4,9-tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxamide (14g) showed potent broad antiproliferative activity against various tumors including leukemia, colon cancer, melanoma, and breast cancer cell lines, better than ACY-1215. Moreover, 14g also showed good pharmacokinetics properties in mice via oral administration | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Antiproliferative | |
| 650 | 4 | |a HDAC6 inhibitor | |
| 650 | 4 | |a Selectivity | |
| 650 | 4 | |a Synthesis | |
| 650 | 4 | |a THβC | |
| 650 | 7 | |a Histone Deacetylase 6 |2 NLM | |
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| 700 | 1 | |a Wang, Jiayun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Dang, Baiyun |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Ting |e verfasserin |4 aut | |
| 700 | 1 | |a Steimbach, Raphael R |e verfasserin |4 aut | |
| 700 | 1 | |a Miller, Aubry K |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Tongtong |e verfasserin |4 aut | |
| 700 | 1 | |a Luan, Xiaofa |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Jiadong |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Jinming |e verfasserin |4 aut | |
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