Carbohydrate-Small Molecule Hybrids as Lead Compounds Targeting IL-6 Signaling
In the past 25 years, a number of efforts have been made toward the development of small molecule interleukin-6 (IL-6) signaling inhibitors, but none have been approved to date. Monosaccharides are a diverse class of bioactive compounds, but thus far have been unexplored as a scaffold for small molecule IL-6-signaling inhibitor design. Therefore, in this present communication, we combined a structure-based drug design approach with carbohydrate building blocks to design and synthesize novel IL-6-signaling inhibitors targeting glycoprotein 130 (gp130). Of this series of compounds, LS-TG-2P and LS-TF-3P were the top lead compounds, displaying IC50 values of 6.9 and 16 µM against SUM159 cell lines, respectively, while still retaining preferential activity against the IL-6-signaling pathway. The carbohydrate moiety was found to improve activity, as N-unsubstituted triazole analogues of these compounds were found to be less active in vitro compared to the leads themselves. Thus, LS-TG-2P and LS-TF-3P are promising scaffolds for further development and study as IL-6-signaling inhibitors.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Molecules (Basel, Switzerland) - 28(2023), 2 vom: 09. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schultz, Daniel C [VerfasserIn] |
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| Links: |
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| Themen: |
Antineoplastic Agents |
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| Anmerkungen: |
Date Completed 25.01.2023 Date Revised 29.04.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/molecules28020677 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 520 | |a In the past 25 years, a number of efforts have been made toward the development of small molecule interleukin-6 (IL-6) signaling inhibitors, but none have been approved to date. Monosaccharides are a diverse class of bioactive compounds, but thus far have been unexplored as a scaffold for small molecule IL-6-signaling inhibitor design. Therefore, in this present communication, we combined a structure-based drug design approach with carbohydrate building blocks to design and synthesize novel IL-6-signaling inhibitors targeting glycoprotein 130 (gp130). Of this series of compounds, LS-TG-2P and LS-TF-3P were the top lead compounds, displaying IC50 values of 6.9 and 16 µM against SUM159 cell lines, respectively, while still retaining preferential activity against the IL-6-signaling pathway. The carbohydrate moiety was found to improve activity, as N-unsubstituted triazole analogues of these compounds were found to be less active in vitro compared to the leads themselves. Thus, LS-TG-2P and LS-TF-3P are promising scaffolds for further development and study as IL-6-signaling inhibitors | ||
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| 700 | 1 | |a Wang, Tiffany |e verfasserin |4 aut | |
| 700 | 1 | |a Booker, Conner |e verfasserin |4 aut | |
| 700 | 1 | |a Hyder, Iram |e verfasserin |4 aut | |
| 700 | 1 | |a Hanold, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Rubin, Garret |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Yousong |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Jiayuh |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Chenglong |e verfasserin |4 aut | |
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