Carbohydrate-Small Molecule Hybrids as Lead Compounds Targeting IL-6 Signaling.
Carbohydrate-Small Molecule Hybrids as Lead Compounds Targeting IL-6 Signaling.
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DOI：
10.3390/molecules28020677
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发表时间：
2023-01-09
期刊：
影响因子：
--
通讯作者：
Li C
中科院分区：
文献类型：
--
作者：
Schultz DC;Pan L;Wang T;Booker C;Hyder I;Hanold L;Rubin G;Ding Y;Lin J;Li C
在过去的25年中，已经做出了许多努力来开发小分子白细胞介素-6（IL-6）信号传导抑制剂，但迄今为止还没有批准。单糖是一类多样的生物活性化合物，但迄今为止尚未开发作为小分子IL-6信号传导抑制剂设计的支架。因此，在本通讯中，我们结合了基于结构的药物设计方法与碳水化合物构建块，设计和合成新的IL-6信号传导抑制剂靶向糖蛋白130（gp 130）。在这一系列化合物中，LS-TG-2 P和LS-TF-3 P是最主要的先导化合物，对SUM 159细胞系的IC 50值分别为6.9和16 μM，同时仍保留对IL-6信号传导途径的优先活性。发现碳水化合物部分改善活性，因为发现这些化合物的N-未取代的三唑类似物与先导物本身相比在体外活性较低。因此，LS-TG-2 P和LS-TF-3 P是作为IL-6信号传导抑制剂进行进一步开发和研究的有前景的支架。
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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影响因子：
8.8
作者：
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影响因子：
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作者：
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通讯作者：
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