Synthesis and biological evaluation of celastrol derivatives as potent antitumor agents with STAT3 inhibition.
Synthesis and biological evaluation of celastrol derivatives as potent antitumor agents with STAT3 inhibition.
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DOI：
10.1080/14756366.2021.2001805
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发表时间：
2022-12
影响因子：
5.6
通讯作者：
Fan Z
中科院分区：
文献类型：
--
作者：
Xu S;Fan R;Wang L;He W;Ge H;Chen H;Xu W;Zhang J;Xu W;Feng Y;Fan Z
使用STAT 3抑制剂作为癌症治疗的潜在策略已引起广泛关注。最近，雷公藤红素被报道在心功能不全模型中可以直接结合并抑制STAT 3的活性。为了探索更有效的抑制STAT 3的抗肿瘤候选药物，我们合成了一系列雷公藤红素衍生物，并用几种人类癌细胞系对其进行了生物学评价。蛋白质印迹分析表明，化合物4 m是活性最高的衍生物，它能抑制STAT 3的磷酸化及其下游基因。表面等离子体共振分析、分子对接和动力学模拟结果表明，4 m与STAT 3蛋白的结合比南蛇藤醇更紧密。结果发现，4 m对HCT-116细胞具有阻滞细胞周期和诱导凋亡的作用。此外，4 m对结直肠癌类器官的抗肿瘤作用得到了验证。这是首次从雷公藤红素衍生物中发现有效的STAT 3抑制剂作为有效的抗肿瘤药物的研究。
Using STAT3 inhibitors as a potential strategy in cancer therapy have attracted much attention. Recently, celastrol has been reported that it could directly bind to and suppress the activity of STAT3 in the cardiac dysfunction model. To explore more effective STAT3 inhibiting anti-tumour drug candidates, we synthesised a series of celastrol derivatives and biologically evaluated them with several human cancer cell lines. The western blotting analysis showed that compound 4 m, the most active derivative, could suppress the STAT3’s phosphorylation as well as its downstream genes. SPR analysis, molecular docking and dynamics simulations’ results indicated that the 4m could bind with STAT3 protein more tightly than celastrol. Then we found that the 4m could block cell-cycle and induce apoptosis on HCT-116 cells. Furthermore, the anti-tumour effect of 4m was verified on colorectal cancer organoid. This is the first research that discovered effective STAT3 inhibitors as potent anti-tumour agents from celastrol derivatives.
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影响因子：
16.6
作者：
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