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一种新型的阿吉拉丁A衍生物作为STAT3抑制剂,并表现出潜在的抗瘤作用

Na He^1,2, Li Li^1,3, Rui Li^1,2

¹Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.

International journal of molecular sciences

|May 27, 2023

概括

化合物25是一种ageladine A衍生物,有效地抑制了Janus激酶/信号转换器和转录3 (JAK/STAT3) 信号的激活器. 这种新型化合物在体内和体外抑制了瘤生长,显示出作为抗瘤剂的潜力.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

简氏激酶/信号转换器和转录3 (JAK/STAT3) 激活器通路对于细胞功能至关重要,但其异常激活驱动癌症的进展.
准JAK/STAT3通路为开发新型抗瘤疗法提供了一个有希望的策略.

研究的目的:

为了合成和评估ageladine A衍生物作为JAK/STAT3通路的潜在抑制剂.
为了研究最强效的化合物的抗瘤功效,被指定为化合物25.

主要方法:

合成阿格拉丁A衍生物和评估它们对STAT3活性的抑制作用,使用光酶记者测定.
分子对接研究,以预测化合物25与STAT3 SH2域的结合相互作用.
西部斑点分析,以评估化合物25对STAT3酸化和下游基因表达的影响.
使用A549和DU145癌细胞系进行体外细胞增殖和迁移测定.
使用A549异种移植模型进行体内研究,以评估化合物25的抗瘤疗效和安全性.

主要成果:

化合物25在合成衍生物中显示出对STAT3光酶活性最显著的抑制.
分子对接表明,化合物25与STAT3 SH2域结合.
化合物25在Tyr705选择性抑制了STAT3酸化,减少了下游基因表达而不影响STAT1或STAT5酸化.
化合物25在体外抑制了A549和DU145细胞的增殖和迁移.
在体内,化合物25 (10 mg/kg) 有效抑制了A549异种移植瘤的生长,而对体重没有显著的不良影响.

结论:

化合物25是一种强大的JAK/STAT3信号的抑制剂,通过阻断STAT3酸化而起作用.
化合物25在体外和体外模型中表现出显著的抗瘤活性.
这些发现强调了25化合物作为进一步开发的有希望的候选人,作为向JAK/STAT3通路的抗瘤剂.

关键词:

在JAK/STAT3信号通道中,这是一种STAT3抑制剂.艾格拉丁A衍生物的衍生品抗瘤活动抗瘤活动抗瘤机制抗瘤机制双胺 - - 醇 - - 伊米达.

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