靶向STAT3信号通路小分子抑制剂的设计、合成及其生物活性

The design, synthesis and biological activity of small molecule inhibitors targeting STAT3 signaling pathway

目的:以嘌呤类STAT3小分子抑制剂S3I-V4-01为先导,设计并合成一系列新型目标化合物,通过初步的体外细胞实验检测其生物活性,以筛选出活性更优的化合物。方法:通过亲核取代反应合成了一系列目标化合物,运用荧光素酶报告基因法检测目标化合物对STAT3信号转导通路的影响,利用MTT实验检测目标化合物对人表皮鳞癌细胞A431和非小细胞肺癌细胞A549增殖的抑制作用。结果:本研究共合成8个终产物(Z2～Z5及H2～H5),其中,优势化合物H3能有效抑制STAT3磷酸化,阻断STAT3信号转导通路,抑制A431和A549的细胞增殖。结论:化合物H3比S3I-V4-01具有更强的p-STAT3抑制能力和抗肿瘤细胞增殖能力,并且可以在H3结构上进行优化,以进一步提高生物活性。

Objective: Based on the lead compound, STAT3 small molecule inhibitor S3I-V4-01, a series of novel target compounds were designed and synthesized and their biological activity were tested by preliminary in vitro cell experiments so as to screen the more potent compounds. Methods: A series of target compounds were synthesized by nucleophilic substitution reaction;Luciferase reporter gene assay was used to measure the effect of target compounds on STAT3 signal transduction pathway;MTT assay was used to detect the inhibitory effect of target compounds on proliferation of human epidermal squamous cell carcinoma A431 and non-small cell lung cancer cell lines A549 cells. Results: In this study, eight target compounds (Z2-Z5 and H2-H5) were synthesized. Among them, the dominant compound H3 could effectively inhibit the phosphorylation of STAT3 and block the STAT3 signal transduction pathway and inhibit the proliferation of A431 and A549 cells. Conclusion: Compound H3 had stronger p-STAT3 inhibition and anti-proliferation ability than S3I-V4-01, and it could also be optimized in H3 structure to further improve biological activity.