肿瘤炎性微环境中巨噬细胞表型转化及炎症介质释放是炎症相关肿瘤发生发展的关键环节。寻找靶向肿瘤炎性微环境抗肿瘤的植物活性成分是当前研究热点。本项目是在我们前期从甘草中分离出可靶向巨噬细胞激活抗肿瘤的黄酮类化合物（新化合物A、B和异甘草素）的基础上，通过TLR4-NF-κB双荧光素酶报告系统和巨噬细胞药筛模型采用活性追踪分离法对甘草中的黄酮类活性成分进一步提取分离；随后通过对酰氯酯化，或引入Mannish碱和异丙醇胺类基团，合成三系列异甘草素衍生物，研究其构效关系。最后采用大鼠诱癌模型、小鼠结肠炎相关性结肠癌模型、裸鼠移植瘤模型和体外试验对其作用和机制进行研究。有望从TLR4-NF-κB信号→花生四烯酸代谢酶→炎症介质→巨噬细胞向M2型转化→肿瘤炎性微环境形成角度阐明甘草中抗肿瘤的黄酮类成分及网络调控机制，可为肿瘤治疗提供新的靶点和候选药物，因而具有重要的理论意义和临床价值。

Functional polarization of macrophages into M2 cells and their secretion of inflammatory mediators are key events in inflammation-associated tumorigenesis. Identification of novel targets and plant active ingredients targeting the tumor inflammatory microenvironment is a hot topic of current research. Our previous work demonstrated that new compound A, B and isoliquiritigenin, from licorice significantly inhibit proliferation of tumour cells in vitro through inhibition of TLR4-NF-kappa B activation and macrophage polarization. Herein, bioassay-guided isolation of flavonoids with antitumor activities from licorice will be further investigated by using the dual luciferase reporter system and macrophage model. In addition, the three types of novel derivatives with isoliquritlgenin as a lead compound will be designed and synthesized through the esterification reaction with acyl chlorides, Mannish reaction with methanal and amines, or etherification reaction with isopropanolamines, and structure-activity relationships will be studied. In a rat lung cancer model induced by 3-methylcholanthrene and a mouse model of colitis-associated colon cancer, the inhibitory activity of the screened compounds for phenotypic transformation of macrophages in the tumor inflammatory microenvironment will be dynamically studied. The effects of the compounds will be further validated in a human tumor xenograft nude mouse model. The effects of the compounds on signaling networks involved in the polarization of macrophages to the M2 phenotype will be finally studied in vitro. Taken together, licorice flavonoids have the potent anti-tumor effect through inhibition of polarization of macrophages and their secretion of inflammatory mediators in the tumor microenvironment via downregulating the cascade of events triggered by TLR4-NF-κB signal pathway. These new concepts have wide-ranging implications for identifyication of promising therapeutic targets and drug candidates, and thus have important theoretical significance and clinical value.