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Discovery of Hydrazineyl Amide Derivative of Pseudolaric Acid B for Reprogramming Tumor-Associated Macrophages Against Tumor Growth

文献类型：期刊论文

作者Peng, Xia5,6,7; Yu, Siqi1,4; Xu, Lin1,4; Wang, Qinghua4; Yang, Lin1,4; Su, Yi5,6,7; Xiong, Zhirou5,6; Shao, Mengjie4; Geng, Meiyu3,5,6,7; Zhang, Ao4
刊名MOLECULES
出版日期2025-05-08
卷号30期号:10页码:22
关键词pseudolaric acid B amide derivatives tumor-associated macrophages anti-tumor repolarization
DOI10.3390/molecules30102088
英文摘要Tumor-associated macrophages (TAMs) are pivotal for tumor development and progression. Reprogramming the M2-like pro-tumoral behavior of TAMs towards the M1-like anti-tumor phenotype to unleash their potential against tumors has become one of the most promising anti-tumor immunotherapy strategies. In this work, the natural product pseudolaric acid B (PAB, 1) was found to markedly decrease ARG1 mRNA expression and significantly increase NOS2 expression in the IL-4/IL-13-pre-stimulated RAW 264.7 cells through cellular phenotype screening of a series of pseudolaric acid-related natural products, suggesting its potential to reprogram the pro-tumoral TAMs towards the M1-like phenotype against tumors. Further chemical modification of the carboxylic acid moiety of 1 led to a series of amide or pyranoside derivatives with ARG1- and NOS2-modulating activity. Among them, hydrazineyl amide 12 stands out as the most potent, without significant diminution in cell viability. It inhibited the M2-like polarized tumor-promoting phenotype of macrophages, as evidenced by a decrease in CD206 expression and an increase in CD86 expression in flow cytometry, as well as a decrease in ARG1 protein level in Western blot assays. In addition, 12 could reverse the suppression of Ki67+, IFN gamma+, and granzyme B+ CD8+ T cell proliferation and activation induced by pro-tumoral macrophages. More importantly, it could reshape the tumor immune microenvironment and inhibit tumor growth in immunocompetent murine tumor models. Hsp90 was predicted to be a potential target of 12 by a target fishing software, which was further demonstrated by molecular docking. Collectively, the amide derivative 12 of PAB demonstrated promising anti-tumor TAM-reprogramming activity, which is worthy of further investigation.
WOS关键词NF-KAPPA-B ; CANCER ; ANGIOGENESIS
资助项目National Key R&D Program of China ; National Natural Science Foundation of China[22177068] ; National Natural Science Foundation of China[81821005] ; National Key R&D Program Strategic Scientific and Technological Innovation Cooperation Key Project[2022YFE0203600] ; Project of Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0120231001] ; [2022YFF1203005]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:001496334800001
出版者MDPI
源URL[http://119.78.100.183/handle/2S10ELR8/317983]  
专题新药研究国家重点实验室
通讯作者Zhang, Lei; Ai, Jing; Ding, Chunyong
作者单位1.Zunyi Med Univ, Sch Pharmaceut Sci, Zunyi 563000, Peoples R China
2.Kaili Univ, Qiandongnan Tradit Med Res & Dev Ctr, Sch Life & Hlth Sci, Key Lab Modernizat Qiandongnan Miao & Dong Med, Kaili 556011, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
4.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharmaceut Sci, Natl Key Lab Innovat Immunotherapy, Shanghai 200240, Peoples R China
5.Univ Chinese Acad Sci, Sch Pharmaceut Sci, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Peng, Xia,Yu, Siqi,Xu, Lin,et al. Discovery of Hydrazineyl Amide Derivative of Pseudolaric Acid B for Reprogramming Tumor-Associated Macrophages Against Tumor Growth[J]. MOLECULES,2025,30(10):22.
APA Peng, Xia.,Yu, Siqi.,Xu, Lin.,Wang, Qinghua.,Yang, Lin.,...&Ding, Chunyong.(2025).Discovery of Hydrazineyl Amide Derivative of Pseudolaric Acid B for Reprogramming Tumor-Associated Macrophages Against Tumor Growth.MOLECULES,30(10),22.
MLA Peng, Xia,et al."Discovery of Hydrazineyl Amide Derivative of Pseudolaric Acid B for Reprogramming Tumor-Associated Macrophages Against Tumor Growth".MOLECULES 30.10(2025):22.

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来源：上海药物研究所

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