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

作者：Peng Xia, Siqi Yu, Lin Xu, Qinghua Wang, Lin Yang, Yi Su, Zhirou Xiong, Mengjie Shao, Meiyu Geng, Ao Zhang, Lei Zhang, Jing Ai, Chunyong Ding · 发表于：Molecules · 年份：2025 · DOI：10.3390/molecules30102088 · 被引用次数：3 · 研究领域：Biological Activity of Diterpenoids and Biflavonoids、Immune cells in cancer、Histone Deacetylase Inhibitors Research

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 γ+, 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 t...