Chang Po-Wei, Wang Jing-Ya, Wang Wan-Ping, Huang Wei-Cheng, Wu Mine-Hsine, Song Jen-Shin, Chen Liuh-Yow, Tung Chun-Wei, Chi Ya-Hui, Ueng Shau-Hua
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan, ROC.
Bioorg Med Chem. 2023 Nov 15;95:117502. doi: 10.1016/j.bmc.2023.117502. Epub 2023 Oct 14.
A structure-activity relationship (SAR) study of stimulator of interferon gene (STING) inhibition was performed using a series of indol-3-yl-N-phenylcarbamic amides and indol-2-yl-N-phenylcarbamic amides. Among these analogs, compounds 10, 13, 15, 19, and 21 inhibited the phosphorylation of STING and interferon regulatory factor 3 (IRF3) to a greater extent than the reference compound, H-151. All five analogs showed stronger STING inhibition than H-151 on the 2',3'-cyclic GMP-AMP-induced expression of interferon regulatory factors (IRFs) in a STING knock-in THP-1 reporter cell line. The half-maximal inhibitory concentration of the most potent compound, 21, was 11.5 nM. The molecular docking analysis of compound 21 and STING combined with the SAR study suggested that the meta- and para-positions of the benzene ring of the phenylcarbamic amide moiety could be structurally modified by introducing halides or alkyl substituents.
利用一系列吲哚-3-基-N-苯基氨基甲酰胺和吲哚-2-基-N-苯基氨基甲酰胺对干扰素基因刺激物（STING）抑制作用进行了构效关系（SAR）研究。在这些类似物中，化合物10、13、15、19和21比参考化合物H-151更能抑制STING和干扰素调节因子3（IRF3）的磷酸化。在STING敲入THP-1报告细胞系中，所有这五种类似物对2',3'-环鸟苷酸-腺苷酸（2',3'-cGAMP）诱导的干扰素调节因子（IRFs）表达的STING抑制作用均强于H-151。最有效化合物21的半数最大抑制浓度为11.5 nM。化合物21与STING的分子对接分析结合SAR研究表明，氨基甲酰苯胺部分苯环的间位和对位可通过引入卤化物或烷基取代基进行结构修饰。
