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From Hit to Lead: Discovery of First-In-Class Furanone Glycoside D228 Derived from Chimonanthus salicifolius for the Treatment of Inflammatory Bowel Disease

文献类型：期刊论文

作者Tang, Mei-Lin5; Xiong, Xiao-Yu3,4; Zhang, Heyanhao5; Wang, Yun-Zhi5; Cheng, Rong-Qian5; Zuo, Jianping2,3; Jin, Lin1; Lin, Ze-Min2,3; Chang, Jun5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-09-19
卷号67期号:19页码:17101-17123
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00591
通讯作者Jin, Lin(jin.lin@zs-hospital.sh.cn) ; Lin, Ze-Min(linzemin@simm.ac.cn) ; Chang, Jun(jchang@fudan.edu.cn)
英文摘要TNF alpha and related inflammatory factor antibody drugs have been orchestrated for the treatment of inflammatory bowel disease (IBD). However, antibody drugs elicited inevitable disadvantages and small molecule drugs are in an urgent need. Herein, we described the discovery, design, synthesis, and SAR studies from furanone glycoside compound Phoenicein (hit) isolated from Chimonanthus salicifolius to D228 (lead). Remarkably, D228 exhibited good inhibitory activity on B and T lymphocyte and excellent anti-IBD efficacy in vivo. Mechanistically, D228 alleviated the inflammation response by downregulating the MyD88/TRAF6/p38 signaling. Importantly, the relationship of D228, Phoenicein, and their aglycone 7a was deduced: D228 could be considered as a prodrug and metabolized to intermediate Phoenicein. In turn, Phoenicein released their shared active aglycone 7a. Additionally, D228 demonstrated good and balanced profiles of safety and efficacy both in vitro and in vivo. These results suggested that D228 could be used as an ideal lead and potentially utilized for IBD chemotherapy.
WOS关键词TUMOR-NECROSIS-FACTOR ; NF-KAPPA-B ; TNF-ALPHA ; IDENTIFICATION ; PATHWAYS ; DERIVATIVES ; INHIBITOR ; CELLS
资助项目Science and Technology Commission of Shanghai Municipality[21S11907400] ; National Natural Science Foundation of China[82374108] ; National Natural Science Foundation of China[81803605]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001317058400001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/313463]  
专题新药研究国家重点实验室
通讯作者Jin, Lin; Lin, Ze-Min; Chang, Jun
作者单位1.Fudan Univ, Zhongshan Hosp, Dept Anesthesia, Shanghai 200032, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Immunopharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Jiangsu, Peoples R China
5.Fudan Univ, Shanghai Pudong Hosp, Human Phenome Inst, Shanghai Key Lab Vasc Les Regulat & Remodeling,Pha, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Tang, Mei-Lin,Xiong, Xiao-Yu,Zhang, Heyanhao,et al. From Hit to Lead: Discovery of First-In-Class Furanone Glycoside D228 Derived from Chimonanthus salicifolius for the Treatment of Inflammatory Bowel Disease[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(19):17101-17123.
APA Tang, Mei-Lin.,Xiong, Xiao-Yu.,Zhang, Heyanhao.,Wang, Yun-Zhi.,Cheng, Rong-Qian.,...&Chang, Jun.(2024).From Hit to Lead: Discovery of First-In-Class Furanone Glycoside D228 Derived from Chimonanthus salicifolius for the Treatment of Inflammatory Bowel Disease.JOURNAL OF MEDICINAL CHEMISTRY,67(19),17101-17123.
MLA Tang, Mei-Lin,et al."From Hit to Lead: Discovery of First-In-Class Furanone Glycoside D228 Derived from Chimonanthus salicifolius for the Treatment of Inflammatory Bowel Disease".JOURNAL OF MEDICINAL CHEMISTRY 67.19(2024):17101-17123.

入库方式： OAI收割

来源：上海药物研究所

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