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Development of ketalized unsaturated saccharides as multifunctional cysteine-targeting covalent warheads

文献类型：期刊论文

作者Dong, Sanfeng6,7,8; Huang, Hui4,5; Li, Jintian3,7; Li, Xiaomei3,7; Bunu, Samuel Jacob3,7; Yang, Yun6; Zhang, Yong7; Jia, Qi6; Xu, Zhijian3,7; Li, Yingxia8
刊名COMMUNICATIONS CHEMISTRY
出版日期2024-09-09
卷号7期号:1页码:10
ISSN号2399-3669
DOI10.1038/s42004-024-01279-z
通讯作者Li, Yingxia(liyx417@fudan.edu.cn) ; Zhou, Hu(zhouhu@simm.ac.cn) ; Li, Bo(boli@simm.ac.cn) ; Zhu, Weiliang(wlzhu@simm.ac.cn)
英文摘要Multi-functional cysteine-targeting covalent warheads possess significant therapeutic potential in medicinal chemistry and chemical biology. Herein, we present novel unsaturated and asymmetric ketone (oxazolinosene) scaffolds that selectively conjugate cysteine residues of peptides and bovine serum albumin under normal physiological conditions. This unsaturated saccharide depletes GSH in NCI-H1299 cells, leading to anti-tumor effects in vitro. The acetyl group of the ketal moiety on the saccharide ring can be converted to other carboxylic acids in a one-pot synthesis. In this way, the loaded acid can be click-released during cysteine conjugation, making the oxazolinosene a potential multifunctional therapeutic agent. The reaction kinetic model for oxazolinosene conjugation to GSH is well established and was used to evaluate oxazolinosene reactivity. The aforementioned oxazolinosenes were stereoselectively synthesized via a one-step reaction of nitriles with saccharides and conveniently converted into a series of alpha, beta-unsaturated ketone N-glycosides as prevalent synthetic building blocks. The reaction mechanisms of oxazolinosene synthesis were investigated through calculations and validated with control experiments. Overall, these oxazolinosenes can be easily synthesized and developed as cysteine-targeted covalent warheads carrying useful click-releasing groups. Multifunctional cysteine targeting covalent warheads possess significant therapeutic potential in medicinal chemistry and chemical biology. Here, the authors develop an oxazolinosene scaffold from nitrile groups and saccharides that can selectively conjugate cysteine residues within peptides and proteins under physiological conditions, as well as deplete glutathione in cancer cells.
WOS关键词CARBOHYDRATE-CARBOHYDRATE INTERACTION ; STEREOSELECTIVE-SYNTHESIS ; CELL-SURFACES ; VISUALIZATION ; REACTIVITY ; INHIBITORS ; FORCE
资助项目National Natural Science Foundation of China (National Science Foundation of China) ; Shanghai Institute of Materia Medica[2022YFA1004304] ; National Key Research and Development Program of China[22077131] ; National Key Research and Development Program of China[22277129] ; National Natural Science Foundation of China ; Shanghai Municipal Science and Technology Major Project[CPAYLJ201908] ; Chinese Pharmaceutical Association-Yiling Biopharmaceutical Innovation Project[K202108] ; State Key Laboratory of Natural and Biomimetic Drugs
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001308533800002
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/313296]  
专题新药研究国家重点实验室
通讯作者Li, Yingxia; Zhou, Hu; Li, Bo; Zhu, Weiliang
作者单位1.Peking Univ, State Key Lab Nat & Biomimet Drugs, 38 Xue Yuan Rd, Beijing 100191, Peoples R China
2.Univ Ottawa, Shanghai Inst Mat Med, Joint Res Ctr Syst & Personalized Pharmacol, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
6.Shanghai Univ Tradit Chinese Med, 1200 Cailun Rd, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
8.Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Dong, Sanfeng,Huang, Hui,Li, Jintian,et al. Development of ketalized unsaturated saccharides as multifunctional cysteine-targeting covalent warheads[J]. COMMUNICATIONS CHEMISTRY,2024,7(1):10.
APA Dong, Sanfeng.,Huang, Hui.,Li, Jintian.,Li, Xiaomei.,Bunu, Samuel Jacob.,...&Zhu, Weiliang.(2024).Development of ketalized unsaturated saccharides as multifunctional cysteine-targeting covalent warheads.COMMUNICATIONS CHEMISTRY,7(1),10.
MLA Dong, Sanfeng,et al."Development of ketalized unsaturated saccharides as multifunctional cysteine-targeting covalent warheads".COMMUNICATIONS CHEMISTRY 7.1(2024):10.

入库方式： OAI收割

来源：上海药物研究所

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