2. Academic Validation
  3. Discovery of novel oridonin sulfamide derivatives as potent NLRP3 inhibitors by a visible-light photocatalysis-enabled peripheral editing

Discovery of novel oridonin sulfamide derivatives as potent NLRP3 inhibitors by a visible-light photocatalysis-enabled peripheral editing

  • Bioorg Med Chem Lett. 2024 Jan 18:99:129621. doi: 10.1016/j.bmcl.2024.129621.
Mochenxuan Li 1,  Chuanhao Wang 2,  Shuang Ye 3,  Wei Li 3,  Yanming Zhang 4,  Jianyu Yan 4,  Yongchuang Wang 5,  Hang Yang 5,  Yuelin Wu 5,  Yongqiang Zhang 6,  Huojun Zhang 7,  Zhenyuan Miao 8
Affiliations

Affiliations

  • 1 School of Pharmacy, The Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China.
  • 2 School of Pharmacy, The Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China; School of Chemistry and Chemical Engineering, Nanjing University of Science and Technology, 200 Xiaolingwei Road, Nanjing 210094, People's Republic of China.
  • 3 Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China.
  • 4 School of Pharmacy, The Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
  • 5 School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, People's Republic of China.
  • 6 Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China. Electronic address: yongqiangzhang@ecust.edu.cn.
  • 7 Department of Radiation Oncology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, People's Republic of China. Electronic address: chyyzhj@163.com.
  • 8 School of Pharmacy, The Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China. Electronic address: miaozhenyuan@hotmail.com.
PMID: 38244941 DOI: 10.1016/j.bmcl.2024.129621
Abstract

The progress of organicsyntheticmethod can promote late-stage lead compound modification and novel active compound discovery. Molecular editing technology in the field of organic synthesis, including peripheral and skeletal editing, facilitates rapid access to molecular diversity of a lead compound. Peripheral editing of CH bond activation is gradually used in lead optimization to afford novel active scaffolds and chemical space exploitation. To develop oridonin derivatives with high anti-inflammatory potency, novel oridonin sulfamides had been designed and synthesized by a scaffoldhopping strategy based on a visible-light photocatalysis peripheral editing. All novel compounds revealed measurable inhibition of IL-1β and low cytotoxicity in THP-1 cells. The docking study indicated that the best active compound ZM640 was accommodated in thebinding site of NLRP3 with two hydrogen bond interaction. These preliminary results confirm that α, β-unsaturated carbonyl of oridonin is not essential for NLRP3 inhibitory effect. This new oridonin scaffold has its potential to be further developed as a promising class of NLRP3 inhibitors.

Keywords

Anti-inflammatory activity; NLRP3 inhibitor; Oridonin; Peripheral editing.

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