2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel 1-amido-2-one-4-thio-deoxypyranose as potential antitumor agents for multiple myeloma

Design, synthesis, and biological evaluation of novel 1-amido-2-one-4-thio-deoxypyranose as potential antitumor agents for multiple myeloma

  • Bioorg Med Chem. 2024 Sep 1:111:117843. doi: 10.1016/j.bmc.2024.117843.
Xiaomei Li 1,  Hui Zhang 2,  Sanfeng Dong 3,  Xuejie Gao 2,  Haiguo Sun 4,  Zhaoyin Zhou 3,  Ke Hu 2,  Shushan Guo 2,  Qikai Zhang 2,  Zhufeng Guo 5,  Samuel Jacob Bunu 4,  Jianming Zhu 5,  Bo Li 4,  Yong Zhang 3,  Jingshan Shen 4,  Haji Akber Aisa 6,  Zhijian Xu 7,  Haiyan Cai 8,  Jumei Shi 9,  Weiliang Zhu 10
Affiliations

Affiliations

  • 1 State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, CAS Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang, China; State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
  • 2 Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
  • 3 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 4 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
  • 5 School of Resources and Environmental Engineering, Shanghai Polytechnic University, No. 2360 Jinhai Road, Shanghai 201209, China.
  • 6 State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, CAS Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang, China; School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
  • 7 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China. Electronic address: zjxu@simm.ac.cn.
  • 8 Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: hanyezi@163.com.
  • 9 Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: shijumei@tongji.edu.cn.
  • 10 State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, CAS Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang, China; State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China. Electronic address: wlzhu@simm.ac.cn.
PMID: 39083980 DOI: 10.1016/j.bmc.2024.117843
Abstract

This study reported the design and synthesis of novel 1-amido-2-one-4-thio-deoxypyranose as inhibitors of potential drug target TRIP13 for developing new mechanism-based therapeutic agents in the treatment of multiple myeloma (MM). In comparison with the positive control DCZ0415, the most active compounds C16, C18, C20 and C32 exhibited strong anti-proliferative activity against human MM cell lines (ARP-1 and NCI-H929) with IC50 values of 1 ∼ 2 μM. While the surface plasmon resonance (SPR) and ATPase activity assays demonstrated that the representative compound C20 is a potent inhibitor of TRIP13, C20 also showed good antitumor activity in vivo on BALB/c nude mice xenografted with MM tumor cells. An initial structure-activity study showed that the carbonyl group is crucial for Anticancer activity. Overall, this study provided novel 1-amido-2-one-4-thio-deoxypyranoses, which are entirely different from previously reported potent inhibitor structures of TRIP13, and thus would aid the development of carbohydrate-based novel agents in MM pharmacotherapy.

Keywords

1-amido-2-one-4-thio-deoxypyranose; In vivo activity; Multiple myeloma; TRIP13 inhibitor.

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