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.
Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Bioorg Med Chem. 2024 Sep 1;111:117843. doi: 10.1016/j.bmc.2024.117843. Epub 2024 Jul 22.
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 IC 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.
本研究报告了新型 1-酰胺-2-酮-4-硫代-脱氧吡喃糖的设计与合成，作为潜在药物靶点 TRIP13 的抑制剂，用于开发治疗多发性骨髓瘤（MM）的新型基于机制的治疗药物。与阳性对照 DCZ0415 相比，最具活性的化合物 C16、C18、C20 和 C32 对人 MM 细胞系（ARP-1 和 NCI-H929）表现出较强的增殖抑制活性，IC 值为 1∼2 μM。表面等离子体共振（SPR）和 ATPase 活性测定表明，代表性化合物 C20 是 TRIP13 的有效抑制剂，C20 对 BALB/c 裸鼠 MM 肿瘤细胞异种移植也显示出良好的体内抗肿瘤活性。初步的构效关系研究表明，羰基对于抗癌活性至关重要。总的来说，本研究提供了新型的 1-酰胺-2-酮-4-硫代-脱氧吡喃糖，它们与先前报道的 TRIP13 强效抑制剂结构完全不同，因此有助于开发用于 MM 治疗的基于碳水化合物的新型药物。
