Michael Acceptor Pyrrolidone Derivatives and Their Activity against Diffuse Large B-cell Lymphoma  

作　　者：Bi-qiong ZHANG Feng-qing WANG Jie YIN Xiao-tan YU Zheng-xi HU Liang-hu GU Qing-yi TONG Yong-hui ZHANG 

机构地区：[1]Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation,School of Pharmacy,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China

出　　处：《Current Medical Science》2024年第5期890-901,共12页当代医学科学（英文）

基　　金：financially supported by the National Natural Science Foundation of China(No.81903461);the Natural Science Foundation of Hubei Province(No.ZRMS2023000340).

摘　　要：Objective This study aimed to design and evaluate the efficacy of pyrrolidone derivatives as potential therapeutic agents against diffuse large B-cell lymphoma(DLBCL),a common and heterogeneous malignancy of the adult lymphohematopoietic system.Given the limitations of current therapies,there is a pressing need to develop new and effective drugs for DLBCL treatment.Methods A series of pyrrolidone derivatives were synthesized,and their antitumor activities were assessed,particularly against DLBCL cell lines.Structure-activity relationship(SAR)analysis was conducted to identify key structural components essential for activity.The most promising compound,referred to as compound 7,was selected for further mechanistic studies.The expression levels of relevant mRNA and protein were detected by RT-qPCR and Western blotting,and the expression of mitochondrial membrane potential and ROS was detected using flow cytometry for further assessment of cell cycle arrest and apoptosis.Results The compound 7 exhibited good antitumor activity among the synthesized derivatives,specifically in DLBCL cell lines.SAR analysis highlighted the critical role ofα,β-unsaturated ketones in the antitumor efficacy of these compounds.Mechanistically,compound 7 was found to induce significant DNA damage,trigger an inflammatory response,cause mitochondrial dysfunction,and disrupt cell cycle progression,ultimately leading to apoptosis of DLBCL cells.Conclusion The compound 7 has good antitumor activity and can induce multiple cellular mechanisms leading to cancer cell death.These findings warrant further investigation of the compound 7 as a potential therapeutic agent for DLBCL.

关 键 词：pyrrolidone analogs Michael acceptor DNA damage mitochondrial dysfunction APOPTOSIS 

分 类 号：R733.1[医药卫生—肿瘤]