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.
Curr Med Sci. 2024 Oct;44(5):890-901. doi: 10.1007/s11596-024-2922-y. Epub 2024 Sep 17.
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.
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.
The compound 7 exhibited good antitumor activity among the synthesized derivatives, specifically in DLBCL cell lines. SAR analysis highlighted the critical role of α, 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.
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.
本研究旨在设计和评估吡咯烷酮衍生物作为治疗弥漫性大 B 细胞淋巴瘤（DLBCL）的潜在治疗剂的功效，DLBCL 是成人淋巴造血系统常见且异质性的恶性肿瘤。鉴于当前治疗方法的局限性，迫切需要开发新的有效的 DLBCL 治疗药物。
合成了一系列吡咯烷酮衍生物，并评估了它们的抗肿瘤活性，特别是对 DLBCL 细胞系的活性。进行了构效关系（SAR）分析，以确定对活性至关重要的关键结构成分。选择最有前途的化合物，称为化合物 7，进行进一步的机制研究。通过 RT-qPCR 和 Western blot 检测相关 mRNA 和蛋白的表达水平，通过流式细胞术检测线粒体膜电位和 ROS 的表达，进一步评估细胞周期停滞和细胞凋亡。
在所合成的衍生物中，化合物 7 表现出良好的抗肿瘤活性，特别是在 DLBCL 细胞系中。SAR 分析强调了α，β-不饱和酮在这些化合物抗肿瘤功效中的关键作用。机制上，发现化合物 7 能诱导显著的 DNA 损伤，引发炎症反应，导致线粒体功能障碍，并破坏细胞周期进程，最终导致 DLBCL 细胞凋亡。
化合物 7 具有良好的抗肿瘤活性，并能诱导多种导致癌细胞死亡的细胞机制。这些发现证明了化合物 7 作为 DLBCL 潜在治疗剂的进一步研究是合理的。
