Gao Jixiang, Liu Jinyi, Yu Tao, Xu Chenggong, Sun Hao, Lu Chunbo, Dan Wenjia, Dai Jiangkun
School of Life Science and Technology, Weifang Medical University, Weifang, Shandong Province, 261053, China.
Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, 250100, China.
BMC Chem. 2023 Dec 20;17(1):184. doi: 10.1186/s13065-023-01102-1.
The discovery of new lead skeleton against melanoma are urgently needed due to its highly malignant and mortality. Herein, a new molecular entity (EU-5) derived from eudistomin U was synthesized with total yield of 46%, which displayed potent activity against malignant melanoma A375 cells (IC = 4.4 µM), no hemolytic toxicity and good physicochemical properties in silico. Colony formation and cell cycle arrest assays revealed that EU-5 suppressed cell proliferation by causing cell cycle arrest at G0/G1 phase. Wound healing and transwell assays suggested that EU-5 could effectively inhibit migration of A375 cells in a dose-dependent manner. Calcein-AM/PI staining, Annexin V-FITC/PI apoptosis detection, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), transcriptomics, quantitative real‑time polymerase chain reaction (qRT‑PCR), spectrometric titration and molecular docking assays indicated that EU-5 could activate p53 signaling pathway and trigger mitochondria-mediated cell apoptosis. Taken together, this study provided a promising lead structure for the design of a new generation of anti-melanoma drugs.
由于黑色素瘤具有高度恶性和致死性，因此迫切需要发现针对黑色素瘤的新的先导骨架。在此，合成了一种源自海兔毒素U的新分子实体（EU-5），总产率为46%，其对恶性黑色素瘤A375细胞显示出强效活性（IC = 4.4 μM），无溶血毒性且在计算机模拟中具有良好的物理化学性质。集落形成和细胞周期阻滞试验表明，EU-5通过使细胞周期阻滞在G0/G1期来抑制细胞增殖。伤口愈合试验和Transwell试验表明，EU-5能够以剂量依赖性方式有效抑制A375细胞的迁移。钙黄绿素-AM/PI染色、膜联蛋白V-FITC/PI凋亡检测、线粒体膜电位（MMP）、活性氧（ROS）、转录组学、定量实时聚合酶链反应（qRT-PCR）、光谱滴定和分子对接试验表明，EU-5可激活p53信号通路并触发线粒体介导的细胞凋亡。综上所述，本研究为新一代抗黑色素瘤药物的设计提供了一个有前景的先导结构。
