Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
Mar Drugs. 2023 Aug 29;21(9):474. doi: 10.3390/md21090474.
A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorhabdins averaged sub-micromolar potency against the MCC cell lines tested and most of the active compounds showed selectivity towards virus-positive MCC cell lines. An investigation of structure-activity relationships resulted in an expanded understanding of the crucial structural features of the discorhabdin scaffold. Mechanistic cell death assays suggested that discorhabdins, unlike many other MCC-active small molecules, do not induce apoptosis, as shown by the lack of caspase activation, annexin V staining, and response to caspase inhibition. Similarly, discorhabdin treatment failed to increase MCC intracellular calcium and ROS levels. In contrast, the rapid loss of cellular reducing potential and mitochondrial membrane potential suggested that discorhabdins induce mitochondrial dysfunction leading to non-apoptotic cell death.
评估了一个天然和半合成 discorhabdins 的文库，以评估它们对 Merkel 细胞癌 (MCC) 细胞活力的影响。该集合包括五个新的天然产物和半合成化合物，其结构通过 NMR、HRMS 和 ECD 技术阐明。几种 discorhabdins 对测试的 MCC 细胞系具有亚微米级的平均效力，大多数活性化合物对病毒阳性 MCC 细胞系表现出选择性。对构效关系的研究导致对 discorhabdin 支架的关键结构特征有了更深入的了解。细胞死亡机制研究表明，与许多其他 MCC 活性小分子不同，discorhabdins 不会诱导细胞凋亡，因为缺乏半胱天冬酶激活、膜联蛋白 V 染色和对半胱天冬酶抑制的反应。同样，discorhabdin 处理未能增加 MCC 细胞内钙和 ROS 水平。相比之下，快速丧失细胞还原电势和线粒体膜电势表明，discorhabdins 诱导线粒体功能障碍导致非凋亡性细胞死亡。
