Park Seong-Hyun, Choi Yoon Pyo, Park Jinhong, Share Andrew, Francesconi Oscar, Nativi Cristina, Namkung Wan, Sessler Jonathan L, Roelens Stefano, Shin Injae
Center for Biofunctional Molecules , Department of Chemistry , Yonsei University , 03722 Seoul , Korea . Email:
College of Pharmacy , Yonsei Institute of Pharmaceutical Sciences , Yonsei University , 21983 Incheon , Korea.
Chem Sci. 2015 Dec 1;6(12):7284-7292. doi: 10.1039/c5sc03200h. Epub 2015 Oct 2.
We report two synthetic aminopyrrolic compounds that induce apoptotic cell death. These compounds have been previously shown to act as receptors for mannosides. The extent of receptor-induced cell death is greater in cells expressing a high level of high-mannose oligosaccharides than in cells producing lower levels of high-mannose glycans. The ability of synthetic receptors to induce cell death is attenuated in the presence of external mannosides. The present results provide support for the suggestion that the observed cell death reflects an ability of the receptors to bind mannose displayed on the cell surface. Signaling pathway studies indicate that the synthetic receptors of the present study promote JNK activation, induce Bax translocation to the mitochondria, and cause cytochrome c release from the mitochondria into the cytosol, thus promoting caspase-dependent apoptosis. Such effects are also observed in cells treated with mannose-binding ConA. The present results thus serve to highlight what may be an attractive new approach to triggering apoptosis modes of action that differ from those normally used to promote apoptosis.
我们报道了两种可诱导凋亡性细胞死亡的合成氨基吡咯化合物。这些化合物先前已被证明可作为甘露糖苷的受体。受体诱导的细胞死亡程度在表达高水平高甘露糖寡糖的细胞中比在产生较低水平高甘露糖聚糖的细胞中更大。在存在外源性甘露糖苷的情况下，合成受体诱导细胞死亡的能力会减弱。目前的结果支持了以下观点：观察到的细胞死亡反映了受体结合细胞表面展示的甘露糖的能力。信号通路研究表明，本研究中的合成受体促进JNK激活，诱导Bax转位至线粒体，并导致细胞色素c从线粒体释放到细胞质中，从而促进半胱天冬酶依赖性凋亡。在用甘露糖结合伴刀豆球蛋白A处理的细胞中也观察到了此类效应。因此，目前的结果有助于突出一种可能有吸引力的触发凋亡的新方法，其作用模式不同于通常用于促进凋亡的模式。
