Two-Step Synthesis of a Clickable Photoaffinity Probe from an Anticancer Saponin OSW-1 and its Photochemical Reactivity
Two-Step Synthesis of a Clickable Photoaffinity Probe from an Anticancer Saponin OSW-1 and its Photochemical Reactivity
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DOI：
10.1002/ajoc.201500505
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发表时间：
2016-03
影响因子：
2.7
通讯作者：
R. Yamada;M. Hiraizumi;S. Narita;K. Sakurai
中科院分区：
文献类型：
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作者：
R. Yamada;M. Hiraizumi;S. Narita;K. Sakurai
OSW-1是一种作用机制未知的高效抗癌皂苷，与目前使用的化疗药物不同。为了研究其结合蛋白，我们设计并合成了一种可点击的OSW-1光亲和探针，并对其光化学反应活性进行了表征。开发了一种温和的两步反应程序，涉及Me2SnCl2介导的酰化反应，以位置选择性地用带有光反应基团和炔标签的连接物来衍生化OSW-1。基于OSW-1的光亲和探针保持了与亲本天然产物类似的强大的抗癌活性，从而提供了OSW-1的细胞渗透性类似物。光亲和标记研究表明，该探针能够以亲和力依赖的方式使模型甾醇结合蛋白发生交联，通过点击化学结合荧光团或生物素可以有效地检测到这种情况。
OSW-1 is a highly potent anticancer saponin with an unknown mechanism of action that is distinct from the currently used chemotherapeutic agents. Toward investigation of its binding proteins, we designed and synthesized a clickable photoaffinity probe from OSW-1 and characterized its photochemical reactivity. A mild, two-step procedure involving a Me2SnCl2-mediated acylation reaction was developed to site-selectively derivatize OSW-1 with a linker that bears a photoreactive group and an alkyne tag. The OSW-1-based photoaffinity probe retained potent anticancer activity similar to that of the parent natural product, thereby providing a cell-permeable analogue of OSW-1. Photoaffinity labeling studies demonstrated that the probe enabled crosslinking of a model sterol-binding protein in an affinity-dependent fashion, which could be efficiently detected by conjugating a fluorophore or biotin by click chemistry.