A novel fluorescent photoaffinity probe of OSW-1 was prepared in two steps from a naturally occurring inactive congener by a sequential site-selective acylation strategy using MeSnCl. It displayed highly potent anticancer activity and a similar intracellular localization property to that of a fluorescently-tagged OSW-1, thereby demonstrating its potential utility in live cell studies.

The structural basis for the intracellular delivery of OSW-1 is investigated using fluorescent derivatives of OSW-1 and its closely related congeners. Despite the large differences in activity, all the fluorescent probes are found to translocate across the plasma membrane to the ER and Golgi apparatus. This observation suggests that the glycosylated cholestane moiety plays an important role in the cell internalization and intracellular localization property of OSW-1.

Chemical probe‐based approaches have proven powerful in recent years in the target identification studies of natural products. OSW‐1 is a saponin class of natural products with highly potent and selective cytotoxicity against various cancer cell lines. Understanding its mechanism of action is important for the development of anticancer drugs with potentially novel target pathways. This account reviews recent progress in the development of OSW‐1 derived probes for exploring the mechanism of its action. The key to the probe development is a judicious choice of functionalization sites and a selective functionalization strategy. The types of probes include fluorescent probes for cellular imaging analysis and affinity probes for target identification analysis.

This cover picture shows that an anticancer saponin OSW‐1 from Ornithogalum saundersiae was derivatized through site‐selective modification to provide a set of chemical probes for biological analysis. See the Personal Account by Rina Komatsu and Kaori Sakurai (DOI: 10.1002/tcr.201900042).

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