Two-Step Synthesis of a Clickable Photoaffinity Probe from an Anticancer Saponin OSW-1 and its Photochemical Reactivity

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. Click for a photo: A clickable photoaffinity probe was semisynthetically prepared from OSW‐1 by a two‐step procedure involving Me2SnCl2‐mediated, site‐selective acylation. The probe retained the potent anticancer activity of the parent natural product. Photochemical studies demonstrated its ability to crosslink a model sterol‐binding protein in an affinity‐dependent fashion and to efficiently conjugate a fluorophore or biotin by click chemistry.