ABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , Cholestenones/chemistry , Saponins/chemistry , Affinity Labels , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Biotinylation , Cell Line, Tumor , Cell Proliferation/drug effects , Cholestenones/chemical synthesis , Cholestenones/pharmacology , Fluorescent Dyes/chemistry , Humans , Proteins/chemistry , Proteins/metabolism , Saponins/chemical synthesis , Saponins/pharmacologyABSTRACT
Sortin1 is an inhibitor of vesicular biogenesis and transport, which is shared among eukaryotes and plants with an unknown mode of action. Toward exploration of its target proteins, we developed alkyne as well as biotin conjugated photoaffinity probes derived from Sortin1. Due to the presence of phenylketone moiety, Sortin1 was anticipated to serve as a photoreactive group in a similar manner to a commonly used photoreactive group, benzophenone. The core structure based on 5-oxo-1,4-dihydroindenopyridine was constructed in one step using three-component Hantzsch dihydropyridine synthesis. We demonstrated that Sortin1 displayed photocrosslinking reactivity against a model binding protein, which would be useful for capturing and detecting binding proteins.
