Discovery of a novel photosensitizer based on the enediyne antibiotic N1999A2 and its application as a glutathione-activatable theranostic agent

Abstract

Abstract The 2-naphthol derivative 2, which corresponds to the aromatic moiety of the enediyne antibiotic N1999A2, was found to degrade protein under irradiation with long-wavelength UV light in the absence of any additives. Structure–activity relationship studies of 2 indicated that 3, in which the primary hydroxyl group at the C5 position of 2 is modified with a t-butyldiphenylsilyl group, has strong protein photodegradation ability. Furthermore, the theranostic molecule 5 was designed and synthesized. Compound 5 comprises a disulfide moiety linked to the hydroxyl group at the C2 position of 3 and to the fluorescent molecule dicyanomethylene-4H-pyran (DCM) chromophore derivative 6. The disulfide moiety is cleaved in the presence of glutathione (GSH), 5 showed significantly reduced photolytic activity and fluorescence compared to 3 and 6, but produced 3 and 6 when reacted with GSH. 5 showed selective fluorescence and photocytotoxicity against cancer cells that highly express GSH.