Glutathione-Triggered Nitrite Release From Organic Nitrites Enhances Nitric Oxide Bioavailability in Mammalian Cells.

The conversion of nitrite (NO₂ ^-) to nitric oxide (NO) represents a key pathway for NO generation under ischemic conditions. Therefore, organic nitro compounds capable of releasing nitrite under physiological environments have attracted considerable attention. Here, we demonstrate that simple 4-nitro-1,8-naphthalimide derivatives efficiently and almost quantitatively liberate nitrite upon reaction with biological thiols, particularly glutathione (GSH). These compounds function as NO prodrugs, enhancing NO bioavailability in mammalian cells through intracellular nitrite-to-NO conversion. Notably, their selectivity toward GSH and the intrinsic fluorescence of the resulting glutathione adducts enable their use as probes for monitoring intracellular GSH levels. Furthermore, cotreatment of endothelial cells with these naphthalimide derivatives and the NO probe DAF-FM diacetate provides a valuable strategy to distinguish between endogenously produced NO and NO generated via synthetic nitro compound-derived nitrite release. Together, these findings highlight 4-nitro-1,8-naphthalimides as a promising platform for both NO delivery and real-time cellular redox sensing.