Structure–Activity Relationship of the Linker Moiety in Photoinduced Electron Transfer-Driven Nitric Oxide Releasers

Abstract

Nitric oxide (NO) is involved in numerous physiological activities including vasodilation, neurotransmission, and immune system regulation. NO-releasing small compounds are used to investigate the physiological activity of NO and to treat circulatory diseases, such as hypertension and angina pectoris. Among them, light-controllable NO releasers (caged NOs) enable spatiotemporal control of NO’s bioactivities. We previously reported NORD-1, a photoinduced electron transfer (PeT)-driven NO releaser that responds to red light. In the PeT-driven NO releasers, the NO release is triggered by photoinduced electron transfer from the N-nitrosoaminophenol to the light-harvesting dye. However, additional functionalization of PeT-driven NO releasers is required to enable introduction of tissue targeting groups or novel release triggers. As such, structure–activity relationship studies are needed to identify a suitable site for modification so as not to affect the NO-releasing efficiency of the PeT. Here, we investigated the functional impact of introducing substituents into the linker region connecting the light-harvesting antenna and NO releasing moiety. Although introduction of various substituents elicited only minor changes in NO-releasing efficiency and vasodilation activity, dialkylamino groups induced pH-dependent changes in NO-releasing reactivity. The structure–activity relationship of the linker moiety could provide fruitful information in further functionalizing PeT-driven NO releasers for biological applications.