Copper is an essential trace element in the human body. It usually is incorporated in the active center of metalloenzymes; however, research findings of the last years also indicate a fundamental role in signal transduction in the central nervous system.1 A disrupted copper homeostasis is linked to several neurodegenerative diseases, but the underlying molecular mechanisms remain poorly understood.1,2
Currently, fluorescence sensors are rarely used tools for the understanding of copper`s role on a molecular level. That is because the d9-configuration of Cu2+quenches the fluorescence. Additionally, most sensors rely on the HSAB concept to discriminate other metal ions in sensing, which can lead to cross-sensitivities with other bio metals.3
To resolve these issues, we established a new copper detection principle that leverages both the HSAB concept and the Lewis acidity for the selective detection of Cu2+. This sensor design comprises the weak linkage of a fluorophore in the non-fluorescent form with a hydrazone-based metal binding unit.4 This design allows Cu2+ to be detected by a multi-step cascade reaction: copper binding induces an intramolecular proton transfer at the metal binding unit, which in turn leads to a conformational change to stabilize the positive charge, resulting in a coordination motif that includes the linker between the fluorophore and hydrazone. The square-planar geometry of this newly generated binding motif enhances the selectivity for Cu2+, which strongly prefers square-planar coordination geometries. The Lewis acidity of Cu2+ polarizes the peptide bond incorporated into the linker, which results in fast hydrolysis, followed by the release of the fluorophore that isomerizes into the fluorescent form and thus, indicates copper with turn-on over 770. To allow the fine-tuning of the sensor properties, the design is based on a modular construction kit. In this contribution, the detection principle and photophysical properties of the sensor are presented.