Development of next-generation photolabile copper cages with improved copper binding properties

Abstract

Seven new nitrogen-donor ligands that contain a photoactive nitrophenyl group within the ligand backbone have been prepared and evaluated for their binding affinity for copper(ii) and zinc(ii). Among this series, the ligand 3Gcage (pyridine-2-carboxylic acid {1-(2-nitro-phenyl)-3-[(pyridin-2-ylmethyl)-amino]-propyl}-amide) has the best affinity for copper(ii), with an apparent dissociation constant at pH 7.4 of 0.18 fM. Exposure of buffered aqueous solutions of 3Gcage or Cu(ii)-bound 3Gcage to UV light induces bond cleavage in the ligand backbone, which reduces the denticity of the ligands. The quantum yields of photolysis for 3Gcage in the absence and presence of Cu(ii) are 0.66 and 0.43, respectively. Prior to photolysis, the 3Gcage ligand inhibits copper from generating hydroxyl radicals in the presence of hydrogen peroxide and ascorbic acid; however, hydroxyl radical formation increases by more than 300% following light activation, showing that the reactivity of the copper center can be triggered by light.

Functional Switching of a Native Neuropeptide Through Interactions with Pathogenic Factors in Dementia

“…This optical band was notably shifted to ca. 720 nm in the presence of a hexadentate chelator, EDTA (ethylenediaminetetraacetic acid), which is consistent with that of Cu(II)(EDTA) 34 . We further carried out fluorescence-quenching experiments 35 to obtain the dissociation constant (Kd) value of Cu(II)-SST.…”

Visualizing metal ions in cells: An overview of analytical techniques, approaches, and probes

“…Such tools permit precise spatial and temporal control of the caged molecule or ion in cells and were instrumental in revealing how oscillatory Ca 2+ signals are decoded by cells [118]. Although there are no caged metal complexes that been used in live cells, advances have been made in recent years for the development and characterization of caged-Zn 2+ , ZinCleave-1 and 2, [119, 120], and one Cu 2+ [121, 122]. In an alternative approach, the genetically encodeable light oxygen voltage (LOV) domain has been used as a light-induced protein switch, giving rise to local activation of GTPases [123] and control of Ca 2+ signals [124], although this approach has not yet been applied to other metal ions.…”

A Zinc(II) Photocage Based on a Decarboxylation Metal Ion Release Mechanism for Investigating Homeostasis and Biological Signaling

“…[11] Alternatively, photolytically breaking a carbon-heteroatom bond provides compounds that release metal ions through the reduction of chelate effects. The Cleav class of photocaged complexes can effectively buffer and release Ca 2+ , [13] Cu 2+/1+ , [14,15] or Zn 2+ depending on the ligand design. [16,17] Photocages based on oNB remain the dominant technology to study signal transduction mediated by biomolecules despite limitations like slow analyte-release kinetics, the requirement of UV light for photolysis and the formation of potentially toxic nitroso photoproducts.…”