Christopher J. Chang

Metals in Neurobiology: Probing Their Chemistry and Biology with Molecular Imaging

The brain is a singular organ of unique biological complexity that serves as the command center for cognitive and motor function. As such, this specialized system also possesses a unique chemical composition and reactivity at the molecular level. In this regard, two vital distinguishing features of the brain are its requirements for the highest concentrations of metal ions in the body and the highest per-weight consumption of body oxygen. In humans, the brain accounts for only 2% of total body mass but consumes 20% of the oxygen that is taken in through respiration. As a consequence of high oxygen demand and cell complexity, distinctly high metal levels pervade all regions of the brain and central nervous system. Structural roles for metal ions in the brain and the body include the stabilization of biomolecules in static (e.g., Mg2+ for nucleic acid folds, Zn2+ in zinc-finger transcription factors) or dynamic (e.g., Na+ and K+ in ion channels, Ca2+ in neuronal cell signaling) modes, and catalytic roles for brain metal ions are also numerous and often of special demand.

Synthetic fluorescent sensors for studying the cell biology of metals

Metals are essential for sustaining all forms of life, but alterations in their cellular homeostasis are connected to severe human disorders, including cancer, diabetes and neurodegenerative diseases. Fluorescent small molecules that respond to metal ions in the cell with appropriate selectivity and sensitivity offer the ability to probe physiological and pathological consequences of the cell biology of metals with spatial and temporal fidelity. Molecular imaging of normal and abnormal cellular metal ion pools using these new chemical tools provides a host of emerging opportunities for visualizing, in real time, aspects of metal accumulation, trafficking, and function or toxicity in living systems. This review presents a brief survey of available synthetic small-molecule sensor types for fluorescence detection of cellular metals.

Reaction-based small-molecule fluorescent probes for chemoselective bioimaging

The dynamic chemical diversity of elements, ions and molecules that form the basis of life offers both a challenge and an opportunity for study. Small-molecule fluorescent probes can make use of selective, bioorthogonal chemistries to report on specific analytes in cells and in more complex biological specimens. These probes offer powerful reagents to interrogate the physiology and pathology of reactive chemical species in their native environments with minimal perturbation to living systems. This Review presents a survey of tools and tactics for using such probes to detect biologically important chemical analytes. We highlight design criteria for effective chemical tools for use in biological applications as well as gaps for future exploration.

A Molecular MoS2 Edge Site Mimic for Catalytic Hydrogen Generation

Edging In on MoS2 Molybdenum disulfide is a widely used catalyst in the petrochemical industry that has recently shown promise for water-splitting applications. Its activity appears to be confined to edge sites with exposed disulfide groups, although the precise geometric details underlying the chemistry remain uncertain. Karunadasa et al. (p. 698) prepared a molecular complex modeling one of these edge sites, in which a triangular Mo-S-S unit is supported by metal coordination to five tethered pyridine rings. The molecule was characterized crystallographically and proved robustly active toward electrochemical generation of hydrogen from water, even when applied to crudely filtered seawater. A small molecule functionally models the active component of an extended solid material with wide catalytic applications. Inorganic solids are an important class of catalysts that often derive their activity from sparse active sites that are structurally distinct from the inactive bulk. Rationally optimizing activity is therefore beholden to the challenges in studying these active sites in molecular detail. Here, we report a molecule that mimics the structure of the proposed triangular active edge site fragments of molybdenum disulfide (MoS2), a widely used industrial catalyst that has shown promise as a low-cost alternative to platinum for electrocatalytic hydrogen production. By leveraging the robust coordination environment of a pentapyridyl ligand, we synthesized and structurally characterized a well-defined MoIV-disulfide complex that, upon electrochemical reduction, can catalytically generate hydrogen from acidic organic media as well as from acidic water.

Chemistry and biology of reactive oxygen species in signaling or stress responses.

Reactive oxygen species (ROS) are a family of molecules that are continuously generated, transformed and consumed in all living organisms as a consequence of aerobic life. The traditional view of these reactive oxygen metabolites is one of oxidative stress and damage that leads to decline of tissue and organ systems in aging and disease. However, emerging data show that ROS produced in certain situations can also contribute to physiology and increased fitness. This Perspective provides a focused discussion on what factors lead ROS molecules to become signal and/or stress agents, highlighting how increasing knowledge of the underlying chemistry of ROS can lead to advances in understanding their disparate contributions to biology. An important facet of this emerging area at the chemistry-biology interface is the development of new tools to study these small molecules and their reactivity in complex biological systems.

Reaction-Based Fluorescent Probes for Selective Imaging of Hydrogen Sulfide in Living Cells

Hydrogen sulfide (H(2)S) is emerging as an important mediator of human physiology and pathology but remains difficult to study, in large part because of the lack of methods for selective monitoring of this small signaling molecule in live biological specimens. We now report a pair of new reaction-based fluorescent probes for selective imaging of H(2)S in living cells that exploit the H(2)S-mediated reduction of azides to fluorescent amines. Sulfidefluor-1 (SF1) and Sulfidefluor-2 (SF2) respond to H(2)S by a turn-on fluorescence signal enhancement and display high selectivity for H(2)S over other biologically relevant reactive sulfur, oxygen, and nitrogen species. In addition, SF1 and SF2 can be used to detect H(2)S in both water and live cells, providing a potentially powerful approach for probing H(2)S chemistry in biological systems.

Covalent organic frameworks comprising cobalt porphyrins for catalytic CO2 reduction in water

Improving cobalt catalysts Tethering molecular catalysts together is a tried and trusted method for making them easier to purify and reuse. Lin et al. now show that the assembly of a covalent organic framework (COF) structure can also improve fundamental catalytic performance. They used cobalt porphyrin complexes as building blocks for a COF. The resulting material showed greatly enhanced activity for the aqueous electrochemical reduction of CO2 to CO. Science, this issue p. 1208 A covalent lattice enhances the activity of a catalyst for electrochemical conversion of carbon dioxideto carbon monoxide. Conversion of carbon dioxide (CO2) to carbon monoxide (CO) and other value-added carbon products is an important challenge for clean energy research. Here we report modular optimization of covalent organic frameworks (COFs), in which the building units are cobalt porphyrin catalysts linked by organic struts through imine bonds, to prepare a catalytic material for aqueous electrochemical reduction of CO2 to CO. The catalysts exhibit high Faradaic efficiency (90%) and turnover numbers (up to 290,000, with initial turnover frequency of 9400 hour−1) at pH 7 with an overpotential of –0.55 volts, equivalent to a 26-fold improvement in activity compared with the molecular cobalt complex, with no degradation over 24 hours. X-ray absorption data reveal the influence of the COF environment on the electronic structure of the catalytic cobalt centers.

A Targetable Fluorescent Probe for Imaging Hydrogen Peroxide in the Mitochondria of Living Cells

We present the design, synthesis, and biological applications of mitochondria peroxy yellow 1 (MitoPY1), a new type of bifunctional fluorescent probe for imaging hydrogen peroxide levels within the mitochondria of living cells. MitoPY1 combines a chemoselective boronate-based switch and a mitochondrial-targeting phosphonium moiety for detection of hydrogen peroxide localized to cellular mitochondria. Confocal microscopy and flow cytometry experiments in a variety of mammalian cell types show that MitoPY1 can visualize localized changes in mitochondrial hydrogen peroxide concentrations generated by situations of oxidative stress.

A molecular molybdenum-oxo catalyst for generating hydrogen from water

A growing awareness of issues related to anthropogenic climate change and an increase in global energy demand have made the search for viable carbon-neutral sources of renewable energy one of the most important challenges in science today. The chemical community is therefore seeking efficient and inexpensive catalysts that can produce large quantities of hydrogen gas from water. Here we identify a molybdenum-oxo complex that can catalytically generate gaseous hydrogen either from water at neutral pH or from sea water. This work shows that high-valency metal-oxo species can be used to create reduction catalysts that are robust and functional in water, a concept that has broad implications for the design of ‘green’ and sustainable chemistry cycles.

Unraveling the Biological Roles of Reactive Oxygen Species

Reactive oxygen species are not only harmful agents that cause oxidative damage in pathologies, they also have important roles as regulatory agents in a range of biological phenomena. The relatively recent development of this more nuanced view presents a challenge to the biomedical research community on how best to assess the significance of reactive oxygen species and oxidative damage in biological systems. Considerable progress is being made in addressing these issues, and here we survey some recent developments for those contemplating research in this area.