Fluorescent chemosensors for ions and neutral analytes have been widely applied in many diverse fields such as biology, physiology, pharmacology, and environmental sciences. The field of fluorescent chemosensors has been in existence for about 150 years. In this time, a large range of fluorescent chemosensors have been established for the detection of biologically and/or environmentally important species. Despite the progress made in this field, several problems and challenges still exist. This tutorial review introduces the history and provides a general overview of the development in the research of fluorescent sensors, often referred to as chemosensors. This will be achieved by highlighting some pioneering and representative works from about 40 groups in the world that have made substantial contributions to this field. The basic principles involved in the design of chemosensors for specific analytes, problems and challenges in the field as well as possible future research directions are covered. The application of chemosensors in various established and emerging biotechnologies, is very bright.

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Fluorescent chemosensors: The past, present and future

Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the cell and mitochondrial membrane potentials, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this Review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

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Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Hydrogen sulfide (H2S), a gaseous species produced by both bacteria and higher eukaryotic organisms, including mammalian vertebrates, has attracted attention in recent years for its contributions to human health and disease. H2S has been proposed as a cytoprotectant and gasotransmitter in many tissue types, including mediating vascular tone in blood vessels as well as neuromodulation in the brain. The molecular mechanisms dictating how H2S affects cellular signaling and other physiological events remain insufficiently understood. Furthermore, the involvement of H2S in metal-binding interactions and formation of related RSS such as sulfane sulfur may contribute to other distinct signaling pathways. Owing to its widespread biological roles and unique chemical properties, H2S is an appealing target for chemical biology approaches to elucidate its production, trafficking, and downstream function. In this context, reaction-based fluorescent probes offer a versatile set of screening tools to visualize H2S pools in living systems. Three main strategies used in molecular probe development for H2S detection include azide and nitro group reduction, nucleophilic attack, and CuS precipitation. Each of these approaches exploits the strong nucleophilicity and reducing potency of H2S to achieve selectivity over other biothiols. In addition, a variety of methods have been developed for the detection of other reactive sulfur species (RSS), including sulfite and bisulfite, as well as sulfane sulfur species and related modifications such as S-nitrosothiols. Access to this growing chemical toolbox of new molecular probes for H2S and related RSS sets the stage for applying these developing technologies to probe reactive sulfur biology in living systems.

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Chemical probes for molecular imaging and detection of hydrogen sulfide and reactive sulfur species in biological systems

The cyanine platforms including cyanine, hemicyanine, and squaraine are good candidates for developing chemosensors because of their excellent photophysical properties, outstanding biocompatibility, and low toxicity to living systems. A huge amount of research work involving chemosensors based on the cyanine platforms has emerged in recent years. This review focuses on the development from 2000 to 2015, in which cyanine, hemicyanine, and squaraine sensors will be separately summarized. In each section, a systematization according to the type of detection mechanism is established. The basic principles about the design of the chemosensors and their applications as bioimaging agents are clearly discussed. In addition, we emphasize the advances that have been made in improving the detection performance through incorporation of the chemosensors into nanoparticles.

Recent Development of Chemosensors Based on Cyanine Platforms

Using methodology developed herein, it is found that reactive persulfides and polysulfides are formed endogenously from both small molecule species and proteins in high amounts in mammalian cells and tissues. These reactive sulfur species were biosynthesized by two major sulfurtransferases: cystathionine β-synthase and cystathionine γ-lyase. Quantitation of these species indicates that high concentrations of glutathione persulfide (perhydropersulfide >100 μM) and other cysteine persulfide and polysulfide derivatives in peptides/proteins were endogenously produced and maintained in the plasma, cells, and tissues of mammals (rodent and human). It is expected that persulfides are especially nucleophilic and reducing. This view was found to be the case, because they quickly react with H2O2 and a recently described biologically generated electrophile 8-nitroguanosine 3′,5′-cyclic monophosphate. These results indicate that persulfides are potentially important signaling/effector species, and because H2S can be generated from persulfide degradation, much of the reported biological activity associated with H2S may actually be that of persulfides. That is, H2S may act primarily as a marker for the biologically active of persulfide species.

https://www.pnas.org/content/pnas/111/21/7606.full.pdf

Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling.

Hydrogen sulfide (H2 S) and hydrogen polysulfides (H2 Sn , n>1) are endogenous regulators of many physiological processes. In order to better understand the symbiotic relationship and cellular cross-talk between H2 S and H2 Sn , it is highly desirable to develop single fluorescent probes which enable dual-channel discrimination between H2 S and H2 Sn . Herein, we report the rational design, synthesis, and evaluation of the first dual-detection fluorescent probe DDP-1 that can visualize H2 S and H2 Sn with different fluorescence signals. The probe showed high selectivity and sensitivity to H2 S and H2 Sn in aqueous media and in cells.

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A Single Fluorescent Probe to Visualize Hydrogen Sulfide and Hydrogen Polysulfides with Different Fluorescence Signals.

The design, synthesis, properties, and cell imaging applications of a series of 2-pyridyl disulfide based fluorescent probes (WSP1, WSP2, WSP3, WSP4 and WSP5) for hydrogen sulfide detection are reported. The strategy is based on the dual-nucleophilicity of hydrogen sulfide. A hydrogen sulfide mediated tandem nucleophilic substitution-cyclization reaction is used to release the fluorophores and turn on the fluorescence. The probes showed high sensitivity and selectivity for hydrogen sulfide over other reactive sulfur species, including cysteine and glutathione.

Fluorescent Probes Based on Nucleophilic Substitution–Cyclization for Hydrogen Sulfide Detection and Bioimaging

A sulfane sulfur mediated benzodithiolone formation was developed. Based on this reaction, two fluorescent probes (SSP1 and SSP2) for the detection of sulfane sulfur species (persulfide, polysulfide, and elemental sulfur) were prepared and evaluated. The probes showed high selectivity and sensitivity to sulfane sulfurs. Moreover, SSP2 was successfully applied for bioimaging sulfane sulfurs in living cells.

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New fluorescent probes for sulfane sulfurs and the application in bioimaging

Reactive sulfur species have received considerable attention due to their various biological functions. Among these molecules, hydrogen polysulfides (H2Sn, n > 1) are recently suggested to be the actual signaling molecules derived from hydrogen sulfide (H2S). Hydrogen polysulfides may also have their own biosynthetic pathways. The research on H2Sn is rapidly growing. However, the detection of H2Sn is still challenging. In this work we report a H2Sn-mediated benzodithiolone formation under mild conditions. Based on this reaction, specific fluorescent probes for H2Sn are prepared and evaluated. The probe DSP-3 shows good selectivity and sensitivity for H2Sn.

http://pubs.acs.org/doi/pdf/10.1021/ja502968x

Wei Chen

Papers

Chemical probes for molecular imaging and detection of hydrogen sulfide and reactive sulfur species in biological systems

A Single Fluorescent Probe to Visualize Hydrogen Sulfide and Hydrogen Polysulfides with Different Fluorescence Signals.

Fluorescent Probes Based on Nucleophilic Substitution–Cyclization for Hydrogen Sulfide Detection and Bioimaging

New fluorescent probes for sulfane sulfurs and the application in bioimaging

Rational Design and Bioimaging Applications of Highly Selective Fluorescence Probes for Hydrogen Polysulfides