Current Organic Chemistry - Volume 17, Issue 6, 2013

In this review, major categories of molecular fluorophores were summarized with emphasis on their synthetic strategies and chemical transformations. Recent advancement in small-molecule fluorophores as novel molecular probes in living cells was also discussed.

Misfolding of a protein is a destructive process for variety of diseases that include neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, Huntington disease, mad cow disease, amyotrophic lateral sclerosis (ALS), and frontal temporal dementia (FTD), and other non-CNS diseases such as diabetes, cystic fibrosis, and lysosomal storage diseases. Formation of various misfunctional large assembles of the misfolded protein is the primary consequence. To detect the formation of the aggregated species is very important for not only basic mechanism research but also very crucial for diagnosis of the diseases. In this review, we updated references related to the new development of the dual functional fluorescent small molecule probes for detecting the aggregated proteins in vitro and in vivo.

Cu-catalyzed azide-alkyne cycloaddition has been developed as a new, simple, efficient, and generally applicable synthetic strategy, known as ‘Click Chemistry’. The reaction utilizes two bioorthogonal functional groups, azide and alkyne, which can be readily incorporated into biological molecules with straightforward chemical modification. The reaction can be performed in low substrate concentration under a wide range of conditions including aqueous physiological conditions, which finds a span of application ranging from material science, chemical biology/bio-conjugation, and pharmaceutical research and development. In this review, we focused on the new progress in developing the metal catalyzed, bioorthogonal azide-alkyne cycloaddition reaction (‘Click chemistry’) about catalyst species, the ligands and substrates and its application in the bio-imaging field from four aspects: (a) labeling of live cell surface; (b) imaging small molecules inside of living cells; (c) modifying cells with nanomaterials; and (d) vivo imaging.

The first reported click reaction, copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition had limited biocompatibility due to the high toxicity of copper. Since alternative bioorthogonal click reactions have been developed, they have strongly influenced the field of chemical biology. Here are summarized three main metal-free click methodologies based on cycloaddition, Staudinger and thioene reactions. This review contains the basic principles, some mechanistic considerations and a collection of reagents that can be used in each method. Firstly, Diels-Alder and strain promoted inverse electron demand Diels-Alder cycloadditions are outlined together with triazole and isoxazole formation by 1,3-dipolar cycloadditions. Secondly, Staudinger-Bertozzi ligation, a chemoselective reaction of azides and engineered triarylphosphines, is discussed. Finally, thio-click chemistries including thiol-ene, thiol-yne, thio-Michael and fluoro-thioclick reactions are reviewed. Among the most important bioapplications of these click methodologies is the labeling of glycans, proteins, lipids and DNA. Additionally, synthetic methods and surface immobilization of biomolecules and biologically useful polymeric materials are also reviewed.

Hydrogen sulfide (H2S) has been recognized as one of the three important gasotransmitters along with nitric oxide (NO) and carbon monoxide (CO). H2S plays regulatory roles in the cardiovascular system (CV), central nervous system (CNS), respiratory system, gastrointestinal system, and endocrine system. The study to understand its molecular mechanism is still ongoing. Current methods for the detection of H2S include chromatographic methods, electrochemical methods, and colorimetric/fluorometric methods. Fluorescent sensors and probes are especially important in modern analysis due to their high sensitivity, which can provide nanomolar detection; their compatibility with high-throughput screening (HTS), which allows for rapid assessment; and their applicability in live cell bioimaging, which allows real-time detection/observation. This review focuses on strategies used in designing fluorescent sensors and probes for H2S and their applications.

Reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), are important byproducts of oxygen metabolites. They are essential to life, but become highly harmful in case of exhaustion of antioxidants, causing oxidative stress through the oxidation of biomolecules. Sensitive and selective tools are needed to study H2O2 in living systems owing to its reactive and transient nature. The fluorescent H2O2 probes are powerful tools due to their high sensitivity, simplicity in data collection, and high spatial resolution in microscopic imaging techniques. This review focuses on the remarkable progress achieved in this field in the last few years.