The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornoe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of ∼5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support.

Cu-catalyzed azide-alkyne cycloaddition.

This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family. There is now information on the enzyme structure at all levels from primary (amino acid sequence) to quaternary (dimerization, association with other proteins) structure. The crystal structures of the oxygenase domains of inducible NOS (iNOS) and vascular endothelial NOS (eNOS) allow us to interpret other information in the context of this important part of the enzyme, with its binding sites for iron protoporphyrin IX (haem), biopterin, L-arginine, and the many inhibitors which interact with them. The exact nature of the NOS reaction, its mechanism and its products continue to be sources of controversy. The role of the biopterin cofactor is now becoming clearer, with emerging data implicating one-electron redox cycling as well as the multiple allosteric effects on enzyme activity. Regulation of the NOSs has been described at all levels from gene transcription to covalent modification and allosteric regulation of the enzyme itself. A wide range of NOS inhibitors have been discussed, interacting with the enzyme in diverse ways in terms of site and mechanism of inhibition, time-dependence and selectivity for individual isoforms, although there are many pitfalls and misunderstandings of these aspects. Highly selective inhibitors of iNOS versus eNOS and neuronal NOS have been identified and some of these have potential in the treatment of a range of inflammatory and other conditions in which iNOS has been implicated.

/pdf/nitric-oxide-synthases-structure-function-and-inhibition-1t31plqilr.pdf

Nitric oxide synthases: structure, function and inhibition

http://image.sciencenet.cn/olddata/kexue.com.cn/blog/admin/images/upfiles/2007101622257911935.pdf

The growing impact of click chemistry on drug discovery.

This review is written with the goal of informing public health concerns related to nanoscience, while raising awareness of nanomaterials toxicity among scientists and manufacturers handling them. We show that humans have always been exposed to nanoparticles and dust from natural sources and human activities, the recent development of industry and combustion-based engine transportation profoundly increasing anthropogenic nanoparticulate pollution. The key to understanding the toxicity of nanoparticles is that their minute size, smaller than cells and cellular organelles, allows them to penetrate these basic biological structures, disrupting their normal function. Among diseases associated with nanoparticles are asthma, bronchitis, lung cancer, neurodegenerative diseases (such as Parkinson`s and Alzheimer`s diseases), Crohn`s disease, colon cancer. Nanoparticles that enter the circulatory system are related to occurrence of arteriosclerosis, and blood clots, arrhythmia, heart diseases, and ultimately cardiac death. We show that possible adverse effects of nanoparticles on human health depend on individual factors such as genetics and existing disease, as well as exposure, and nanoparticle chemistry, size, shape, and agglomeration state. The faster we will understand their causes and mechanisms, the more likely we are to find cures for diseases associated with nanoparticle exposure. We foresee a future with better-informed, and hopefully more cautious manipulation of engineered nanomaterials, as well as the development of laws and policies for safely managing all aspects of nanomaterial manufacturing, industrial and commercial use, and recycling.

Nanomaterials and nanoparticles: Sources and toxicity

This review is presented as a common foundation for scientists interested in nanoparticles, their origin, activity, and biological toxicity. It is written with the goal of rationalizing and informing public health concerns related to this sometimes-strange new science of “nano,” while raising awareness of nanomaterials’ toxicity among scientists and manufacturers handling them. We show that humans have always been exposed to tiny particles via dust storms, volcanic ash, and other natural processes, and that our bodily systems are well adapted to protect us from these potentially harmful intruders. The reticuloendothelial system, in particular, actively neutralizes and eliminates foreign matter in the body, including viruses and nonbiological particles. Particles originating from human activities have existed for millennia, e.g., smoke from combustion and lint from garments, but the recent development of industry and combustion-based engine transportation has profoundly increased anthropogenic particulate pollution. Significantly, technological advancement has also changed the character of particulate pollution, increasing the proportion of nanometer-sized particles-“nanoparticles”-and expanding the variety of chemical compositions. Recent epidemiological studies have shown a strong correlation between particulate air pollution levels, respiratory and cardiovascular diseases, various cancers, and mortality. Adverse effects of nanoparticles on human health depend on individual factors such as genetics and existing disease, as well as exposure, and nanoparticle chemistry, size, shape, agglomeration state, and electromagnetic properties. Animal and human studies show that inhaled nanoparticles are less efficiently removed than larger particles by the macrophage clearance mechanisms in the lungs, causing lung damage, and that nanoparticles can translocate through the circulatory, lymphatic, and nervous systems to many tissues and organs, including the brain. The key to understanding the toxicity of nanoparticles is that their minute size, smaller than cells and cellular organelles, allows them to penetrate these basic biological structures, disrupting their normal function. Examples of toxic effects include tissue inflammation, and altered cellular redox balance toward oxidation, causing abnormal function or cell death. The manipulation of matter at the scale of atoms, “nanotechnology,” is creating many new materials with characteristics not always easily predicted from current knowledge. Within the nearly limitless diversity of these materials, some happen to be toxic to biological systems, others are relatively benign, while others confer health benefits. Some of these materials have desirable characteristics for industrial applications, as nanostructured materials often exhibit beneficial properties, from UV absorbance in sunscreen to oil-less lubrication of motors. A rational science-based approach is needed to minimize harm caused by these materials, while supporting continued study and appropriate industrial development. As current knowledge of the toxicology of “bulk” materials may not suffice in reliably predicting toxic forms of nanoparticles, ongoing and expanded study of “nanotoxicity” will be necessary. For nanotechnologies with clearly associated health risks, intelligent design of materials and devices is needed to derive the benefits of these new technologies while limiting adverse health impacts. Human exposure to toxic nanoparticles can be reduced through identifying creation-exposure pathways of toxins, a study that may someday soon unravel the mysteries of diseases such as Parkinson’s and Alzheimer’s. Reduction in fossil fuel combustion would have a large impact on global human exposure to nanoparticles, as would limiting deforestation and desertification. While nanotoxicity is a relatively new concept to science, this review reveals the result of life’s long history of evolution in the presence of nanoparticles, and how the human body, in particular, has adapted to defend itself against nanoparticulate intruders.

https://avs.scitation.org/doi/pdf/10.1116/1.2815690

The copper-catalyzed cycloaddition reaction between azides and alkynes functions efficiently in aqueous solution in the presence of a tris(triazolyl)amine ligand. The process has been employed to make rapid and reliable covalent connections to micromolar concentrations of protein decorated with either of the reactive moieties. The chelating ligand plays a crucial role in stabilizing the Cu(I) oxidation state and protecting the protein from Cu(triazole)-induced denaturation. Because the azide and alkyne groups themselves are unreactive with protein residues or other biomolecules, their ligation is of potential utility as a general bioconjugation method.

Bioconjugation by Copper(I)-Catalyzed Azide-Alkyne [3 + 2] Cycloaddition

A fluorogenic 1,3-dipolar cycloaddition reaction of 3-azidocoumarins and acetylenes.

Nanochemistry is the synthesis and study of well-defined structures with dimensions of 1 ± 100 nanometers (nm), and thus spans the size range between molecules and materials.[1] While supramolecular chemistry (making small molecules bigger) and microfabrication techniques (making big structures smaller) attack from the flanks, biology employs many constructs of this size. Examples include the photosynthetic reaction center, the ribosome, and membrane-bound receptor-signaling complexes, all notable because of their sophisticated yet modular function. The burgeoning field of nanotechnology[2] seeks to mimic the information-handling, materials-building, and responsive sensing capabilities of biological systems at the nanometer scale. The special requirements of this enterprise would be well served by building blocks of the proper size with predictable and programmable chemistry. Cowpea mosaic virus (CPMV) particles are 30 nm-diameter icosahedra, formed by 60 copies of two different types of protein subunits (Figure 1a).[3] The physical, biological, and genetic properties of CPMV have been well characterized.[4] Approximately one gram of virus is easily and routinely obtained from a kilogram of infected leaves of the black-eye pea plant. The structure of CPMV has been characterized at 2.8 ä resolution by X-ray crystallography and an atomic model of the particle has been constructed.[5] The virion displays icosahedral symmetry to the resolution of the crystal structure and an infectious clone of the virus allows sitedirected and insertional mutagenesis to be performed in a straightforward and rapid manner.[6] The particles are remarkably stable; they maintain their integrity at 60 C (pH 7) for at least one hour and at pH values from 3.5 to 9 indefinitely at room temperature. Different crystal forms of the virus can be readily produced under well-defined conditions (Figure 1d).[7, 8] Here we report on the selective Experimental Section

Qian Wang

Papers

Bioconjugation by Copper(I)-Catalyzed Azide-Alkyne [3 + 2] Cycloaddition

A fluorogenic 1,3-dipolar cycloaddition reaction of 3-azidocoumarins and acetylenes.

Icosahedral Virus Particles as Addressable Nanoscale Building Blocks

Natural supramolecular building blocks. Wild-type cowpea mosaic virus.

Head-to-tail peptide cyclodimerization by copper-catalyzed azide-alkyne cycloaddition.