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.

In 2001, Sharpless and co-workers introduced "click" chemistry, a new approach in organic synthesis that involves a handful of almost perfect chemical reactions. Among these carefully selected reactions, Huisgen 1,3-dipolar cycloadditions were shown to be the most effective and versatile and thus became the prime example of click chemistry. Hence, these long-neglected reactions were suddenly re-established in organic synthesis and, in particular, have gained popularity in materials science. The number of publications dealing with click chemistry has grown exponentially over the last two years. The Minireview discusses whether click chemistry is a miracle tool or an ephemeral trend.

1,3‐Dipolar Cycloadditions of Azides and Alkynes: A Universal Ligation Tool in Polymer and Materials Science

Dendron-mediated self-assembly, disassembly, and self-organization of complex systems have been investigated. The most ideal building blocks would need to display shape persistence in solution and in the solid state, since only this feature provides access to the use of complementary methods of structural analysis. Most supramolecular dendrimers are chiral even when they are constructed from nonchiral building blocks and are equipped with mechanisms that amplify chirality. This poses additional challenges associated with the understanding of the structural origin of chirality in different supramolecular structures through combinations of structural analysis methods. While many supramolecular structures assembled from dendrimers and dendrons resemble some of the related morphologies generated from block-copolymers, they are much more complex and are not determined by the volume ratio between the dissimilar parts of the molecule.

Dendron-Mediated Self-Assembly, Disassembly, and Self-Organization of Complex Systems

The copper(I)-catalyzed 1,2,3-triazole-forming reaction between azides and terminal alkynes has become the gold standard of 'click chemistry' due to its reliability, specificity, and biocompatibility. Applications of click chemistry are increasingly found in all aspects of drug discovery; they range from lead finding through combinatorial chemistry and target-templated in vitro chemistry, to proteomics and DNA research by using bioconjugation reactions. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen-bonding and dipole interactions. The present review will focus mainly on the recent literature for applications of this reaction in the field of medicinal chemistry, in particular on use of the 1,2,3-triazole moiety as pharmacophore.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/asia.201100432

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

The copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) “click” reaction and its applications. An overview

Click chemistry in combination with ultrafiltration has allowed the quick, efficient, and reliable multivalent conjugation of unprotected alkyne-derived carbohydrates to three generations of azido-terminated gallic acid−triethylene glycol dendrimers under aqueous conditions. The reported procedure allows the atom economical incorporation of up to 27 unprotected fucose, mannose, and lactose residues, in reproducible high yields (up to 92%), requiring only catalytic amounts of Cu. The completion of the conjugation process was clearly established in all cases by both 1H NMR and MALDI-TOF MS.

A Click Approach to Unprotected Glycodendrimers

"Clickable" PEG-dendritic block copolymers.

Experiments by Surface Plasmon Resonance (SPR) illustrate the relevance of lectin density for the reliable evaluation of binding efficiencies in surface-based multivalent carbohydrate recognition. The difference between affinity data obtained by solution and surface-based experiments is also stressed.

Probing the relevance of lectin clustering for the reliable evaluation of multivalent carbohydrate recognition.

Multivalency is a key, ubiquitous phenomenon in nature characterized by a complex combination of binding mechanisms, with special relevance in carbohydrate-lectin recognition. Herein we introduce an original surface plasmon resonance kinetic approach to analyze multivalent interactions that has been validated with dendrimers as monodisperse multivalent analytes binding to lectin clusters. The method, based on the analysis of early association and late dissociation phases of the sensorgrams provides robust information of the glycoconjugate binding efficiency and real-time structural data of the binding events under the complex scenario of the glyco-cluster effect. Notably, it reveals the dynamic nature of the interaction and offers experimental evidence on the contribution of binding mechanisms.

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Real-time evaluation of binding mechanisms in multivalent interactions: a surface plasmon resonance kinetic approach.

/pdf/dendrimers-reduce-toxicity-of-ab-1-28-peptide-during-3qyukmnh80.pdf

Juan Correa

Papers

A Click Approach to Unprotected Glycodendrimers

"Clickable" PEG-dendritic block copolymers.

Probing the relevance of lectin clustering for the reliable evaluation of multivalent carbohydrate recognition.

Real-time evaluation of binding mechanisms in multivalent interactions: a surface plasmon resonance kinetic approach.

Dendrimers reduce toxicity of Aβ 1-28 peptide during aggregation and accelerate fibril formation.