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    Click Chemistry | November 2019 Newsletter

    Click-Chemistry-MaxVal-Newsletter

    We provide a technology overview of click chemistry, and throws light on the seemingly endless applications of these unique reactions.

    Click chemistry was defined by Nobel Laureate Karl Barry Sharpless and his co-workers at the Scripps Research Institute in 2001 as a collection of versatile organic reactions that can be used for the synthesis of useful new compounds with capabilities for generating combinatorial libraries in drug discovery, the pharmaceutical industry and material science. The concept of click chemistry is a stepwise, selective, stereospecific coupling procedure of two molecules, A and B, to generate an adduct of commercial and scientific importance.

    Although there are many reactions under this set, the primary Click reaction utilized in polymer chemistry involves Huisgen copper-catalyzed reaction scheme between a terminal alkyne and a terminal azide to exclusively form the 1,2,3-triazole units. The other reactions in click reactions set can include copper(I) catalyzed azide-alkyne cycloaddition (CuAAC), strain-promoted alkyne-nitrone and azide-alkyne cycloaddition, inverse-demand Diels-Alder reaction, Ruthenium-catalyzed azide alkyne cycloaddition, nucleophilic ring openings, Staudinger ligation, certain Michael additions, thiol-ene radical reaction illustrated below (Figure 2).

    image2-51Figure 2: Click Reaction set
     

    Since its inception in 1999, click chemistry has been applied in a wide variety of fields ranging from microelectronics to virus labeling and cancer treatment. The research areas and applications of click chemistry cover drug discovery, natural product discovery, dendrimer design, carbohydrate conjugation, bio-conjugation, oligonucleotide modification, biopolymers, biomaterials, chemical libraries, material science and nanotechnology.

    The need to replace non-renewable resources has played a vital role in the development of biodegradable resources, such as modified macromolecular architecture. As a green chemistry approach, click chemistry is used for modification of macromolecules such as cellulose, dextran, chitosan, starch and other major macromolecules by azidation, esterification and propargylation methods. There are several molecules, such as unnatural amino acid, which can be synthesized by click reactions. Click chemistry is also used for quantitatively synthesizing step-growth polymers. The Click gel developed for DNA electrophoresis to crosslink functional polymer using CuAAC cycloaddition chains has considerably improved resolution and separation efficiency. It is also preferentially used in the oligonucleotide labeling method due to the level of selectivity and ability to add covalent linkages between biochemical species.

    The principal driving force behind the development of click chemistry is the pharmaceutical industry’s need to synthesize large molecules that can be used as drugs. Click chemistry has stimulated research in biodegradable agents and diagnostics. One example is the conversion of commercial polycaprolactone-diol (PCL-diol) into diazido-polycaprolactone for making cellulose ester biodegradable films. Thanks to click chemistry’s ability to produce mimics of ‘traditional’ pharmacophores and natural products, there is active research in natural products and pharmaceuticals. One of the leading examples is the development of a series of triazole-bearing caged xanthone derivatives of DDO-6101 with oral antitumor activity and drug-like properties by coupling hydrophilic groups and caged xanthone.

    Patent filings depict a rise in filing activity until 2017, then a sudden downfall in filings (illustrated in Figure 3) with the US being the top filer of all patent families. China is at a distant second position, whereas Europe and PCT Filings account for approximately 70 and 25 families, respectively.

    image3-55image1-64

    Figure 3: Chart Illustrating the Patent Filing Trend and Map Indicating Geographical Origins of First Filing. EP and PCT Filings Account for about 70 and 25 Families Respectively

    In addition to several research publications, there have also been a number of interesting patent applications with click chemistry involvement over the past few years. US8193335B2 discloses methods of producing reporter molecules suitable for the detection of nucleic acids. Another patent application, US20090306310A1, discusses the preparation of functionalized dendritic macromolecules with minimal purification steps using CuAAC reaction. For sealants and adhesive applications, US20180327553A1 provides information on a reaction product of a functionalized polymer backbone and a functionalized silane with azide-alkyne cycloaddition. In terms of major players, the Scripps Research Institute has a patent portfolio on click-chemistry.

    Selected patent holders and licensees include Invitrogen, Allozyne, Aileron, Integrated Diagnostics. BaseClick, a BASF subsidiary, holds a worldwide license for the research and diagnostic market in the nucleic acid field.

    The future prospect of click chemistry looks exciting as it can open up a wide field of discoveries in biotechnology, biochemistry, medicinal chemistry, material sciences and nanosciences. It can cover a wide range of synthetic reactions to generate different types of functional molecules that are biocompatible, biodegradable and require minimal purification.

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    Companion Diagnostics | November 2019 Newsletter
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