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Zastosowanie chemii "klik" do syntezy biokoniugatów salinomycyny

Sulik Michał, Antoszczak Michał, Huczyński Adam

Wiadomości Chemiczne

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2022

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[Z] 76, 11-12

883--907

EN

Bioconjugation is a well-known method of designing new drug candidates for many different diseases, including cancer. The idea of the process is to join two or more bioactive molecules by means of a covalent bond. Thus, obtained hybrids often exhibit higher efficiency compared to that of the starting compounds. Recently, the use of click chemistry, especially Huisgen 1,3-dipolar cycloaddition, has attracted much attention for the synthesis of bioconjugates of natural compounds. The great advantage of this reaction is its high yield and enzymatic stability of the 1,2,3-triazole ring. Mild conditions of this reaction guarantee that it can be used to modify compounds with low stability, such as salinomycin – a representative of ionophore antibiotics. Salinomycin is a naturally occurring lipophilic compound isolated from Streptomyces albus. It is capable of forming complexes with metal cations and transport them across the lipid membranes. This process disturbs the intercellular Na+ /K+ concentration gradient and leads to apoptosis (programmed cell death). Salinomycin exhibits high anticancer activity, including efficiency against multidrug-resistant cancer cells and cancer stem cells of different origin. Chemical modification of the salinomycin skeleton to increase its biological activity is a very interesting research direction. Our review article is focused on the application of click chemistry for the synthesis of salinomycin bioconjugates with many different biologically active compounds (Cinchona alkaloids, nucleosides, triphenylphosphonium cation, betulinic acid and other ionophore antibiotics). Some of the obtained hybrids exhibit higher efficiency compared to that of the starting compounds, e.g., increased anticancer activity, the ability to overcome multi-drug resistance, or improved ionophoretic properties. These results are a good starting point for further research on the use of click chemistry in the synthesis of highly functional hybrids of natural compounds.

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Wykorzystanie reakcji 1,3-dipolarnej cykloaddycji Huisgena do modyfikacji nukleozydów i ligonukleotydów

Radzikowska E.

Wiadomości Chemiczne

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2011

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[Z] 65, 3-4

207-234

EN

The 1,3-dipolar cycloaddition reaction between azides and terminal alkynes, known as the Huisgen reaction, constitutes a powerful tool for the synthesis of versatile molecules containing carbon – heteroatom bond. The use of a copper(I) salt in this reaction allowed Sharpless to develop the concept of „click chemistry” [1]. This strategy is based on reactions between small units characterized by mild reaction conditions, versatility, high yields and stereospecificity. The chemistry of nucleic acids and nucleoside analogues is undergoing rapid developments and numerous compounds from these classes of compounds are used in medicinal treatment. Analogues of nucleoside constitute a class of drugs that possesses either anticancer or/and antiviral activity (against HIV, HSV, VZV or HCV viruses) [3]. Many modified oligonucleotides show biological activity. As potential drugs oligonucleotides are employed in antisense, antigen and aptamer strategies. An antisense therapeutic agent acts on the pathogenic mRNA causing inactivation of the target whereas an antigen agent acts on DNA and aptamer on unwanted protein. It is not surprising that number of research groups are trying to join the concept of click chemistry with nucleic acids chemistry. In this way, it is possible to obtain new molecules like base- or sugar-modified nucleosides, nucleosides, bioconjugates and olignucleotides. The copper-catalyzed 1,3-dipolar cycloaddition CuAAC allows to functionalize DNA, for example by labelling it through attaching small molecules to DNA. Two general strategies have been developed for this purpose: presynthetic and postsynthetic labelling. In the presynthetic method nucleotide monomers are labelled before DNA synthesis and purification. In the postsynthetic strategy DNA containing small reactive groups is synthesized first and then it is conjugated with the desired molecules. CuAAC is also a convenient method for the synthesis of modified oligonucleotides in which phosphodiester linkage is replaced by 1,2,3- -triazole or for a solid phase synthesis. Such molecules appear to be useful in medicine, molecular diagnostic (e.g. fluorescent dyes) or mechanistic molecular model in the future.

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Click chemistry - czyżby rewolucja w syntezie organicznej?

Kacprzak K.

Wiadomości Chemiczne

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2005

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[Z] 59, 7-8

583--611

EN

In 2001 prof. K.B. Sharpless from Scripps Institute has announced a new idea for an easier and faster molecular discovery, named click chemistry. This concept bases on the following observations: -currently organic chemists invest too much effort in assembling the structure, although it is the function that is sought. The function can be also found in molecules that are more easy to synthesise. -nature prefers carbon-heteroatom bond formation and most biomolecules are formed from small building blocks containig and connected by such bonds. Thus, the focus should be given to the efficient carbon-heteroatom bond formation. -estimated pool of potential drug-like molecules (<500 Da, <30 non-hydrogen atoms, only C, H, O, N, S, P, F, Cl, Br, stable at room temperature, in the presence of water and air) is between 1062-1063. This is the space for exploration. Click chemistry embraces therefore a set of powerful! reactions which must be modular, wide in scope, highly yielding, generating easily removable byproducts (with no need for chromatographic purification) and stereoselective. These reaction should be also insensitive to oxygen and water and preferably carried out under simple conditions. Click reactions achieve their efficienty due to the high thermody-namic driving force, usually greater than > 20 kcal/mol (thus can be recognized as spring-loaded for a single trajectory). Examples of these reactions include: nucleo-philic opening of strained rings (epoxides, aziridines), cycloadditions (e.g. 1,3-di-polar or Diels-Alder type reaction), additions to carbon-carbon multiple bond (epo-xidation, dihydroxylation, Michael addition) and some types of carbonyl chemistry . An illustration of this concept is multigram 4-step synthesis of products 2a and 2b (Scheme 2) without the use of chromatography. Click chemistry idea was discussed in detail by Sharpless in [1] and [4]. Huisgen 1,3-dipolar cycloadditon is cream of the crop of various click reactions and was used in many notable applications of click chemistry concept, high-ligh-ted in this review. This reaction is strongly thermodynamically activated (35-50 kcal/mol), modular and of wide scope, it shows also perfect atom economy and provides products with high yield after usually simple workup. Moreover, due to the stability of reactants and 1,2,3-triazoles to various reactions conditions, including oxygen and water, this cycloaddition can be carried out in water. Target guide synthesis combined with 1,3-dipolar Huisgen reaction was used for finding new, most potent (active in femtomolar concentration) acetylcholine este-rase inhibitors and carbonic anhydrase inhibitors 5a,b. Other inhibitors developed by synthesis and screening of 1,2,3-triazole libraries include a-l,3-fukosyltransferase VI, HlV-prote-ase. 1,3-Dipolar cycloaddition was also used for modification of antibiotic tyrosidine and vancomycine and the modified products 10a,b and 11a,b exhibit better therapeutic index and activity respectively. Important applications of Huisgen reaction in molecular biology include bioconiugation and labeling techniques. Cowpea virus was efficiently labeled by fluorescein derivatives and cell surfaces were decorated by various biotin derivatives using appropriate azide-alkyne components. Click chemistry in this field was also used for designing new methods for labeling protein, in vitro or in vivo protein profiling (Scheme 11) [27] and DNA sequencing. Many important applications of 1,3-Huisgen cycloaddition are found in material chemistry. These include efficient synthesis of dendrimers wihout the use of chromatography ordendronised polymers. 1,2,3-Triazole linker formation was utilised for functionalisation of poly(norbornenes), modular copolymer synthesis and silicon waffers or gold surface modification. 1,3-Dipolar cycloaddition was also used in the synthesis of new fluorescent cumarines 54, two-photon absorption chromophores 55 and water-soluble calixarenes 56. Huisgen reaction was recently widely explored for modification of natural products and biomolecules and many interesting 1,2,3-triazole derivatives of sugars, aminoacids and peptides, lipids, steroids and alkaloids were synthesised (62-74). In summary, in a relatively short period of time after its introduction, click chemistry concept was widely approved in various areas and resulted in many important applications. Thus it can be regared as a versatile toolbox for "production of molecular properties".