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Metody chemicznej ligacji w syntezie peptydów i białek. Część 1

Kropidłowska M., Jędrzejewska K., Wieczerzak E.

Wiadomości Chemiczne

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2017

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[Z] 71, 9-10

727--746

EN

Proteins are biological macromolecules affecting very important functions in the body. They are involved in many biochemical processes. They can perform catalytic functions acting as enzymes. They also participate in the transport of many small molecules and ions – for example one molecule of hemoglobin carries four molecules of oxygen. In addition, proteins serve as antibodies and are involved in transmission of nerve impulses as receptor proteins. Because peptides and proteins perform so important functions, to study them it is essential to obtain these compounds in the greatest possible amounts. The compounds can be obtained generally by three main methods: • by isolation of the native peptides and proteins • by expression in microorganisms • by chemical synthesis. Each of the above methods has its advantages and disadvantages, but only the chemical synthesis gives the possibility to introduce modifications to the structure of the resulting protein, such as the insertion of new functional groups, to give the product in the final form and with satisfactory yield. In this review we present the application of chemical ligation methods in the synthesis of peptides and proteins. We describe in details mechanism of native chemical ligation method and the conditions necessary to carry the reaction [1]. The synthesis of long polypeptide chains by kinetically controlled ligation (KCL) is also depicted [2]. This part of the paper also details a number of approaches to noncysteine containing peptides by chemical ligation methods.

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Metody chemicznej ligacji w syntezie peptydów i białek. Część 2

Jędrzejewska K., Kropidłowska M., Wieczerzak E.

Wiadomości Chemiczne

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2017

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[Z] 71, 9-10

747--761

EN

Proteins are synthesized only by living organisms. Today, we are able to receive them by recombinant protein expression in bacterial cells. This technique is very useful and gives satisfactory amount of desirable material but it precludes the possibility of introduction of some chemical modifications that are often obligatory. For this reason, chemical synthesis of longer peptide chains is still important and is the object of scientists attention. Over the last century, notion of peptide synthesis took a new meaning. Nowadays, we know a number of innovative methods and also automated devices which help us to make progress in this area. Nevertheless, the synthesis of longer, more complicated peptide chains and proteins still constitutes a problem. Native chemical ligation (NCL) has facilitated the synthesis of numerous complex peptide and protein targets. Expansion of ligation techniques has allowed the entry of peptides into the world of therapeutic drugs [1]. NCL reactions are carried out in aqueous solution and give good yields. Due to mild conditions, NCL overcomes racemic and solubility problems encountered in classical peptide synthesis using protected fragments. The challenge is to synthesize the C-terminal thioester-containing peptide necessary for the transesterification reaction, which is the first step of linking the peptide fragments [2]. In this review we discuss the evolution, advantages and potential applications of chemical ligation reactions. In the first part of this article we described the utility of native chemical ligation approach to non-cysteine containing peptides. This part details a number of important approaches to the synthesis of peptides bearing a C-terminal thioester. Contemporary applications of these techniques to the total chemical synthesis of proteins are also presented.

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Azepeptydy

Wieczerzak E.

Wiadomości Chemiczne

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2004

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[Z] 58, 5-6

427--448

EN

Peptides, as neurotransmitters, neuromodulators and hormones take part in a number of physiological processes and thus are of enormous medical interest. However, the use of peptides as drugs is limited for example by degradation by proteases or poor bioavailability. One of the solutions of these problems seems to be application of peptidomimetics - compounds that act as substitutes for peptides in their interaction with receptors and can show higher metabolic stability, better bioavailability and longer duration of action. Azapeptides, peptide analogs in which α-CH group of one or more amino acid residues in the peptide chain is replaced by a nitrogen atom, have proved to be a class of useful peptidomimetics. Azaamino acids provide unique conformational and configurational properties to the peptide chain which are caused by loss of asymmetry connected with a-carbon and free rotation around Cα-C' bond in the amino acid residue. According to the position of azaamino acid residue in the sequence, azapeptides can adopt different kinds of secondary structures and particularly - β-turns. This review presents different methods of azapeptide synthesis, either in solution or on solid-phase. Isoelectronic replacement of the α-CH group by nitrogen atom leads to some changes in the direct neighbourhood of the pseudoamide bond, which influence the biological activity of the azaanalogs of the natural substances. Azapeptides were synthesized and tested as analogs of hormones as well as inhibitors of different types of enzymes. Especially worth noting is application of azapeptides as protease inhibitors. Incorporation of the azaamino acid residue in the P1 position of an enzyme substrate allows the formation of an acyl-enzyme complex and on the other hand deactivates the complex toward nucleophilic attack of a water molecule in the last step of peptide bond hydrolysis. In last years azapeptidic compound - ReyatazTM (Atazanavir, BM-232632) has been discovered which seems to be a promising drug in the treatment of AIDS as it acts by blocking the activity of HIV-1 protease.

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The Efficient Synthesis of Azaamino Acids

Wieczerzak E., Kozlowska J., Łankiewicz L., Grzonka Z.

Polish Journal of Chemistry

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2002

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Vol. 76 / nr 12

1693-1697

EN

An efficient method of synthesis of N-t-butoxycarbonyl-azaamino acid ethyl esters has been described. This method consisted of three stages including: hydrazone formation, its reduction and acylation with ethyl chloroformate. The second step - reduction of the hydrazones to the appropriate hydrazides - was the most challenging. Some reducing agents have been tested, though NaBH3CN was found to lead to the final products with the highest yields in relatively short time and even to allow the selective reduction of C-N bond in the presence of nitro group.

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Wybrane zastosowania bornan-10,2-sultamu (sultamu Oppolzera) w asymetrycznej syntezie organicznej

Szymańska A., Wieczerzak E., Łankiewicz L.

Wiadomości Chemiczne

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2000

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[Z] 54, 9-10

759-791

EN

Among many methods of asymmetric synthesis, the second-generation reactions i.e. the ones applying chiral auxiliary to generate new chiral centers are the most popular and widely used. In the last two decades many new and highly effective chiral auxiliaries were described. Bornane-10,2-sultam, introduced by Oppolzer and co-workers, is one of the most popular and most effective in generating new chiral centers. Utility of bornane-10,2-sultam is due to: - simplicity of a method of its synthesis from the natural, cheap source - camphore, - high yield of connecting to prochiral substrates, - almost quantitative asymmetric induction, - straight-forward removal of the formed product from bornane-sultam, which does not cause the loss of chirality at a new chiral center , - its high recovery after removal of product and possibility of multiple applications. One of the most popular reactions studied in asymmetric synthesis is aldol condensation. This reaction was also studied with application of bornane-10,2-sultam. Depending on the type of used base and Lewis acid either pure "cis" or "trans" isomer can be obtained. The chemical yields of the reactions were also high (50÷90%) N-acylated derivatives of bornane-10,2-sultam have been revealed also as facile precursors of chiral alkylated carboxylic acids, ketones, aldehydes and alcohols. Diastereoisomeric excesses were in many cases above 99% and chemical yields were also very good (in most cases above 80%). Alkylation step can be also applied for asymmetric synthesis of a-amino acids (building blocks of peptides) but it is necessary to use N-[bis(methylthio)methylene]glycine methyl ester for acylation of the sultam. Quite nice selection of amino acids in optically pure form can be obtained by this method. Other possibilities of the sultam usage arise from nucleophilic and electrophilic amination reactions. These methods were applied to obtain amino, azido, hydrazino and N-hydroxyamino acids with high chemical yield and optical purity. Applications of bornane-10,2-sultam derivatives with a,b-unsaturated side chain are also very wide in asymmetric organic synthesis. One of the most popular reaction involving unsaturated compounds is Diels-Alder's cycloaddition. Cyclic compounds formed during this addition are mostly endo-structures. Stereoselectivity is very high (higher than 90 %) and depends on a type of Lewis acid used. Another interesting precursor in this kind of addition reaction seems to be the sultam derivative obtained by the modification with glyoxalic acid. Its application can lead to piran derivatives and substrates of sugar moieties. N-acylated with a,b-unsaturated carboxylic acids sultam derivatives are also good substrates for carbonyl compounds stereoselectively substituted on a- or/and b-carbons (aldehydes, ketones, carboxylic acids) as well as alcohols. For preparation of optically active a,b-disubstituted compounds either Grignard's reagents or Gilman's reagents can be applied with diastereoselectivity in range 70÷95 %. Other possibilities of the "unsaturated" sultam derivatives usage arise from reactions with "hydrogen sources" or oxidation agents. Asymmetric hydride addition or catalytic hydrogenation leads to a,b-disubstituted chiral compounds with good yield and stereoselectivity. Oxidation of double bond, on the other hand, is facile method for obtaining 1,2-diols - superior substrates for ketones, acetals and sugars.