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Zastosowania „click chemistry” w modyfikacjach nukleozydów i oligonukleotydów

Gładysz M., Milecki J.

Wiadomości Chemiczne

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2014

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[Z] 68, 7-8

617--643

EN

Since the year 2001 new ideology of clean and simple synthesis in organic chemistry has been established. The outstanding scientists Meldal and Sharpless presented their concepts of Click Chemistry. Among the reactions chosen for this concept the reaction of Copper(I) Catalyzed Alkyne-Azide Cycloaddition (CuAAC) became the most popular one. It is the basis of syntheses employed for building blocks synthesis in medicinal chemistry and material science. Libraries of potentially pharmacologically active anticancer and antivirus compounds possessing neutral triazol linkage could be easily obtained. Remarkable efficiency of CuAAC reaction influenced on DNA- and RNAbased synthesis of novel oligonucleotides derivatives. Many of nucleic acid molecular modifications found applications in enzymatic transformation, nucleic acid hybridization, molecular tagging and gene silencing. The CuAAC reaction allows for introducing modifications into practically every region of nucleoside/nucleotide/ oligonucleotide. This includes versatile modifications of the base moiety both aiming at the base pairing ability or specific labeling of the nucleoside unit. Different conjugates (bio-, fluorescent-, affinity- or spin labels) are being attached to the base part of the nucleic acid taking advantage of the presence of azide or alkyne substituents, which can be installed without great difficulty. Labeling at the sugar part of the nucleoside can be realized at the position 2’, 3’ or 5’, the latter two giving rise to the end-labeled oligonucleotides and the 2’ position serving as the attachment point for labeling inside the oligonucleotide chain. These kind of nucleic acid modifications are very promising. Versatility of CuAAC reactions is demonstrated by numerous examples of introducing modifications into practically every reactive site of the nucleotide/oligonucleotide molecule. The review systematically presents application of the “click” technique for modification of nitrogenous base, sugar or pseudosugar moiety or phosphorus center. Possibility of creating new kind of chain linkage, devoid of negative charge and nuclease resistant is also shown. This allows to design a new class of nucleic acid analogues, similar in its DNA-mimicking properties to PNA’s.

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Adenosine-N6-crown Ethers as a New Class of Ionophores

Milecki J., Schroeder G.

Polish Journal of Chemistry

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2005

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Vol. 79 / nr 11

1781-1785

EN

Adenosine bear ing 18-crown-6 and 15-crown-5 ether moiety was synthesized. Comparison of complexing ability to wards alkali metal ions revealed strong potassium and sodium preference. Complex formation constants were estimated and thermodynamic parameters calculated.

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Chemiczna synteza oligorybonukleotydów

Milecki J.

Wiadomości Chemiczne

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2002

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[Z] 56, 3-4

255-277

EN

Basic issues and problems of chemical synthesis of oligoribonucleotides are presented. The paper describes three methods for construction of oligonucleotide chains: (1) a triester method which involves activation of nucleoside phosphodiesters with different azole sulfonates, and currently widely used methods employing PIII synthetic intermediates: (2) a phosphoramidite method which makes use of activation of nucleoside phosphoramidites by weakly acidic azoles or azole salts, (3) an H-phosphonate method, which uses nucleoside H-phosphonates activated by acid chlorides, both PIII intermediates are applied mainly in solid-support synthetic methodology. Problems of choosing appropriate protecting group for the synthesis are discussed. The article presents properties of basic types of protecting groups for lactam, exo-amino (base-labile protection), and hydroxyl groups (acid-labile for 5' protection, acid- or specific reagent-labile for 2' protection). The problem of 2'OH protection is described in detail. In this respect acid-labile groups and alkylsilyl groups are compared and their advantages and disadvantages are discussed. More detailed discussion is devoted to the phenomenon of the silyl group migration during the synthesis of monomeric units for oligonucleotide chain assembly. Basing on the NMR study of the isomerisation reaction it was possible to determine limits of safety of the reaction conditions.