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Synteza modyfikowanych oligonukleotydów zawierających stereozdefiniowane internukleotydowe wiązania tiofosforanowe

Radzikowska E., Kaczmarek R., Baraniak J.

Wiadomości Chemiczne

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2015

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[Z] 69, 11-12

957--981

EN

Synthetic oligonucleotides constitute an important class of compounds which can exhibit biological activity. As potential drugs they could be employed in antisense strategy by acting on the pathogenic mRNA, causing inactivation of the target molecules during the translation process [1]. Ideal antisense agent (ASO) should be resistant to exo and/or endonucleases, exhibit a suitable pharmacological and pharmacokinetic profile and exhibits high binding affinity towards the target mRNA. To improve some properties of the ASO plethora of the chemical modifications introduced within the nucleobase, sugar unit and internucleotide linkage are investigated [3]. Among them, phosphorothioate oligonucleotides (PS-oligo), created by replacing one of the nonbridging oxygen atoms with a sulfur atom, are the major representatives of DNA analogs. PS-oligo display several attractive features like nuclease resistance, activation of RNase H, and good pharmacokinetic properties [1]. Replacement of one of two nonbridging oxygens at phosphorus by sulfur induces asymmetry at the phosphorus atom. Hence, the synthesized oligo(nucleoside phosphorothioate) is a mixture of 2n diastereomers (where n is the number of internucleotide phosphorothioate functions). Therefore the actual biological activity of the P-chiral oligonucleotide analogues, (e.g., interactions with proteins or nucleic acids) may depend on stereochemical factors [7]. One has to keep in mind that the phosphoramidite [5] and H-phosphonate [32] methodologies (commonly used to prepare PS-oligo) are nonstereospecific and give a mixture of 2n diastereomers. Thus, various methods have been elaborated to synthesize these P-chiral oligonucleotide analogs in a stereocontrolled manner [15, 17], among them the oxathiaphospholane method developed by Stec et al. [18], the method utilizing nucleoside 3’-O-(3-N-acyl)oxazaphospholidine derivatives as monomer units [19], and the method based on a stereoselective synthesis of nucleoside 3’-O-oxazaphospholidine monomers [21, 22] are the most significant.

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Modyfikowane oligodeoksyrybonukleotydy zawierające w wiązaniu internukleotydowym w pozycji mostkowej atom azotu

Radzikowska E.

Wiadomości Chemiczne

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2013

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[Z] 67, 11-12

1003--1025

EN

Synthetic oligonucleotides (ONs) constitute an important class of compounds which exhibit biological activity. As potential drugs ONs are employed in the antisense strategy [1]. The antisense therapeutic agent acts on the pathogenic mRNA causing inactivation of the target. Ideal antisense agent should be resistant to exo and/or endonucleases, have a suitable pharmacological and pharmacokinetic profile and high affinity for the target. To improve some properties of antisense oligonucleotides plethora of chemical modifications introduced within both sugar unit and internucleotides linkage were investigated. Among numerous ONs modified in internucleotide phosphodiester bond, one of the most interesting are oligonucleotide phosphoramidates (NP-oligos) in which one of the bridging oxygens is replaced by nitrogen atom (at 3’ or 5’ position). Hence, two classes of compounds are formed: oligonucleotide-(N5’→P3’)phosphoramidates and oligonucleotide(N3’→P5’)-phosphoramidates. These compounds, similar to native DNA and RNA, possess an achiral phosphorous atom and all internucleotides bonds are negatively charged. Additionally, NP-oligo shows good resistance to nucleolytic degradation and can bind to the target DNA or RNA with high affinity [12]. In literature several synthetic strategies concerning both (N5’→P3’) and (N3’→P5’) NP-oligos have been described. Some of them allowed to obtain only corresponding dimers. In the light of recent discoveries the most promising candidates for therapeutic and diagnostic applications are oligonucleotide-(N3’→P5’)thiophosphoramidates. Gryaznov et al. have found that such compounds can act as potent and selective telomerase inhibitors [29]. Human telomerase (TA) is a reverse transcriptase ribonucleoprotein that synthesizes de novo d-(TTAGGG)n repeats at chromosomal DNA ends. Whereas activity of this enzyme is observed in ~85% of all human tumors, most of normal somatic cells either lack TA activity or express it only at low levels. For these reasons TA constitute an attractive and nearly universal anticancer target for rational drug development.

3

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.

4

Koniugaty peptyd-oligonukleotyd : synteza i zastosowanie

Kaczmarek R., Radzikowska E., Baraniak J.

Wiadomości Chemiczne

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2008

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[Z] 62, 11-12

1091-1113

EN

Recently major advances have been made in the development of oligonucleotides as potential therapeutic agents [1-3]. However, a frequent limitation of their use is poor cellular uptake [5]. Among the many molecules that have been reported to enhance cell delivery of oligonucleotides there is a number of peptide carriers. They are preferably linked by covalent bond in many possible ways, resulting in a new class of compounds known as peptide-oligonucleotide conjugates (POCs) [6a, 9]. A variety of chemical linkages have been used to link the peptide and oligonucleotide fragments. A peptide can be conjugated either at the base-, 3'-, or 5'-position of the sugar unit or at the backbone of the oligonucleotide [10]. Similarly, the point of conjugation in a peptide can be either the C- or N-terminus or the side chain. Two different strategies have been adopted for the synthesis of POCs: in-line solid-phase synthesis (divergent method) and fragment conjugation (convergent method) [11]. In divergent method, the peptide and oligonucleotide fragments are assembled on automatic synthesizers, sequentially on the same solid support, until the final step. In predominant cases, the peptides are assembled first by the Fmoc method, while the oligonucleotides are assembled next using the phosphoramidite method [12]. In-line synthesis could be most direct for preparing POCs, but finding the right combination of protecting groups is the key problem. The first step in preparation of POCs involves modification of solid supports with suitable linkers [10]. A number of monofunctionalized as well as bifunctionalized linkers were immobilized over solid supports through suitable spacers (Figure 1). In the fragment conjugation, the peptide and oligonucleotide fragments are synthesized individually, cleaved from their solid supports, deprotected and purified, separately. Therefore, the most appropriate synthetic chemistry can be used for each component without concern for incompatibility. Both biopolimers are finally linked postsynthetically utilizing the reactive functional groups which are attached at the desired site of conjugation (Figure 4) [5]. If the postsynthetic conjugation is performed with one of the oligomers still joined to the solid phase, it is called the solid-phase fragment conjugation method. Alternatively, if the conjugation is effected after complete isolation and purification of the peptides and oligonucleotides, it is called fragment conjugation in the liquid phase [10]. Besides their potential use for therapeutic applications, POCs can serve as research tools, for example, as fluorescent probes [44] or PCR primers [25, 45]. With increased specificity and strength of target binding, POCs may be useful in diagnostic applications or as affinity purification reagents.

5

Microstretch model of type II superconductors

Radzikowska E.

Journal of Technical Physics

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2003

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Vol. 44, no 3

261-276

EN

The Eringen theory of microstretch electromagnetic elastic solids is applied to describe the behaviour oftype-II superconductors interacting with a pinned dense vortex lattice. The electromagnetic, mechanical and thermal fields interactions in superconductors are considered. The electromagnetic interactions are described within the framework of the classical electrodynamics of microstretch elastic solids. The complete system of field equations is presented consisting of the balance laws, the constitutive relations and the jump conditions on the discontinuity surfaces. The linear magnetoelasticity equations of microstretch superconductors are presented.

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Micropolar model of high-temperature superconductors

Radzikowska E.

Journal of Technical Physics

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2001

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Vol. 42, no 4

419-435

EN

The micropolar continuum theory is applied to superconductors of type II containing a vortex lattice. The classical electrodynamic theory of micropolar continua is supplemented by quantum-mechanical notions describing the phenomenon of superconductivity. A variational principle for dissipative processes taking place in high-temperature superconductors is formulated. The electromagnetic, mechanical and thermal fields interactions in superconductors are considered. Finally, the complete system of field equations describing these interactions is obtained together with the constitutive relations and the jump conditions on the discontinuity surface.

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Variational principle in thermo-electro-magneto-dynamics of micropolar media

Kotowski R., Radzikowska E.

Journal of Technical Physics

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1998

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Vol. 39, no 2

283-295

EN

The variational principle for micropolar continua interacting with thermal, electromagnetic and mechanical fields is formulated. The potential character of the electromagnetic fields (E, B) and the conservation of electric charge, mass and microinertia are postulated. The remaining equations and the boundary conditions are obtained from the variational principle. The expression for the entropy production is obtained too. We conclude that the proposed variational principle describes both the thermodinamically reversible and dissipative processes.

8

Coupled fields and the variational description of microelasticity

Kotowski R., Radzikowska E.

Journal of Technical Physics

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1998

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Vol. 39, no 3-4

511-522

EN

The aim of the paper is to construct the variational principle for the microelestic media interacting with external electromagnetic and thermal fields. The system of governing equations, constitutive relations and boundary conditions are obtained. The constrains imposed by the second law of thermodynamics on the constitutive relations are discussed.