Modyfikowane oligodeoksyrybonukleotydy zawierające w wiązaniu internukleotydowym w pozycji mostkowej atom azotu
Journal Title: Wiadomości Chemiczne - Year 2013, Vol 67, Issue 11
Abstract
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.
Authors and Affiliations
Ewa Radzikowska
Keywords
Related Articles
- EP ID EP587067
- DOI -
- Views 154
- Downloads 0
Biologiczna aktywność siarkowodoru
Hydrogen sulfide (H2S) is a well known toxic gas that is synthesized from amino acids: cysteine (Cys) and homocysteine (Hcys) by two enzymes: cystathionine-â- -synthase and cystathionine-ă-lyase (Fig. 1) [3]. Hydrogen su...
Synteza i redukcja prochiralnych imin
Natural chemical compounds and their derivatives could be used for designing new classes of anticancer, antifungal or antiviral drugs. One of those compounds is gossypol, isolated from grains of wool. Gossypol’s derivati...
Metody chemicznej ligacji w syntezie peptydów i białek. Część 2
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 materia...
Badanie oddziaływania wankomycyny z fragmentem peptydoglikanu ściany komórkowej bakterii
Unfortunately, despite of work involved in understanding of the mechanism of bacterial virulence, especially Staphylococcus aureus, it has not been developed effective therapy against this bacteria. The first antibiotic...
Metody obliczania napięcia międzyfazowego z symulacji komputerowych
Interfaces have been recently a subject of profound interest for physicists, chemists and biologists because of the processes taking place in the interfacial region like adsorption, catalysis of chemical reactions etc. C...