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    Tytuł:
    Modyfikowane oligodeoksyrybonukleotydy zawierające w wiązaniu internukleotydowym w pozycji mostkowej atom azotu
    Modified oligodeoxyribonucleotides containing nitrogen at a bridging position of an internucleotide bond
    Autorzy:
    Radzikowska, E.
    Powiązania:
    https://bibliotekanauki.pl/articles/172442.pdf
    Data publikacji:
    2013
    Wydawca:
    Polskie Towarzystwo Chemiczne
    Tematy:
    analogi kwasów nukleinowych
    modyfikacje wiązania internukleotydowego
    oligodeoksyrybonukleozydo-(P3’→N5’)amidofosforany
    oligodeoksyrybonukleozydo-(N3’→P5’)amido(tio)fosforany
    strategia antysensowa
    telomeraza
    reakcja Athertona-Todda
    nucleic acids analogues internucleotide linkage modifications
    oligodeoxyribonucleoside-(P3’→N5’)phosphoramidates
    oligodeoxyribonucleoside-
    (N3’→P5’)(thio)phosphoramidates antisense strategy
    telomerase
    Atherton-Todd reaction
    Opis:
    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.
    Źródło:
    Wiadomości Chemiczne; 2013, 67, 11-12; 1003-1025
    0043-5104
    2300-0295
    Pojawia się w:
    Wiadomości Chemiczne
    Dostawca treści:
    Biblioteka Nauki
    Artykuł
    Tytuł:
    Pronukleotydy o strukturze amidofosforanów i ich wewnątrzkomórkowy mechanizm aktywacji
    Phosphoramidate pronucleotides and their intracellular activation mechanism
    Autorzy:
    Kulik, K.
    Baraniak, J.
    Powiązania:
    https://bibliotekanauki.pl/articles/171604.pdf
    Data publikacji:
    2014
    Wydawca:
    Polskie Towarzystwo Chemiczne
    Tematy:
    pronukleotydy
    amidofosforany
    aktywność fosforoamidazowa
    Hint
    białko triady histydynowej wiążącej nukleotyd
    prolek
    pronucleotides
    phosphoramidates
    phosphoramidase activity
    histidine triad nucleotide binding protein
    prodrug
    Opis:
    Nucleoside analogues have great therapeutic potential for the treatment of cancer and viral diseases. Once inside the cell, they are activated by a series of intracellular phosphorylation steps to produce 5’-triphosphate derivatives, which can be incorporated to DNA or RNA and act as terminators of growing polynucleotide chains [1c]. In many cases, nucleoside analogues are poor substrates for the cellular kinases needed for their activation [5]. It is clear that intracellular introduction of nucleoside analogues as phosphorylated metabolites (so called pronucleotides) could circumvent difficulties associated with the use of non-phosphorylated nucleoside analogues and could even activate inactive compounds or could increase the activity of the nucleoside analogues. However, polarity and a ready degradation by phosphatases make the use of free nucleotide analogues impractical. Therefore, much of the recent efforts have been focused on finding suitable prodrugs of nucleoside analogue monophosphates. Among the current diverse prodrug approaches, nucleoside phosphoramidate derivatives appear to be an interesting class of antiviral and anticancer agents [1c]. These prodrugs, as are devoid of negative charge, should be able to cross the cell membrane either by diffusion or utilizing transport protein [1c]. Conducted cell extract studies have provided evidence of a bioactivation mechanism that relies on enzyme-catalyzed P-N bond hydrolysis in phosphoramidate pronucleotides [1a,b]. It was assumed that phosphoramidate derivatives should generate nucleoside monophosphates inside the cell at rates that are influenced by both the nature of the amino group and the pH of the medium. Then nucleoside monophosphates should be phosphorylated in two different steps to the corresponding 5’-O-triphosphates (NTP) which can inhibit polymerase or be incorporated into the DNA strand being synthesized in the cell. Over the last decade extensive studies has been carried out to establish the mechanism of action of phosphoramidates and identification of enzymes responsible for bioactivation this pronucleotides to phosphorylated nucleosides [7, 21, 24]. Investigation of metabolism pathways provided evidence that phosphoramidase activity of Hint (histidine triad nucleotide-binding proteins) play a key role in the activation of phosphoramidate pronucleotides [23–27].
    Źródło:
    Wiadomości Chemiczne; 2014, 68, 9-10; 811-831
    0043-5104
    2300-0295
    Pojawia się w:
    Wiadomości Chemiczne
    Dostawca treści:
    Biblioteka Nauki
    Artykuł
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