Synteza modyfikowanych oligonukleotydów zawierających stereozdefiniowane internukleotydowe wiązania tiofosforanowe

• Autorzy: Radzikowska E. , Kaczmarek R. , Baraniak J.

Warianty tytułu

EN

Synthesis of modified oligonucleotides containing stereodefined internucleotide phosphorothioate bonds

• Języki publikacji: PL

Abstrakty

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.

Słowa kluczowe

PL

oligonukleozydotiofosforany; oligonukleotydy antysensowne; synteza modyfikowanych oligonukleotydów; synteza stereospecyficzna

EN

oligo(deoxy)ribonucleoside phosphorothioates; antisense oligonucleotides; synthesis of modified oligonucleotide; stereospecific synthesis

• Wydawca: Polskie Towarzystwo Chemiczne
• Czasopismo: Wiadomości Chemiczne
• Rocznik: 2015
• Tom: [Z] 69, 11-12
• Strony: 957--981
• Opis fizyczny: Bibliogr. 32 poz., schem.

Twórcy

autor

Radzikowska E.

• Centrum Badań Molekularnych i Makromolekularnych Polskiej Akademii Nauk, Zakład Chemii Bioorganicznej ul. Sienkiewicza 112, 90-363 Łódź

autor

Kaczmarek R.

• Centrum Badań Molekularnych i Makromolekularnych Polskiej Akademii Nauk, Zakład Chemii Bioorganicznej ul. Sienkiewicza 112, 90-363 Łódź

autor

Baraniak J.

• Wydział Matematyczno-Przyrodniczy, Instytut Chemii i Ochrony Środowiska, Akademia im. Jana Długosza al. Armii Krajowej 13/15, 42-200 Częstochowa

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