Wyniki wyszukiwania - BazTech

Ograniczanie wyników

2 Wiadomości Chemiczne

Znaleziono wyników: 2

Liczba wyników na stronie

Wyniki wyszukiwania

Wyszukiwano:
w słowach kluczowych: metoda H-fosfonianowa

Sortuj według:

Ogranicz wyniki do:

Perspektywy stosowania metody blokowej do syntezy modyfikowanych oligonukleotydów w roztworze i na stałym podłożu

Bukowiecka-Matusiak M., Ziemecka I.

Wiadomości Chemiczne

2009

[Z] 63, 1-2

63-83

Studies on properties and function of nucleic acids constitute the most fascinating cognitive area in biology, chemistry and medicine. Dynamic development of the required techniques, primarily Nuclear Magnetic Resonance (NMR) [4], or crystallization techniques, allowed to obtain a detailed information about structural diversity of complicated biological compounds, for example peptides and nucleic acids. The replacement of one of the nonbonding oxygens of internucleotide bond by sulfur, selenium, methyl or other functionalized alkyl groups creates a stereogenic centre at the modified phosphorus atom [16]. This arises a question about availability of stereoregular, P-defined analogues of DNA and RNA. Short synthetic oligonucleotides are indispensable tools in biomolecular and structural studies [5, 6]. They also have potential as therapeutics [13, 14] for manipulation of genes expression in a sequence specific manner. The block synthesis assuming incorporation of P-chiral, diastereomerically pure dimeric building blocks is attractive, reliable and patent for automated approach to the synthesis of "chimeric oligonucleotides", both in solution and on solid support [23]. The attention of researches turned toward chimeric constructs of 16 containing, in successive internucleotide positions, phosphates and methanephosphonates. Reynolds et al. [34] found that for therapeutic applications, only chimeric oligonucleotides 16 with incorporated RP-dinucleoside methanephosphonates had acceptable binding affinity towards complementary template of DNA and RNA. Isosequential chimeric oligomers, constructed either from diastereomeric mixtures of dinucleoside methanephosphonates, or from those with SP-configuration, form less stable duplexes with the same complementary RNA templates. The preparation of the aforementioned chimeras utilized a "dimeric building blocks" approach [23]. The corresponding dinucleoside (3',5')-methanephosphonates 17 were separated into diastereomers by chromatographic methods. After removal of the 3'-O-protecting group, the required RP-isomers were activated at the 3'-O-position, and used as such for condensation via the phosphoramidite method [25]. Attempts towards their P-epimerization and recycling have failed. Such situation was notwithstanding the requirement of a cost-effective synthesis of new potential therapeutics. Therefore, Stec et al. [36-38], and efforts were undertaken in the design of a cost-effective synthesis of RP-dinucleoside (3',5')-methanephosphonates 17.

Synteza chemiczna oligonukleotydów na fazie stałej. Możliwości i ograniczenia nośników stałych

Burzyńska-Pędziwiatr I., Woźniak L.

Wiadomości Chemiczne

2008

[Z] 62, 7-8

571-594

Synthesis of biopolymers (peptides, proteins and nucleic acids) has long been in the range of interest of numerous chemists. The primary structure of biomolecules consists of linear and repeating sequences of monomeric units (aminoacids, nucleic bases, sugars) in a specifically determined orientation. Therefore, chemical synthesis of biopolymers comprises a lot of identical, repetitive steps (condensation, chain elongation and purification). Solid phase method is currently used also for the oligonucleotide [2, 3] (Figure 1) and oligosaccharide synthesis. There exist interesting applications of analogous approach to combinatorial synthesis of small molecules (Solid Phase Organic Chemistry - SPOC) [4, 5]. Automation of the phosphoramidite method of oligonucleotide synthesis process proposed by Caruthers [6] made an enormous impact on biological, medical and biotechnological sciences. It is beyond any doubt that this is the fastest and the most convenient method of oligonucleotide synthesis aimed at biological research. Solid phase synthesis has many advantages, however, it is not free of drawbacks either. Depending on the synthesis method, various types of supports are used. An ideal support should have an appropriate and reactive chemical group on its surface, e.g. -NH2, -OH, -COOH, by means of which it is connected to the linker and the first unit of the monomer. Surface functionalization of the solid phase determines the number of available reactive groups and characterizes support loading expressed in micromoles per gram. Nucleosides are attached to the support by a linker, the choice of which depends on the reaction conditions. The linker arm must be designed in such a way that it is adjusted to the cleavage conditions and deprotection procedures. Depending on the synthesis purpose and the type of a oligonucleotide, various linker arms are used. They include: linker arms cleaved after synthesis, labile linker arms, universal linkers [21, 22], and the linker arms for deprotection of the immobilized products [26, 27]. Among numerous methods of oligonucleotide synthesis, the phosphoramidite method is the most common. The phosphoramidite approach (Figure 10) allows for obtaining both natural DNA/RNA and plenty of modified analogs (phosphorothioates, phosphoroselenoathes, triesters and others). Its alternative is the H-phosphonate method (Figure 11) [40-42]. Particular advantage of this method is that it can be used in the synthesis without protection of nucleobases. Depending on its destination, the synthesis must be very carefully designed considering the strategy of group protection to make them stable under reaction conditions. A decision must be also made whether to use the phosphoramidite method or the H-phosphonate method taking also into account whether the product is to be immobilized on the support or not, which depends on expected results.