Synthesis and properties of DNA oligomers containing stereopure phosphorothioate linkages and C-5 modified deoxyuridine derivatives

Abstract

The combination of 5-propynyluracil and (Rp)-PS linkages in a DNA strand could significantly increase the thermal stability of a DNA/RNA hybrid duplex.

Chemically modified aptamers for improving binding affinity to the target proteins via enhanced non-covalent bonding

“…This reaction would form two isomers (Blackburn et al, 2006;Frederiksen and Piccirilli, 2009). It was worth noting that single PS modification could be separated by HPLC, and multiple PS modified pure diastereomers can be obtained by synthesis methods (Stec and Wilk, 1994;Hara et al, 2020). In the following, several examples could be presented to describe the PS modification for enhancing the affinity between aptamers and targets.…”

Characterizing the Diastereoisomeric Distribution of Phosphorothioate Oligonucleotides by Metal Ion Complexation Chromatography, In-Series Reversed Phase-Strong Anion Exchange Chromatography, and 31P NMR

“…Figure 3A−C shows the PCA plots obtained using the three methods. All three techniques grouped the lots prepared by tetrazole (1, 2, 3, and 4) and DCI/NMI (11,14,18,21,23) together. Lot 5 (0.5 DCI) was grouped with the other DCI lots by 31 P NMR and RP-SAX, and closer to the tetrazole lots by MICC, perhaps indicating a greater sensitivity of the approach to changes resulting from the presence of NMI.…”

“…Several drugs have been approved and many more are under development. − Improvements in pharmacokinetic, pharmacodynamic, and biodistribution properties can be achieved by modifications of the oligonucleotide base and sugar moieties and the internucleotide linkages. − Replacement of one of the non-bridging oxygen atoms of the natural phosphate diester linkage creates a phosphorothioate (PS) linkage, which confers nuclease resistance and enhanced protein binding. − Incorporation of sulfur creates a chiral center at phosphorus, therefore PS oligonucleotides comprise 2 n diastereoisomers, where n is the number of PS linkages. Methods have been introduced for the synthesis of stereopure PS oligonucleotides − but the advantages of such molecules have been debated. − However, and regardless of whether the intention is to develop PS oligonucleotides as chirally pure or diastereoisomeric mixtures of molecules, the availability of analytical methods to assess chiral purity or, in the latter case, reproducibility of diastereoisomeric composition would be beneficial to oligonucleotide drug research and development.…”

The Modification Strategies for Enhancing the Metabolic Stabilities and Pharmacokinetics of Aptamer Drug Candidates

“…Two isomers would be produced as a result of this reaction [25]. Through high-performance liquid chromatography (HPLC), a single PS modification can be isolated, and synthetic methods can produce several pure diastereomers of PS modifications [26]. The PS modification's ability to enhance the affinity between aptamers and targets can be illustrated with the following examples.…”