A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Expanding the Scope of the Cleavable N-(Methoxy)oxazolidine Linker for the Synthesis of Oligonucleotide Conjugates




Julkaisun tekijät: Aho Aapo, Äärelä Antti, Korhonen Heidi, Virta Pasi

Kustantaja: MDPI

Julkaisuvuosi: 2021

Journal: Molecules

Tietokannassa oleva lehden nimi: MOLECULES

Lehden akronyymi: MOLECULES

Volyymi: 26

Julkaisunumero: 2

Sivujen määrä: 11

eISSN: 1420-3049

DOI: http://dx.doi.org/10.3390/molecules26020490


Tiivistelmä
Oligonucleotides modified by a 2 '-deoxy-2 '-(N-methoxyamino) ribonucleotide react readily with aldehydes in slightly acidic conditions to yield the corresponding N-(methoxy)oxazolidine-linked oligonucleotide-conjugates. The reaction is reversible and dynamic in slightly acidic conditions, while the products are virtually stable above pH 7, where the reaction is in a ''switched off-state''. Small molecular examinations have demonstrated that aldehyde constituents affect the cleavage rate of the N-(methoxy)oxazolidine-linkage. This can be utilized to adjust the stability of this pH-responsive cleavable linker for drug delivery applications. In the present study, Fmoc-beta-Ala-H was immobilized to a serine-modified ChemMatrix resin and used for the automated assembly of two peptidealdehydes and one aldehyde-modified peptide nucleic acid (PNA). In addition, a triantennary N-acetyl-d-galactosamine-cluster with a beta-Ala-H unit has been synthesized. These aldehydes were conjugated via N-(methoxy)oxazolidine-linkage to therapeutically relevant oligonucleotide phosphorothioates and one DNA-aptamer in 19-47% isolated yields. The cleavage rates of the conjugates were studied in slightly acidic conditions. In addition to the diverse set of conjugates synthesized, these experiments and a comparison to published data demonstrate that the simple conversion of Gly-H to beta-Ala-H residue resulted in a faster cleavage of the N-(methoxy)oxazolidine-linker at pH 5, being comparable (T-0.5 ca 7 h) to hydrazone-based structures.

Ladattava julkaisu

This is an electronic reprint of the original article.
This reprint may differ from the original in pagination and typographic detail. Please cite the original version.




Last updated on 2021-24-06 at 08:24