Journal
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
Volume 2019, Issue 33, Pages 5636-5645Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/ejoc.201900740
Keywords
Conjugation; RNA; Disulfide bridge; Carbamate; Hydroxyl modification
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Funding
- University of Montpellier
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A post-synthesis conjugation method was developed to functionalize oligoribonucleotides with various small molecules of biological interest using a reduction-sensitive disulfide linker connected to 2 ' OH via a carbamate function. For this, first we prepared a 2 '-O-[(N-(acetylthio)-ethylcarbamoyl] (2 '-O-AcSEC) uridine phosphoramidite as the key precursor of the disulfide linker, that was incorporated into 21-mer RNAs. Next the 2 '-O-AcSEC group was converted on solid support to the activated 2 '-O-[N-(2-pyridyldisulfanyl)-ethylcarbamoyl] (2 '-O-PySSEC) group. Finally, the coupling between 2 '-O-PySSEC-modified RNA and diverse small molecules bearing a thiol function was based on a thiol-disulfide exchange reaction in solution. Several RNA-small molecule conjugates were obtained with satisfactory conjugation yields. An RNA was successfully double-conjugated with an anticancer drug (doxorubicin) attesting the efficiency and the robustness of the conjugation method. We have shown that the disulfide-linked RNA-small molecule conjugates were cleaved upon 5.6 mm glutathione treatment, featuring the release of the small molecules in cells.
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