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Article Dans Une Revue European Journal of Organic Chemistry Année : 2019

Conjugation of Small Molecules to RNA Using a Reducible Disulfide Linker Attached at the 2′-OH Position through a Carbamate Function

Résumé

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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Dates et versions

hal-02307249 , version 1 (06-11-2020)

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Florian Gauthier, Astrid Malher, Jean-Jacques Vasseur, Christelle Dupouy, Françoise Debart. Conjugation of Small Molecules to RNA Using a Reducible Disulfide Linker Attached at the 2′-OH Position through a Carbamate Function. European Journal of Organic Chemistry, 2019, 2019 (33), pp.5636-5645. ⟨10.1002/ejoc.201900740⟩. ⟨hal-02307249⟩
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