The pro-oligonucleotide approach: solid phase synthesis and preliminary evaluation of model pro-dodecathymidylates - Archive ouverte HAL Access content directly
Journal Articles Nucleic Acids Research Year : 1998

The pro-oligonucleotide approach: solid phase synthesis and preliminary evaluation of model pro-dodecathymidylates

Guilhem Tosquellas
  • Function : Author
Karine Alvarez
Christelle Dell'Aquila
  • Function : Author
François Morvan
  • Function : Author
Jean-Jacques Vasseur
Jean-Louis Imbach
  • Function : Author
Bernard Rayner
  • Function : Author

Abstract

A modified phosphoramidite method has been designed for the solid-phase synthesis of two dodecathymidine phosphotriesters and two dodecathymidine thiono-phosphotriesters. In these analogs, each internucleoside link bears an S-acyl-2-thioethyl (Me-SATE or tBu-SATE) group removable upon esterase activation. Efficient synthesis of these lipophilic analogs was achieved thanks to the use of a photolabile linker anchored to the solid support in combination with thymidine-3′-O-phosphoramidites having a SATE group in place of the regular 2-cyanoethyl one. Both dodecathymidine phosphotriester and thionophosphotriester having S-acetyl-2-thioethyl groups were found to be stable in the presence of snake venom and calf spleen phos-phodiesterases whereas, upon incubation in CEM cell extracts, they were selectively hydrolyzed to the anionic parent dodecathymidylate and dodecathymidine phosphorothioate, respectively. In addition, Me-SATE-protected dodecathymidine thionophosphotriester was stable in mouse and human sera as well as in human gastric juice. These results depict the potential of SATE-protected oligonucleotides as prodrugs of antisense oligonucleotides.
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hal-03008426 , version 1 (16-11-2020)

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J.J. Vasseur, Guilhem Tosquellas, Karine Alvarez, Christelle Dell'Aquila, François Morvan, et al.. The pro-oligonucleotide approach: solid phase synthesis and preliminary evaluation of model pro-dodecathymidylates. Nucleic Acids Research, 1998, 26 (9), pp.2069-2074. ⟨10.1093/nar/26.9.2069⟩. ⟨hal-03008426⟩
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