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

J.J. Vasseur (1) , Guilhem Tosquellas , Karine Alvarez , Christelle Dell'Aquila , François Morvan , Jean-Jacques Vasseur , Jean-Louis Imbach , Bernard Rayner

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]

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.

Domaines: Chimie analytique; Chimie thérapeutique; Chimie organique; Chimie

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⟩