The pro-oligonucleotide approach: solid phase synthesis and preliminary evaluation of model pro-dodecathymidylates
| Autor: | Vasseur, J.J., Tosquellas, Guilhem, Alvarez, Karine, Dell'Aquila, Christelle, Morvan, François, Vasseur, Jean-Jacques, Imbach, Jean-Louis, Rayner, Bernard |
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| Přispěvatelé: | Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM) |
| Jazyk: | angličtina |
| Rok vydání: | 1998 |
| Předmět: |
Stereochemistry
[CHIM.THER]Chemical Sciences/Medicinal Chemistry Biology 010402 general chemistry 01 natural sciences Esterase chemistry.chemical_compound Mice Solid-phase synthesis Organophosphorus Compounds Drug Stability [CHIM.ANAL]Chemical Sciences/Analytical chemistry Genetics Thymidine Monophosphate Animals Humans Thymine Nucleotides [CHIM]Chemical Sciences Phosphoramidite Thymidine monophosphate 010405 organic chemistry Oligonucleotide [CHIM.ORGA]Chemical Sciences/Organic chemistry Prodrug Thionucleotides 0104 chemical sciences Blood chemistry Biochemistry Oligodeoxyribonucleotides Evaluation Studies as Topic Thymidine Linker Research Article |
| Zdroj: | Nucleic Acids Research Nucleic Acids Research, Oxford University Press, 1998, 26 (9), pp.2069-2074. ⟨10.1093/nar/26.9.2069⟩ |
| ISSN: | 0305-1048 1362-4962 |
| DOI: | 10.1093/nar/26.9.2069⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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