Synthesis, physico-chemical and biological properties of DNA and RNA oligonucleotides containing short alkylamino internucleotide bond
- 7 December 2011
- journal article
- Published by Institute of Organic Chemistry & Biochemistry in Collection of Czechoslovak Chemical Communications
- Vol. 76 (12), 1471-1486
- https://doi.org/10.1135/cccc2011090
Abstract
The condensation of the 5′-O-DMT-3′-deoxy-3′-aminothymidine with 3′-O-TBDMS-thymidine- 5′-aldehyde, followed by reduction of the resultant imine derivative and removal of tert-butyldimethylsilyl (TBDMS) protecting group, provided a dimer (denoted as TNHT), which is a congener of dithymidine phosphate with the phosphate linkage 3′-O-P(O)(OH)-O-5′ replaced with an amino group (–NH–). After phosphitylation of the 3′-OH group, the dimer TNHT was introduced (by the standard phosphoramidite approach) into a central part of the nonadecathymidylate. This oligomer exhibited lower affinity to the complementary single and double stranded DNA complements as compared to unmodified T19 oligonucleotide. The cleavage of modified oligomer with the snake venom and calf spleen phosphodiesterases was completely suppressed at the site of modification. RNA oligomers containing the TNHT dimer were used for preparation of siRNA molecules directed towards mRNA of BACE1 (beta-site amyloid precursor protein cleaving enzyme). The presence of the TNHT units at the 3′-ends of the RNA strands of the siRNA molecule (the siRNA itself is an effective gene expression inhibitor for BACE1) preserved the gene silencing activity and improved the stability of the modified siRNA in 10% fetal bovine serum.Keywords
This publication has 37 references indexed in Scilit:
- Phosphorothioate Nucleotides and Oligonucleotides – Recent Progress in Synthesis and ApplicationChemistry & Biodiversity, 2011
- Automated synthesis of phosphorus–sulfur analogs of nucleic acids—25 years on: potential therapeutic agents and proven utility in biotechnologyNew Journal of Chemistry, 2010
- The versatility of oligonucleotides as potential therapeuticsExpert Opinion on Biological Therapy, 2007
- P-chiral oligonucleotides in biological recognition processes.Current Topics in Medicinal Chemistry, 2007
- Backbone modifications in oligonucleotides and peptide nucleic acid systemsCurrent Opinion in Structural Biology, 1995
- Synthesis and hybridization studies of urea and carbamate linked thymidine dimers incorporated into oligodeoxynucleosidesBioorganic & Medicinal Chemistry Letters, 1994
- Carbamate analogs of oligonucleotidesThe Journal of Organic Chemistry, 1977
- Synthetic analogues of polynucleotides: X. The synthesis of poly-(3′-O-carboxymethyl-2′-deoxyadenosine) and its interaction with polynucleotidesBiochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis, 1973
- The preparation of nucleoside carbonatesJournal of the Chemical Society C: Organic, 1971
- Synthesis of carbonate analogs of dinucleosides. 3'-Thymidinyl 5'-thymidinyl carbonate, 3'-thymidinyl 5'-(5-fluoro-2'-deoxyuridinyl) carbonate, and 3'-(5-fluoro-2'-deoxyuridinyl) 5'-thymidinyl carbonateJournal of Medicinal Chemistry, 1969