title: Anti-parallel triplexes: Synthesis of 8-aza-7-deazaadenine nucleosides with a 3-aminopropynyl side-chain and its corresponding LNA analog.
abstract: The phosphoramidites of DNA monomers of 7-(3-aminopropyn-1-yl)-8-aza-7-deazaadenine (Y) and 7-(3-aminopropyn-1-yl)-8-aza-7-deazaadenine LNA (Z) are synthesized, and the thermal stability at pH 7.2 and 8.2 of anti-parallel triplexes modified with these two monomers is determined. When, the anti-parallel TFO strand was modified with Y with one or two insertions at the end of the TFO strand, the thermal stability was increased 1.2°C and 3°C at pH 7.2, respectively, whereas one insertion in the middle of the TFO strand decreased the thermal stability 1.4°C compared to the wild type oligonucleotide. In order to be sure that the 3-aminopropyn-1-yl chain was contributing to the stability of the triplex, the nucleobase X without the aminopropynyl group was inserted in the same positions. In all cases the thermal stability was lower than the corresponding oligonucleotides carrying the 3-aminopropyn-1-yl chain, especially at the end of the TFO strand. On the other hand, the thermal stability of the anti-parallel triplex was dramatically decreased when the TFO strand was modified with the LNA monomer analog Z in the middle of the TFO strand (ΔTm=-9.1°C). Also the thermal stability decreased about 6.1°C when the TFO strand was modified with Z and the Watson-Crick strand with adenine-LNA (A(L)). The molecular modeling results showed that, in case of nucleobases Y and Z a hydrogen bond (1.69 and 1.72Ǻ, respectively) was formed between the protonated 3-aminopropyn-1-yl chain and one of the phosphate groups in Watson-Crick strand. Also, it was shown that the nucleobase Y made a good stacking and binding with the other nucleobases in the TFO and Watson-Crick duplex, respectively. In contrast, the nucleobase Z with LNA moiety was forced to twist out of plane of Watson-Crick base pair which is weakening the stacking interactions with the TFO nucleobases and the binding with the duplex part.
authors: Department of Physics, Chemistry and Pharmacy, Nucleic Acid Center, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark; Department of Chemistry, Faculty of Science, Damietta University, 34517 New Damietta, Damietta, Egypt.
authors: Tamer R
authors: TR
authors: Kosbar
authors: Department of Chemistry, Faculty of Science, Damietta University, 34517 New Damietta, Damietta, Egypt.
authors: Mamdouh A
authors: MA
authors: Sofan
authors: Department of Chemistry, Faculty of Science, Damietta University, 34517 New Damietta, Damietta, Egypt.
authors: Mohamed A
authors: MA
authors: Waly
authors: Department of Physics, Chemistry and Pharmacy, Nucleic Acid Center, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark. Electronic address: erik@sdu.dk.
authors: Erik B
authors: EB
authors: Pedersen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D020029:Base Pairing; D001483:Base Sequence; D004355:Drug Stability; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000138:chemical synthesis*; D009943:Organophosphorus Compounds / Q000737:chemistry; D011437:Propylamines / Q000737:chemistry
chemical_list: D009841:Oligonucleotides; D009943:Organophosphorus Compounds; D011437:Propylamines; C477371:locked nucleic acid; C434331:phosphoramidite; C414764:8-aza-7-deazaadenine; D000225:Adenine
keywords: 8-Aza-7-deazaadenine; Anti-parallel triplex; G-rich TFO; LNA; Nucleoside