Synthesis and properties of 3'-amino-2',4'-BNA, a bridged nucleic acid with a N3'-->P5' phosphoramidate linkage.
The synthesis and properties of a bridged nucleic acid analogue containing a N3'-->P5' phosphoramidate linkage, 3'-amino-2',4'-BNA, is described. A heterodimer containing a 3'-amino-2',4'-BNA thymine monomer, and thymine and methylcytosine monomers of 3'-amino-2',4'-BNA and their 5'-phosphoramidites, were synthesized efficiently. The dimer and monomers were incorporated into oligonucleotides by conventional 3'-->5' assembly, and 5'-->3' reverse assembly phosphoramidite protocols, respectively. Compared to a natural DNA oligonucleotide, modified oligonucleotides containing the 3'-amino-2',4'-BNA residue formed highly stable duplexes and triplexes with single-stranded DNA (ssDNA), single-stranded RNA (ssRNA), and double-stranded DNA (dsDNA) targets, with the average increase in melting temperature (T(m)) against ssDNA, ssRNA and dsDNA being +2.7 to +4.0 degrees C, +5.0 to +7.0 degrees C, and +5.0 to +11.0 degrees C, respectively. These increases are comparable to those observed for 2',4'-BNA-modified oligonucleotides. In addition, an oligonucleotide modified with a single 3'-amino-2',4'-BNA thymine residue showed extraordinarily high resistance to nuclease degradation, much higher than that of 2',4'-BNA and substantially higher even than that of 3'-amino-DNA and phosphorothioate oligonucleotides. The above properties indicate that 3'-amino-2',4'-BNA has significant potential for antisense and antigene applications.
Obika
Satoshi
S
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. obika@phs.osaka-u.ac.jp
Rahman
S M Abdur
SM
Song
Bingbing
B
Onoda
Mayumi
M
Koizumi
Makoto
M
Morita
Koji
K
Imanishi
Takeshi
T
D000577:Amides / Q000737:chemistry*; D000588:Amines / Q000737:chemistry*; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D019281:Dimerization; D015394:Molecular Structure; D009691:Nucleic Acid Denaturation; D009696:Nucleic Acids / Q000737:chemistry*; D009711:Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D010756:Phosphoric Acids / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013696:Temperature
C527205:2',4'-BNA(NC); D000577:Amides; D000588:Amines; D001952:Bridged-Ring Compounds; D009696:Nucleic Acids; D009711:Nucleotides; D010756:Phosphoric Acids; C011067:phosphoramidic acid