Effective syntheses of 2',4'-BNANC monomers bearing adenine, guanine, thymine, and 5-methylcytosine, and the properties of oligonucleotides fully modified with 2',4'-BNANC

Aki Fujisaka; Yoshiyuki Hari; Hiroko Takuma; S M Abdur Rahman; Haruhisa Yoshikawa; Juanjuan Pang; Takeshi Imanishi; Satoshi Obika

doi:10.1016/j.bmc.2019.02.034

Effective syntheses of 2',4'-BNA^NC monomers bearing adenine, guanine, thymine, and 5-methylcytosine, and the properties of oligonucleotides fully modified with 2',4'-BNA^NC

Bioorg Med Chem. 2019 Apr 15;27(8):1728-1741. doi: 10.1016/j.bmc.2019.02.034. Epub 2019 Feb 22.

Authors

Aki Fujisaka¹, Yoshiyuki Hari², Hiroko Takuma³, S M Abdur Rahman⁴, Haruhisa Yoshikawa⁵, Juanjuan Pang³, Takeshi Imanishi⁵, Satoshi Obika⁶

Affiliations

¹ Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Faculty of Pharmacy, Osaka Ohtani University, Nishikiori-Kita 3-11-1, Tondabayashi, Osaka 584-8540, Japan.
² Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Nishihama, Yamashiro-cho, Tokushima 770-8514, Japan.
³ Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁴ Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Clinical Pharmacy & Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh.
⁵ Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; BNA Inc, 7-7-20 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
⁶ Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: obika@phs.osaka-u.ac.jp.

PMID: 30862430
DOI: 10.1016/j.bmc.2019.02.034

Abstract

We efficiently synthesized 2'-O,4'-C-aminomethylene-bridged nucleic acid (2',4'-BNA^NC) monomers bearing the four nucleobases, guanine, adenine, thymine, and 5-methylcytosine and incorporated these monomers into oligonucleotides. Initially, we carried out the transglycosylation reaction on several 2'-O-substituted 5-methyluridines to evaluate the effects of 2'-substitutions on this reaction. Under the optimized conditions, purine nucleobases were successfully introduced, and 2',4'-BNA^NC monomers bearing adenine or guanine were obtained over several steps. In addition, the improved synthesis of the 2',4'-BNA^NC monomers bearing thymine or 5-methylcytosine was also achieved. The obtained 2',4'-BNA^NC monomers were subsequently incorporated into oligonucleotides and the duplex-forming abilities of the modified oligonucleotides were investigated. Duplexes containing 2',4'-BNA^NC monomers in both or either strands were found to possess excellent thermal stabilities.

Keywords: Bridged nucleic acids; Nucleotides; Oligonucleotides; Sugar modifications.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5-Methylcytosine / chemistry*
Adenine / chemistry*
Bridged-Ring Compounds / chemistry*
Glycosylation
Guanine / chemistry*
Nucleotides / chemistry*
Oligonucleotides / chemical synthesis*
Oligonucleotides / chemistry
Thymine
Transition Temperature
Ultraviolet Rays

Substances

2',4'-BNA(NC)
Bridged-Ring Compounds
Nucleotides
Oligonucleotides
Guanine
5-Methylcytosine
Adenine
Thymine