TY - JOUR
T1 - Synthesis and properties of GuNA purine/pyrimidine nucleosides and oligonucleotides
AU - Kumagai, Shinji
AU - Sawamoto, Hiroaki
AU - Takegawa-Araki, Tomo
AU - Arai, Yuuki
AU - Yamakoshi, Shuhei
AU - Yamada, Katsuya
AU - Ohta, Tetsuya
AU - Kawanishi, Eiji
AU - Horie, Naohiro
AU - Yamaguchi, Takao
AU - Obika, Satoshi
N1 - Funding Information:
We thank Chieko Okagaki, Eri Oboki and Kaori Murakoshi (Mitsubishi Tanabe Pharma Corporation) for the technical support of synthesis and analysis of compounds. A part of this work was supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Number JP19am0101084.
Publisher Copyright:
© The Royal Society of Chemistry.
PY - 2020/12/14
Y1 - 2020/12/14
N2 - We recently designed guanidine-bridged nucleic acids (GuNA), and GuNA bearing a thymine (T) nucleobase was synthesized and successfully incorporated into oligonucleotides. The GuNA-T-modified oligonucleotides possessed high duplex-forming ability towards their complementary single-stranded RNAs and were highly stable against 3-exonuclease. Therefore, GuNA is a promissing artificial nucleic acid for therapeutic antisense oligonucleotides. We herein report the facile synthesis of GuNA phosphoramidites bearing adenine (A), guanine (G), and 5-methylcytosine (mC) nucleobases and a robust method for the preparation of GuNA-modified oligonucleotides, even with sequences having acid-sensitive purine nucleobases. Oligonucleotides modified with GuNA-A,-G, or-mC possessed high duplex-forming ability, similar to those modified with GuNA-T. Moreover, some of the GuNA-modified oligonucleotides were revealed to have high base discriminating ability compared with that of their natural counterparts. GuNA nucleosides exhibited no genotoxicity in bacterial reverse mutation assays. Thus, all GuNAs (GuNA-T,-A,-G, and-mC) are now available to be examined in therapeutic applications.
AB - We recently designed guanidine-bridged nucleic acids (GuNA), and GuNA bearing a thymine (T) nucleobase was synthesized and successfully incorporated into oligonucleotides. The GuNA-T-modified oligonucleotides possessed high duplex-forming ability towards their complementary single-stranded RNAs and were highly stable against 3-exonuclease. Therefore, GuNA is a promissing artificial nucleic acid for therapeutic antisense oligonucleotides. We herein report the facile synthesis of GuNA phosphoramidites bearing adenine (A), guanine (G), and 5-methylcytosine (mC) nucleobases and a robust method for the preparation of GuNA-modified oligonucleotides, even with sequences having acid-sensitive purine nucleobases. Oligonucleotides modified with GuNA-A,-G, or-mC possessed high duplex-forming ability, similar to those modified with GuNA-T. Moreover, some of the GuNA-modified oligonucleotides were revealed to have high base discriminating ability compared with that of their natural counterparts. GuNA nucleosides exhibited no genotoxicity in bacterial reverse mutation assays. Thus, all GuNAs (GuNA-T,-A,-G, and-mC) are now available to be examined in therapeutic applications.
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U2 - 10.1039/d0ob01970d
DO - 10.1039/d0ob01970d
M3 - Article
C2 - 33179694
AN - SCOPUS:85097417227
SN - 1477-0520
VL - 18
SP - 9461
EP - 9472
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
IS - 46
ER -