Synthesis and Properties of Gapmer Oligonucleotides Containing 4′-Carboxy- and 4′-Carbamoyl-Thymidine Analogs

被引:0
|
作者
Ishikawa, Kaede [1 ]
Fuchi, Yasufumi [1 ]
Ito, Yuta [1 ]
Hari, Yoshiyuki [1 ]
机构
[1] Tokushima Bunri Univ, Fac Pharmaceut Sci, Yamashiro Cho, Tokushima 7708514, Japan
基金
日本学术振兴会;
关键词
gapmer oligonucleotides; modified nucleosides; postsynthetic modifications; RNA; RNase H; NUCLEIC-ACID; RNASE-H; DUPLEX STABILITY; DNA; OLIGODEOXYNUCLEOTIDES; NUCLEOSIDE; RESISTANCE; ABILITY; 2'F-ANA;
D O I
10.1002/cbic.202500137
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Gapmer oligonucleotides (ONs) contain a gap region consisting of DNA, whose heteroduplex with RNA can be a substrate for RNase H. Herein, the synthesis and properties of gapmer ONs containing 4 '-carboxy- and 4 '-carbamoyl-thymidine analogs at the gap region are reported. Synthesis of the ONs was performed by postsynthetic modification of 4 '-(methoxycarbonyl)thymidine through hydrolysis and nucleophilic substitution. Concerning the synthesis of ONs containing 4 '-(propylcarbamoyl)thymidine, postsynthetic conversion of 4 '-carboxythymidine or 4 '-(phenoxycarbonyl)thymidine on the support is effective. The duplex stabilities of the modified ONs are comparable to those of the unmodified ON. Several types of modified ONs can elicit the RNase H-mediated degradation of target RNA. Furthermore, modified ON containing 4 '-carboxy-thymidine at the gap region shows improved stability in fetal bovine serum solution. The analogs used in this study can be modified nucleosides for the gap region of gapmer ONs.
引用
收藏
页数:8
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