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.
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页数:8
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