Synthesis and Structure of 4'-CF3-Uridine Modified Oligoribonucleotides

doi:10.6023/cjoc202103058

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (10): 4059-4065.DOI: 10.6023/cjoc202103058 Previous Articles Next Articles

Special Issue: 南开大学化学学科创立100周年

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4'-三氟甲基尿苷修饰的寡核苷酸合成及修饰位点构象研究

郭丰敏^a, Marko Trajkovski^b, 李强^a, Janez Plavec^b, 席真^a, 周传政^a^,^*()

a 南开大学化学学院元素有机化学国家重点实验室天津 300071
b 斯洛文尼亚国家化学研究所核磁中心卢布尔雅那大学化学和化工学院卢布尔雅那 1000 斯洛文尼亚

收稿日期:2021-03-29 修回日期:2021-05-08 发布日期:2021-06-17
通讯作者: 周传政
基金资助:
国家自然科学基金(21877064); 国家自然科学基金(91953115); 天津市自然科学基金(20JCZDJC00830)

Synthesis and Structure of 4'-CF₃-Uridine Modified Oligoribonucleotides

Fengmin Guo^a, Marko Trajkovski^b, Qiang Li^a, Janez Plavec^b, Zhen Xi^a, Chuanzheng Zhou^a()

a State Key Laboratory of Elemento-organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071
b Slovenian NMR Centre, National Institute of Chemistry, University of Ljubljana, Faculty of Chemistry and Chemical Technology, Ljubljana, EN-FIST Centre of Excellence, Hajdrihova 19, Ljubljana 1000, Slovenia

Received:2021-03-29 Revised:2021-05-08 Published:2021-06-17
Contact: Chuanzheng Zhou
Supported by:
National Natural Science Foundation of China(21877064); National Natural Science Foundation of China(91953115); Natural Science Foundation of Tianjin City(20JCZDJC00830)

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Abstract

The synthesis and structure of 4'-CF₃-uridine modified ribonucleotides are reported. Active 4'-CF₃-uridine (^4'-TfMU) phosphoramidite was prepared and successfully incorporated into oligonucleotides based on solid-supported synthesis. Molecular dynamics simulations and NMR studies of the ^4'-TfMU modified oligonucleotides revealed that the ribose of ^4'-TfMU was constrained in the South conformation, which was corroborated by the biochemical properties of the ^4'-TfMU modified oligonucleotide, such as their affinity to complementary strands and transesterification kinetics. The South-constrained conformation, together with the intense ¹⁹F NMR signal of the ^4'-TfMU makes it an ideal probe for studying the structure and function of RNA.

Key words: nucleic acids, RNA structures, fluorine chemistry

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Fengmin Guo, Marko Trajkovski, Qiang Li, Janez Plavec, Zhen Xi, Chuanzheng Zhou. Synthesis and Structure of 4'-CF₃-Uridine Modified Oligoribonucleotides[J]. Chinese Journal of Organic Chemistry, 2021, 41(10): 4059-4065.

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Fig. & Tab. 5

Figure 1. Modulation of the ribose conformation by chemical modifications (A) Two principal ribose puckering modes; (B) structures of 4' modified ribonucleotides

Scheme 1. Synthesis of 4'-CF3-uridine phosphoramidite

Oligos	Sequence (5'-3')	Vs cDNA		Vs cRNA
Oligos	Sequence (5'-3')	T_m	∆T_m	T_m	∆T_m
Oligo 1	r(CCAUUAUAGC)	27.9	—	39.7	—
Oligo 2	r(CCAU^4'-TfMUAUAGC)	20.1	–7.8	33.5	–6.2
Oligo 3	d(CCATTATAGC)	29.8	—	27.2	—
Oligo 4	d(CCAT^4'-TfMUATAGC)	28.5	–1.3	27.3	+0.1

Table 1. Thermal denaturation (Tm, ℃) of Oligos/DNA and Oligos/RNA duplexesa

Figure 2. Ribose conformation of the 4'-TfMU in the context of RNA strands (A) REMD simulations of the 4'-TfMU in single-stranded RNA; (B) DQF COSY NMR spectrum of dsRNA showing the resolved H1'-H2' cross-peak of the 4'-TfMU residue

	5'-d(CTTCTTTNTTACTTC)
	Oligo 5^b	Oligo 6^b	Oligo 7
	N=U	N=^4'-MeU	N=^4'-TfMU
t_1/2 at pH 12.4	3.3±0.3 h	1.4±0.1 h	0.9±0.1 h
t_1/2 at pH 14.0	33±2 min	8±1 min	6±1 min
t_1/2 at pH 4.0	379±11 h	206±19 h	73±3 h

Table 2. Half-lives for embedded ribonucleotide cleavage in single-stranded DNAa

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4'-三氟甲基尿苷修饰的寡核苷酸合成及修饰位点构象研究

Synthesis and Structure of 4'-CF₃-Uridine Modified Oligoribonucleotides

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