Discovery and Structure-Activity Relationship Studies of Thiazole- Oxazole Tandem Heterocyclic RNA Splicing Inhibitors

doi:10.6023/cjoc202202033

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (9): 2925-2939.DOI: 10.6023/cjoc202202033 Previous Articles Next Articles

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噻唑-噁唑串联杂环类RNA剪接抑制剂的发现及构效关系研究

张蓉^a^,^b, 郜祥^a^,^c^,^d, 陈玲玲^a^,^c^,^d, 南发俊^a^,^b^,^*()

a 中国科学院大学北京 100049
b 上海药物研究所上海 201203
c 上海生物化学和细胞生物学研究所上海 200031
d 上海科技大学生命科学院上海 201210

收稿日期:2022-02-25 修回日期:2022-05-19 发布日期:2022-05-31
通讯作者: 南发俊

Discovery and Structure-Activity Relationship Studies of Thiazole- Oxazole Tandem Heterocyclic RNA Splicing Inhibitors

Rong Zhang^a^,^b, Xiang Gao^a^,^c^,^d, Lingling Chen^a^,^c^,^d, Fajun Nan^a^,^b()

a University of Chinese Academy of Sciences, Beijing 100049
b Shanghai Institute of Materia Medica, Shanghai 201203
c Shanghai Institute of Biochemistry and Cell Biology, Shanghai 200031
d School of Life Science and Technology, ShanghaiTech University, Shanghai 201210

Received:2022-02-25 Revised:2022-05-19 Published:2022-05-31
Contact: Fajun Nan

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Abstract

Precursor mRNAs (pre-mRNAs) undergo splicing to remove introns and ligation of their exons to yield mature mRNAs. Pre-mRNA splicing is an essential component of gene expression and proteomic diversity in higher organisms. However, the alternative splicing or mutation of splicing factors have been found in human diseases. By the use of the small molecules modulate the splicing process will provide potential treatment for related diseases. In this paper, circmcherry expression system was used to screen compounds that could affect splicing process. Several simple derivatives of natural product Leucamide A have been found to have inhibitory effects, and 36 compounds with thiazole-oxazole tadem structural core were designed and synthesized, of which methyl 2-((S)-1-(2-(2-((S)-1-(4-methoxybenzamido)-2-methylpropyl)thiazol-4- yl)-5-methyloxazole-4-carboxamido)ethyl)oxazole-4-carboxylate (9l) shows most potent inhibitory activity on splicing.

Key words: splicing inhibitors, circmCherry-expression system, Leucamide A derivatives, structure-activity relationships

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Rong Zhang, Xiang Gao, Lingling Chen, Fajun Nan. Discovery and Structure-Activity Relationship Studies of Thiazole- Oxazole Tandem Heterocyclic RNA Splicing Inhibitors[J]. Chinese Journal of Organic Chemistry, 2022, 42(9): 2925-2939.

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Fig. & Tab. 12

Figure 1. Liner splicing inhibitors

Figure 2. Screening of active compounds

Figure 3. Design idea of Leucamide A derivatives

Scheme 1. Synthesis of Leucamide A derivatives

Figure 4. Cytotoxicity and dose-effect relationship of W3/W11/W12

Figure 5. Investigation of R1 group

Figure 6. Activity after isopropyl removal

Figure 7. Activity after ester hydrolysis

Figure 8. Activity after removal and replacement of oxazole

Figure 9. Cytotoxicity of compound 9l and its activity results at dose concentration of 20 μmol/L

Figure 10. Structure-activity relationship of thiazole-oxazole tadem heterocyclic RNA splicing inhibitors

Primer	Sequence
qEGFP-F	GACCACATGAAGCAGCACGA
qEGFP-R	TGAAGTCGATGCCCTTCAG
qCircmCherry-F	TGCGCTTCAAGGTGCACATG
qCircmCherry-R	ACAGGATGTCCCAGGCGAAG
qEGFP-mCherry-F	GACCACATGAAGCAGCACGA
qEGFP-mCherry-R	ACAGGATGTCCCAGGCGAAG

Table 1. Primers for screening reporter gene

References 15

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噻唑-噁唑串联杂环类RNA剪接抑制剂的发现及构效关系研究

Discovery and Structure-Activity Relationship Studies of Thiazole- Oxazole Tandem Heterocyclic RNA Splicing Inhibitors

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