Design, synthesis, and evaluation of fluoroquinolone derivatives as microRNA-21 small-molecule inhibitors

Yuan-Yuan Hei; Si Wang; Xiao-Xiao Xi; Hai-Peng Wang; Yuanxu Guo; Minhang Xin; Congshan Jiang; Shemin Lu; San-Qi Zhang

doi:10.1016/j.jpha.2021.12.008

Volume 12 Issue 4

Sep. 2022

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Article Navigation > Journal of Pharmaceutical Analysis > 2022 > 12(4): 653-663

Yuan-Yuan Hei, Si Wang, Xiao-Xiao Xi, Hai-Peng Wang, Yuanxu Guo, Minhang Xin, Congshan Jiang, Shemin Lu, San-Qi Zhang. Design, synthesis, and evaluation of fluoroquinolone derivatives as microRNA-21 small-molecule inhibitors[J]. Journal of Pharmaceutical Analysis, 2022, 12(4): 653-663. doi: 10.1016/j.jpha.2021.12.008

Citation:

Yuan-Yuan Hei, Si Wang, Xiao-Xiao Xi, Hai-Peng Wang, Yuanxu Guo, Minhang Xin, Congshan Jiang, Shemin Lu, San-Qi Zhang. Design, synthesis, and evaluation of fluoroquinolone derivatives as microRNA-21 small-molecule inhibitors[J]. Journal of Pharmaceutical Analysis, 2022, 12(4): 653-663. doi: 10.1016/j.jpha.2021.12.008

Citation:

Yuan-Yuan Hei, Si Wang, Xiao-Xiao Xi, Hai-Peng Wang, Yuanxu Guo, Minhang Xin, Congshan Jiang, Shemin Lu, San-Qi Zhang. Design, synthesis, and evaluation of fluoroquinolone derivatives as microRNA-21 small-molecule inhibitors[J]. Journal of Pharmaceutical Analysis, 2022, 12(4): 653-663. doi: 10.1016/j.jpha.2021.12.008

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Design, synthesis, and evaluation of fluoroquinolone derivatives as microRNA-21 small-molecule inhibitors

doi: 10.1016/j.jpha.2021.12.008

Yuan-Yuan Hei^a,c,
Si Wang^b,c,
Xiao-Xiao Xi^a,
Hai-Peng Wang^d,
Yuanxu Guo^b,c,
Minhang Xin^a,c,
Congshan Jiang^{b,c
,
,},
Shemin Lu^b,c,
San-Qi Zhang^{a,c
,
,}

a. Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China;
b. Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China;
c. Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China;
d. Department of Medical Oncology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China

Funds:

Financial support from the National Natural Science Foundation of China (Grant No.: 81673354) is gratefully acknowledged.

Received Date: Jul. 12, 2021
Accepted Date: Dec. 31, 2021
Rev Recd Date: Dec. 31, 2021
Publish Date: Jan. 03, 2022

Abstract

Abstract

MicroRNA-21 (miRNA-21) is highly expressed in various tumors. Small-molecule inhibition of miRNA-21 is considered to be an attractive novel cancer therapeutic strategy. In this study, fluoroquinolone derivatives A1-A43 were synthesized and used as miRNA-21 inhibitors. Compound A36 showed the most potent inhibitory activity and specificity for miRNA-21 in a dual-luciferase reporter assay in HeLa cells. Compound A36 significantly reduced the expression of mature miRNA-21 and increased the protein expression of miRNA-21 target genes, including programmed cell death protein 4 (PDCD4) and phosphatase and tensin homology deleted on chromosome ten (PTEN), at 10 μM in HeLa cells. The Cell Counting Kit-8 assay (CCK-8) was used to evaluate the antiproliferative activity of A36; the results showed that the IC₅₀ value range of A36 against six tumor cell lines was between 1.76 and 13.0 μM. Meanwhile, A36 did not display cytotoxicity in BEAS-2B cells (lung epithelial cells from a healthy human donor). Furthermore, A36 significantly induced apoptosis, arrested cells at the G₀/G₁ phase, and inhibited cell-colony formation in HeLa cells. In addition, mRNA deep sequencing showed that treatment with A36 could generate 171 dysregulated mRNAs in HeLa cells, while the expression of miRNA-21 target gene dual-specificity phosphatase 5 (DUSP5) was significantly upregulated at both the mRNA and protein levels. Collectively, these findings demonstrated that A36 is a novel miRNA-21 inhibitor.
- Quinolone derivatives,
- Small-molecule miRNA-21 inhibitor,
- Antitumor agent,
- Drug design

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References(40)

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