Design,synthesis,and evaluation of fluoroquinolone derivatives as microRNA-21 small-molecule inhibitors
- Author:
Hei YUAN-YUAN
1
,
2
;
Wang SI
;
Xi XIAO-XIAO
;
Wang HAI-PENG
;
Guo YUANXU
;
Xin MINHANG
;
Jiang CONGSHAN
;
Lu SHEMIN
;
Zhang SAN-QI
Author Information
1. Department of Medicinal Chemistry,School of Pharmacy,Xi'an Jiaotong University Health Science Center,Xi'an,710061,China
2. Key Laboratory of Environment and Genes Related to Diseases(Xi'an Jiaotong University),Ministry of Education,Xi'an,710061,China
- Keywords:
Quinolone derivatives;
Small-molecule miRNA-21 inhibitor;
Antitumor agent;
Drug design
- From:
Journal of Pharmaceutical Analysis
2022;12(4):653-663
- CountryChina
- Language:Chinese
-
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 de-rivatives Al-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 phos-phatase and tensin homology deleted on chromosome ten(PTEN),at 10 uM 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.
