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.

MicroRNA-21 (miRNA-21) 在各种肿瘤中高度表达。miRNA-21的小分子抑制被认为是一种有吸引力的新型癌症治疗策略。在本研究中，合成了氟喹诺酮衍生物 A1-A43 并用作 miRNA-21 抑制剂。在 HeLa 细胞中的双荧光素酶报告基因测定中，化合物 A36 显示出对 miRNA-21 最有效的抑制活性和特异性。化合物 A36 在 HeLa 中以 10 μM 显着降低成熟 miRNA-21 的表达并增加 miRNA-21 靶基因的蛋白质表达，包括程序性细胞死亡蛋白 4 (PDCD4) 和 10 号染色体上缺失的磷酸酶和张力蛋白同源性 (PTEN)细胞。Cell Counting Kit-8 检测（CCK-8）用于评估 A36 的抗增殖活性；结果表明，IC ₅₀A36 对六种肿瘤细胞系的值范围在 1.76 和 13.0 μM 之间。同时，A36 在 BEAS-2B 细胞（来自健康人类供体的肺上皮细胞）中没有表现出细胞毒性。此外，A36 显着诱导细胞凋亡，使细胞停滞在 G ₀ /G ₁期，并抑制 HeLa 细胞中的细胞集落形成。此外，mRNA 深度测序显示，A36 处理可在 HeLa 细胞中产生 171 个失调的 mRNA，而 miRNA-21 靶基因双特异性磷酸酶 5 (DUSP5) 的表达在 mRNA 和蛋白质水平均显着上调。总之，这些发现表明 A36 是一种新型 miRNA-21 抑制剂。