Volume 12 Issue 4
Sep.  2022
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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

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

doi: 10.1016/j.jpha.2021.12.008
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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
  • 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.
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  • R.C. Friedman, K.K. Farh, C.B. Burge, et al., Most mammalian mRNAs are conserved targets of microRNAs, Genome Res. 19 (2009) 92-105
    S.M. Hammond, An overview of microRNAs, Adv. Drug Deliv. Rev. 87 (2015) 3-14
    B.R. Cullen, Transcription and processing of human microRNA precursors, Mol. Cell 16 (2004) 861-865
    A.M. Denli, B.B. Tops, R.H. Plasterk, et al., Processing of primary microRNAs by the Microprocessor complex, Nature 432 (2004) 231-235
    R.I. Gregory, K.-P. Yan, G. Amuthan, et al., The Microprocessor complex mediates the genesis of microRNAs, Nature 432 (2004) 235-240
    E. Bernstein, A.A. Caudy, S.M. Hammond, et al., Role for a bidentate ribonuclease in the initiation step of RNA interference, Nature 409 (2001) 363-366
    A. Grishok, A.E. Pasquinelli, D. Conte, et al., Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing, Cell 106 (2001) 23-34
    S.M. Hammond, E. Bernstein, D. Beach, et al., An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells, Nature 404 (2000) 293-296
    D.P. Bartel, MicroRNAs:target recognition and regulatory functions, Cell 136 (2009) 215-233
    S.M. Hammond, MicroRNAs as oncogenes, Curr. Opin. Genet. Dev. 16 (2006) 4-9
    Y. Peng, C.M. Croce, The role of MicroRNAs in human cancer, Signal Transduct Target Ther. 1 (2016) 15004-15012
    M.A. Jafri, M.H. Al-Qahtani, J.W. Shay, Role of miRNAs in human cancer metastasis:Implications for therapeutic intervention, Semin. Cancer Biol. 44 (2017) 117-131
    Y.H. Feng, C.J. Tsao, Emerging role of microRNA-21 in cancer, Biomed. Rep. 5 (2016) 395-402
    X. Li, S. Xin, Z. He, et al., MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor PDCD4 and promotes cell transformation, proliferation, and metastasis in renal cell carcinoma, Cell Physiol. Biochem. 33 (2014) 1631-1642
    L.K. Rushworth, A.M. Kidger, L. Delavaine, et al., Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRasQ61L)-driven SerpinB2 expression, Proc. Natl. Acad. Sci. U.S.A. 111 (2014) 18267-18272
    Y. Lou, X. Yang, F. Wang, et al., MicroRNA-21 promotes the cell proliferation, invasion and migration abilities in ovarian epithelial carcinomas through inhibiting the expression of PTEN protein, Int. J. Mol. Med. 26 (2010) 819-827
    X. Yu, Y. Chen, R. Tian, et al., miRNA-21 enhances chemoresistance to cisplatin in epithelial ovarian cancer by negatively regulating PTEN, Oncol. Lett. 14 (2017) 1807-1810
    Y. Naro, N. Ankenbruck, M. Thomas, et al., Small molecule inhibition of MicroRNA miR-21 rescues chemosensitivity of renal-cell carcinoma to topotecan, J. Med. Chem. 61 (2018) 5900-5909
    A. Markou, M. Zavridou, E.S. Lianidou, miRNA-21 as a novel therapeutic target in lung cancer, Lung Cancer (Auckl) 7 (2016) 19-27
    E.N. Van Meter, J.A. Onyango, K.A. Teske, A review of currently identified small molecule modulators of microRNA function, Eur. J. Med. Chem. 188 (2020), 112008
    M.G. Costales, J.L. Childs-Disney, H.S. Haniff, et al., How we think about targeting RNA with small molecules, J. Med. Chem. 63 (2020) 8880-8900
    J.S. Matarlo, L.R.H. Krumpe, W.F. Heinz, et al., The natural product butylcycloheptyl prodiginine binds pre-miR-21, inhibits dicer-mediated processing of pre-miR-21, and blocks cellular proliferation, Cell Chem. Biol. 10 (2019) 1133-1142.e4
    A.L. Garner, D.A. Lorenz, J. Sandoval, et al., Tetracyclines as Inhibitors of Pre-microRNA Maturation:A Disconnection between RNA Binding and Inhibition, ACS Med. Chem. Lett. 10 (2019) 816-821
    S.P. Velagapudi, M.G. Costales, B.R. Vummidi, et al., Approved anti-cancer drugs target oncogenic non-coding RNAs, Cell Chem. Biol. 25 (2018) 1086-1094.e7
    K. Gumireddy, D.D. Young, X. Xiong, et al., Small-molecule inhibitors of microrna miR-21 function, Angew. Chem. Int. Ed. Engl. 47 (2008) 7482-7484
    D. Bose, G. Jayaraj, H. Suryawanshi, et al., The tuberculosis drug streptomycin as a potential cancer therapeutic:inhibition of miR-21 function by directly targeting its precursor, Angew. Chem. Int. Ed. Engl. 51 (2012) 1019-1023
    Z. Shi, J. Zhang, X. Qian, et al., AC1MMYR2, an inhibitor of dicer-mediated biogenesis of Oncomir miR-21, reverses epithelial-mesenchymal transition and suppresses tumor growth and progression, Cancer Res. 73 (2013) 5519-5531
    Y. Naro, M. Thomas, M.D. Stephens, et al., Aryl amide small-molecule inhibitors of microRNA miR-21 function, Bioorg. Med. Chem. Lett. 25 (2015) 4793-4796
    C.M. Connelly, R.E. Boer, M.H. Moon, et al., Discovery of inhibitors of MicroRNA-21 processing using small molecule microarrays, ACS Chem. Biol. 12 (2017) 435-443
    C.S. Jiang, X.M. Wang, S.Q. Zhang, et al., Discovery of 4-benzoylamino-N-(prop-2-yn-1-yl)benzamides as novel microRNA-21 inhibitors, Bioorg. Med. Chem. 23 (2015) 6510-6519
    H. Sun, G. Tawa, A. Wallqvist, Classification of scaffold-hopping approaches, Drug Discov. Today 17 (2012) 310-324
    Y.Y. Hei, Y.X. Guo, C.S. Jiang, et al., The dual luciferase reporter system and RT-qPCR strategies for screening of MicroRNA-21 small-molecule inhibitors, Biotechnol. Appl. Biochem. 66 (2019) 755-762
    T. Felicetti, V. Cecchetti, G. Manfroni, Modulating microRNA Processing:Enoxacin, the Progenitor of a New Class of Drugs, J. Med. Chem. 63 (2020) 12275-12289
    S. Melo, A. Villanueva, C. Moutinho, et al., Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing, Proc. Natl. Acad. Sci. U.S.A. 108 (2011) 4394-4399
    E. Sousa, I. Graca, T. Baptista, et al., Enoxacin inhibits growth of prostate cancer cells and effectively restores microRNA processing, Epigenetics 8 (2013) 548-558
    G. Shan, Y. Li, J. Zhang, et al., A small molecule enhances RNA interference and promotes microRNA processing, Nat. Biotechnol. 26 (2008) 933-940
    Y. Zhou, X. Xu, Y. Sun, et al., Synthesis, cytotoxicity and topoisomerase II inhibitory activity of lomefloxacin derivatives, Bioorg. Med. Chem. Lett. 23 (2013) 2974-2978
    S.P. Velagapudi, S.M. Gallo, M.D. Disney, Sequence-based design of bioactive small molecules that target precursor microRNAs, Nat. Chem. Biol. 10 (2014) 291-297
    M. Maiti, K. Nauwelaerts, P. Herdewijn, Pre-microRNA binding aminoglycosides and antitumor drugs as inhibitors of Dicer catalyzed microRNA processing, Bioorg. Med. Chem. Lett. 22 (2012) 1709-1711
    B. Meeusen, V. Janssens, Tumor suppressive protein phosphatases in human cancer:Emerging targets for therapeutic intervention and tumor stratification, Int. J. Biochem. Cell Biol. 96 (2018) 98-134
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