Tommaso Felicetti, Nicola Di Iacovo, Maria Agnese Della Fazia, Danilo Piobbico, Stefania Pieroni, Martina Pacetti, Jialing Yu, Yilun Sun, Serena Massari, Maria Letizia Barreca, Stefano Sabatini, Oriana Tabarrini, Violetta Cecchetti, Fei Wang, Yves Pommier, Mariangela Morlando, Giuseppe Servillo, Giuseppe Manfroni
{"title":"通过调节 microRNA 处理机制发挥作用的新型抗卵巢癌喹诺酮衍生物。","authors":"Tommaso Felicetti, Nicola Di Iacovo, Maria Agnese Della Fazia, Danilo Piobbico, Stefania Pieroni, Martina Pacetti, Jialing Yu, Yilun Sun, Serena Massari, Maria Letizia Barreca, Stefano Sabatini, Oriana Tabarrini, Violetta Cecchetti, Fei Wang, Yves Pommier, Mariangela Morlando, Giuseppe Servillo, Giuseppe Manfroni","doi":"10.1039/d4md00649f","DOIUrl":null,"url":null,"abstract":"<p><p>MicroRNAs (miRNAs) play a crucial role in ovarian cancer (OC) pathogenesis and miRNA processing can be the object of pharmacological intervention. By exploiting our in-house quinolone library, we combined a cell-based screening with medicinal chemistry efforts, ultimately leading to derivative 33 with anti-OC activity against distinct cell lines (GI<sub>50</sub> values 13.52-31.04 μM) and CC<sub>50 Wi-38</sub> = 142.9 μM. Compound 33 retained anticancer activity against additional cancer cells and demonstrated a synergistic effect with cisplatin against cisplatin-resistant A2780 cells. Compound 33 bound TRBP by SPR (<i>K</i> <sub>D</sub> = 4.09 μM) and thermal shift assays and its activity was TRBP-dependent, leading to modulation of siRNA and miRNA maturation. Derivative 33 exhibited augmented potency against OC cells and a stronger binding affinity for TRBP compared to enoxacin, the sole quinolone identified as a modulator of miRNA maturation. Consequently, 33 represents a promising template for developing novel anti-OC agents with a distinctive mechanism of action.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1000,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467779/pdf/","citationCount":"0","resultStr":"{\"title\":\"New anti-ovarian cancer quinolone derivatives acting by modulating microRNA processing machinery.\",\"authors\":\"Tommaso Felicetti, Nicola Di Iacovo, Maria Agnese Della Fazia, Danilo Piobbico, Stefania Pieroni, Martina Pacetti, Jialing Yu, Yilun Sun, Serena Massari, Maria Letizia Barreca, Stefano Sabatini, Oriana Tabarrini, Violetta Cecchetti, Fei Wang, Yves Pommier, Mariangela Morlando, Giuseppe Servillo, Giuseppe Manfroni\",\"doi\":\"10.1039/d4md00649f\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>MicroRNAs (miRNAs) play a crucial role in ovarian cancer (OC) pathogenesis and miRNA processing can be the object of pharmacological intervention. By exploiting our in-house quinolone library, we combined a cell-based screening with medicinal chemistry efforts, ultimately leading to derivative 33 with anti-OC activity against distinct cell lines (GI<sub>50</sub> values 13.52-31.04 μM) and CC<sub>50 Wi-38</sub> = 142.9 μM. Compound 33 retained anticancer activity against additional cancer cells and demonstrated a synergistic effect with cisplatin against cisplatin-resistant A2780 cells. Compound 33 bound TRBP by SPR (<i>K</i> <sub>D</sub> = 4.09 μM) and thermal shift assays and its activity was TRBP-dependent, leading to modulation of siRNA and miRNA maturation. Derivative 33 exhibited augmented potency against OC cells and a stronger binding affinity for TRBP compared to enoxacin, the sole quinolone identified as a modulator of miRNA maturation. Consequently, 33 represents a promising template for developing novel anti-OC agents with a distinctive mechanism of action.</p>\",\"PeriodicalId\":21462,\"journal\":{\"name\":\"RSC medicinal chemistry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-09-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467779/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"RSC medicinal chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1039/d4md00649f\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"RSC medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1039/d4md00649f","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
New anti-ovarian cancer quinolone derivatives acting by modulating microRNA processing machinery.
MicroRNAs (miRNAs) play a crucial role in ovarian cancer (OC) pathogenesis and miRNA processing can be the object of pharmacological intervention. By exploiting our in-house quinolone library, we combined a cell-based screening with medicinal chemistry efforts, ultimately leading to derivative 33 with anti-OC activity against distinct cell lines (GI50 values 13.52-31.04 μM) and CC50 Wi-38 = 142.9 μM. Compound 33 retained anticancer activity against additional cancer cells and demonstrated a synergistic effect with cisplatin against cisplatin-resistant A2780 cells. Compound 33 bound TRBP by SPR (KD = 4.09 μM) and thermal shift assays and its activity was TRBP-dependent, leading to modulation of siRNA and miRNA maturation. Derivative 33 exhibited augmented potency against OC cells and a stronger binding affinity for TRBP compared to enoxacin, the sole quinolone identified as a modulator of miRNA maturation. Consequently, 33 represents a promising template for developing novel anti-OC agents with a distinctive mechanism of action.
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