New anti-ovarian cancer quinolone derivatives acting by modulating microRNA processing machinery.

IF 4.1 4区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

RSC medicinal chemistry Pub Date : 2024-09-27 DOI:10.1039/d4md00649f

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

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引用次数: 0

Abstract

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 CC_{50 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 (K _D = 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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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。

微RNA（miRNA）在卵巢癌（OC）发病机制中起着至关重要的作用，而miRNA的处理可作为药物干预的对象。通过利用我们内部的喹诺酮化合物库，我们将基于细胞的筛选与药物化学工作相结合，最终得到了对不同细胞系具有抗卵巢癌活性的衍生物 33（GI50 值为 13.52-31.04 μM），CC50 Wi-38 = 142.9 μM。化合物 33 对其他癌细胞也具有抗癌活性，并且与顺铂一起对顺铂耐药的 A2780 细胞具有协同作用。通过 SPR（K D = 4.09 μM）和热转移试验，化合物 33 与 TRBP 结合，其活性依赖于 TRBP，从而调节 siRNA 和 miRNA 的成熟。与恩诺沙星（唯一被鉴定为 miRNA 成熟调节剂的喹诺酮类药物）相比，衍生物 33 对 OC 细胞的效力增强，与 TRBP 的结合亲和力更强。因此，33 是开发具有独特作用机制的新型抗 OC 制剂的理想模板。

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来源期刊

RSC medicinal chemistry Multiple-

CiteScore

5.80

自引率

2.40%

发文量

129