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Harnessing Nitric Oxide-Donating Benzofuroxans for Targeted Inhibition of Carbonic Anhydrase IX in Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-29 , DOI: 10.1021/acs.jmedchem.4c01563 Silvia Bua 1 , Alessio Nocentini 1 , Alessandro Bonardi 1 , Giuseppe Palma 2 , Giulia Ciampi 3 , Angela Giliberti 3 , Federica Iannelli 4 , Francesca Bruzzese 2 , Claudiu T Supuran 1 , Filomena de Nigris 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-29 , DOI: 10.1021/acs.jmedchem.4c01563 Silvia Bua 1 , Alessio Nocentini 1 , Alessandro Bonardi 1 , Giuseppe Palma 2 , Giulia Ciampi 3 , Angela Giliberti 3 , Federica Iannelli 4 , Francesca Bruzzese 2 , Claudiu T Supuran 1 , Filomena de Nigris 3
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We describe here the design and antitumor evaluation of benzofuroxan-based nitric oxide (NO)-donor hybrid derivatives targeting human carbonic anhydrases (hCAs) IX and XII. The most effective compounds, 27 and 28, demonstrated potent dual action, exhibiting low nanomolar inhibition constants against hCA IX and significant NO release. Notably, compound 27 showed significant antiproliferative effects against various cancer cell lines, particularly renal carcinoma A-498 cells. In these cells, it significantly reduced the expression of CA IX and iron-regulatory proteins, inducing apoptosis via mitochondrial caspase activity and ferroptosis pathways, as evidenced by increases in ROS, nitrite, and down-regulated expression of ferritin-encoding genes. In three-dimensional tumor models, compound 27 effectively reduced spheroid size and viability. In vivo toxicity studies in mice indicated that the compounds were well-tolerated, with no significant alterations in kidney function. These findings underscore the potential of benzofuroxan-based CA inhibitors for further preclinical evaluations as therapeutic agents targeting renal cell carcinoma.
中文翻译：
利用提供一氧化氮的苯并呋喃酮靶向抑制癌症中的碳酸酐酶 IX
我们在此描述了针对人碳酸酐酶 (hCA) IX 和 XII 的苯并呋喃氧 (NO) 供体杂化衍生物的设计和抗肿瘤评估。最有效的化合物27和28表现出有效的双重作用，表现出针对hCA IX的低纳摩尔抑制常数和显着的NO释放。值得注意的是，化合物27对多种癌细胞系，特别是肾癌A-498细胞显示出显着的抗增殖作用。在这些细胞中，它显着降低了 CA IX 和铁调节蛋白的表达，通过线粒体 caspase 活性和铁死亡途径诱导细胞凋亡，这一点可以通过 ROS、亚硝酸盐的增加和铁蛋白编码基因的表达下调来证明。在三维肿瘤模型中，化合物27有效降低球体尺寸和活力。小鼠体内毒性研究表明，这些化合物具有良好的耐受性，对肾功能没有显着改变。这些发现强调了苯并呋喃类 CA 抑制剂作为肾细胞癌治疗药物的进一步临床前评估的潜力。
更新日期：2024-08-29
中文翻译：
利用提供一氧化氮的苯并呋喃酮靶向抑制癌症中的碳酸酐酶 IX
我们在此描述了针对人碳酸酐酶 (hCA) IX 和 XII 的苯并呋喃氧 (NO) 供体杂化衍生物的设计和抗肿瘤评估。最有效的化合物27和28表现出有效的双重作用，表现出针对hCA IX的低纳摩尔抑制常数和显着的NO释放。值得注意的是，化合物27对多种癌细胞系，特别是肾癌A-498细胞显示出显着的抗增殖作用。在这些细胞中，它显着降低了 CA IX 和铁调节蛋白的表达，通过线粒体 caspase 活性和铁死亡途径诱导细胞凋亡，这一点可以通过 ROS、亚硝酸盐的增加和铁蛋白编码基因的表达下调来证明。在三维肿瘤模型中，化合物27有效降低球体尺寸和活力。小鼠体内毒性研究表明，这些化合物具有良好的耐受性，对肾功能没有显着改变。这些发现强调了苯并呋喃类 CA 抑制剂作为肾细胞癌治疗药物的进一步临床前评估的潜力。
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