在本研究中，报道了新型香豆素衍生物 8a-h、11a-d 和 16a-c 的设计和合成，作为肿瘤相关人碳酸酐酶亚型（hCA IX 和 XII）的潜在选择性抑制剂。所有新合成的衍生物都对目标 CA IX (KI = 0.08-9.57 µM) 表现出强效至温和的活性，选择性指数高于 CA I (SI = 2.0-21.9) 和 CA II (SI = 1.1-15.7)。他们对 CA XII (KI = 0.06-9.48 µM) 表现出类似的活性，选择性指数高于 CA I (SI = 1.4-21.2) 和 CA II (SI = 0.9-15.5)。具有磺酰胺功能的化合物 16b 对目标异构体 CA IX 和 XII 具有良好的抑制活性，KI 值分别为 0.08 和 0.06 µM。有趣的是，发现使用无毒浓度的化合物16b作为佐剂与阿霉素一起对抗MCF-7细胞，在缺氧下的细胞毒性增强了近3.5倍； IC50 从 25.74 降至 7.43 µM。因此，化合物16b在缺氧条件下恢复了多柔比星对MCF-7细胞的细胞毒性，几乎与常氧条件下一样。此外，化合物16b和阿霉素联合治疗MCF7细胞系的流式细胞术分析显示，G2/M期细胞周期停滞增加，并且比单独使用阿霉素具有更有效的细胞凋亡作用。此外，化合物 16b 对正常乳腺 MCF-10A 细胞系没有细胞毒性 (IC50 = 296.25 µM)。版权所有 © 2024 Elsevier Inc. 保留所有权利。

In the present study, the design and synthesis of novel coumarin derivatives 8a-h, 11a-d and 16a-c as potential selective inhibitors for the tumor associated human carbonic anhydrase isoforms (hCA IX and XII) was reported. All the newly synthesized derivatives showed potent to mild activity against the targeted CA IX (KI = 0.08-9.57 µM), with selectivity indices over CA I (SI = 2.0-21.9) and over CA II (SI = 1.1-15.7). They showed similar activities against CA XII (KI = 0.06-9.48 µM) with selectivity indices over CA I (SI = 1.4-21.2) and CA II (SI = 0.9-15.5). Compound 16b featuring sulfonamide function possessed promising inhibitory activities against the targeted isoforms CA IX and XII with KI values of 0.08 and 0.06 µM, respectively. Interestingly, it was found that using compound 16b at a nontoxic concentration as an adjuvant with Doxorubicin against MCF-7 cells enhanced the cytotoxicity under hypoxia by almost 3.5 folds; IC50 decreased from 25.74 to 7.43 µM. Therefore, compound 16b restored the cytotoxicity of Doxorubicin against MCF-7 cells under hypoxia, almost as normoxia. Furthermore, flow cytometry analysis of a combination treatment of compound 16b and Doxorubicin to the MCF7 cell line revealed an increase in cell cycle arrest at the G2/M phase and a more efficient apoptotic effect than Doxorubicin alone. Furthermore, compound 16b showed no cytotoxicity against normal breast MCF-10A cell line (IC50 = 296.25 µM).Copyright © 2024 Elsevier Inc. All rights reserved.