在当前的研究中，设计并合成了一系列新的苯磺酰胺6a-r，作为具有抗癌活性的VEGFR-2和FGFR1双重激酶抑制剂。 4-三氟甲基苯磺酰胺 6l 表现出最高的双重 VEGFR-2/FGFR1 抑制活性，IC50 值分别为 0.025 和 0.026 µM。它的活性分别比索拉非尼和十字孢菌素高 1.8 倍和 1.3 倍。此外，化合物 6l 在 EGFR 和 PDGFR-β 激酶上进行了进一步测试，显示 IC50 值分别为 0.106 和 0.077 µM。测试了目标化合物在 10 µM 浓度下对 NCI-60 组癌细胞系的抗癌活性，其中化合物 6l 表现出最高的平均生长抑制百分比 (GI%)，为 60.38%。化合物 6a、6b、6e、6f、6h-l 和 6n-r 对乳腺癌细胞系（MCF-7、T-47D 和 MDA-MB-231）显示出令人鼓舞的 GI%，并进行了 IC50 测定这些细胞系。与使用的参考标准相比，测试化合物对 T-47D 和 MCF-7 细胞系表现出比 MDA-MB-231 细胞系更高的活性；索拉非尼。化合物 6e、6h-j、6l 和 6o 对 T-47D 细胞系的 IC50 值≤20 µM，此外，发现它们对 Vero 正常细胞系无细胞毒性。此外，还研究了 T-47D 细胞中最活跃的化合物 6i 和 6l 对细胞周期分析进程、细胞凋亡和凋亡标记物的影响。两种化合物均将细胞周期进程阻滞在 G1 期，此外，它们还增强早期和晚期细胞凋亡以及坏死。化合物6i和6l诱导细胞凋亡的能力通过其提高处理的细胞中的BAX/BCl-2比率和caspase-3水平的能力而得到进一步证实。细胞迁移测定表明，与对照 T-47D 细胞相比，化合物 6i 和 6l 在 24 和 48 小时后均具有抗迁移作用。化合物 6a-r 在 VEGFR-2 和 FGFR1 结合位点上的分子对接研究表明，它们在两种靶激酶中表现出类似的结合模式，与 II 型激酶抑制剂的结合模式一致。版权所有 © 2024 Elsevier Inc. 保留所有权利。

In the current study, a new series of benzenesulfonamides 6a-r was designed and synthesized as dual VEGFR-2 and FGFR1 kinase inhibitors with anti-cancer activity. The 4-trifluoromethyl benzenesulfonamide 6l exhibited the highest dual VEGFR-2/FGFR1 inhibitory activity with IC50 values of 0.025 and 0.026 µM, respectively. It showed a higher activity than sorafenib and staurosporine by 1.8- and 1.3-fold, respectively. Furthermore, compound 6l was further tested on EGFR and PDGFR-β kinases showing IC50 values of 0.106 and 0.077 µM, respectively. The target compounds were tested for their anticancer activity against NCI-60 panel of cancer cell lines at 10 µM concentration, where compound 6l displayed the highest mean growth inhibition percent % (GI%) of 60.38%. Compounds 6a, 6b, 6e, 6f, 6h-l, and 6n-r revealed promising GI% on breast cancer cell lines (MCF-7, T-47D, and MDA-MB-231), and were subjected to IC50 determination on these cell lines. The tested compounds showed a higher activity on T-47D and MCF-7 cell lines over MDA-MB-231 cell line compared to the used reference standard; sorafenib. Compounds 6e, 6h-j, 6l and 6o revealed IC50 values ≤ 20 µM against T-47D cell line, furthermore, they were found to be non-cytotoxic on Vero normal cell line. Furthermore, the effect of the most active compounds 6i, and 6l in T-47D cells on cell cycle analysis progression, cell apoptosis, and apoptosis markers was investigated. Both compounds arrested cell cycle progression at G1 phase, furthermore, they enhanced early and late apoptosis, as well as necrosis. The capability of compounds 6i, and 6l to induce apoptosis was further confirmed by their ability to raise BAX/BCl-2 ratio and caspase-3 level in the treated cells. Cell migration assay revealed that both compounds 6i and 6l have anti-migratory effects compared to control T-47D cells after 24, and 48 h. Molecular docking studies for compounds 6a-r on VEGFR-2 and FGFR1 binding sites showed that they exhibit an analogous binding mode in both target kinases which agrees with that of type II kinase inhibitors.Copyright © 2024 Elsevier Inc. All rights reserved.