当前的研究调查了十种磺胺衍生的Isatin的细胞毒性作用,在分子杂交之后,根据协会原则,肝细胞癌(HCC)HepG2和Huh7细胞系,比较使用人正常视网膜色素上皮(RPE-1)细胞的安全性。10个化合物对HepG2和Huh7细胞显示出可变的体外细胞毒性,使用MTT测定法。四个化合物(4/10)对HepG2和HuH7均具有高度细胞毒性。然而,在体外和体内急性(14天)口服毒性研究中,这4个中只有3个在RPE-1细胞上具有最高的安全边际.这些后来,上三个化合物\'结构是3-羟基-3-(2-氧代-2-(对-甲苯基)乙基)-5-(哌啶-1-基磺酰基)吲哚啉-2-酮(3a),N-(4-(2-(2-氧代-5-(哌啶-1-基磺酰基)吲哚啉-3-亚基)乙酰基)苯基)乙酰胺(4b),和N-(3-(2-(2-氧代-5-(哌啶-1-基磺酰基)吲哚啉-3-亚基)乙酰基)苯基)乙酰胺(4c)。测试化合物的半最大抑制浓度(IC50)(3a,4b,和4c)在HepG2细胞上约为16.8、44.7和39.7μM,分别。3a,4b,和4c化合物显着降低血管生成标志物上皮生长因子受体(EGFR)水平,并且通过EFGR活性位点内的分子对接进一步证实(PDB:1M17)。与厄洛替尼(-25.65Kcal/mol)相比,结合自由能范围在-19.21和-21.74Kcal/mol之间。最有前途的化合物,3a,4b,4c,在“癌症标志”上显示出可变的抗癌潜力,显著的细胞毒性,和凋亡抗血管生成和抗侵袭作用,表现为抑制Bcl-2,尿激酶纤溶酶原激活,和乙酰肝素酶在HepG2处理的细胞裂解物中的表达,与未处理的HepG2细胞相比。总之,化合物\“3a\”在细胞周期停滞在G2/M时与多柔比星高度可比,前G0期以及早期和晚期凋亡诱导,在与EGFR活性位点的结合方面与厄洛替尼相当。因此,目前的研究可能表明,化合物“3a”是,希望,用于HCC管理的最安全和最活跃的合成Isatin磺酰胺衍生物。
The current study investigated the cytotoxic effect of ten sulfonamide-derived isatins, following molecular hybridization, based on the association principles, on hepatocellular carcinoma (HCC) HepG2 and Huh7 cell lines, compared for safety using human normal retina pigmented epithelial (RPE-1) cells. The ten compounds showed variable in vitro cytotoxicity on HepG2 and Huh7 cells, using the MTT assay. Four compounds (4/10) were highly cytotoxic to both HepG2 and HuH7. However, only 3 of these 4 were of the highest safety margin on RPE-1 cells in vitro and in the in vivo acute (14-day) oral toxicity study. These later, superior three compounds\' structures are 3-hydroxy-3-(2-oxo-2-(p-tolyl)ethyl)-5-(piperidin-1-ylsulfonyl)indolin-2-one (3a), N-(4-(2-(2-oxo-5-(piperidin-1-ylsulfonyl)indolin-3-ylidene)acetyl)phenyl)acetamide (4b), and N-(3-(2-(2-oxo-5-(piperidin-1-ylsulfonyl)indolin-3-ylidene)acetyl)phenyl)acetamide (4c). The half-maximal inhibitory concentration (IC50) of the tested compounds (3a, 4b, and 4c) on HepG2 cells were approximately 16.8, 44.7, and 39.7 μM, respectively. The 3a, 4b, and 4c compounds significantly decreased the angiogenic marker epithelial growth factor receptor (EGFR) level and that was further confirmed via molecular docking inside the EFGR active site (PDB: 1M17). The binding free energies ranged between -19.21 and -21.74 Kcal/mol compared to Erlotinib (-25.65 Kcal/mol). The most promising compounds, 3a, 4b, and 4c, showed variable anticancer potential on \"hallmarks of cancer\", significant cytotoxicity, and apoptotic anti-angiogenic and anti-invasive effects, manifested as suppression of Bcl-2, urokinase plasminogen activation, and heparanase expression in HepG2-treated cells\' lysate, compared to non-treated HepG2 cells. In conclusion, compound \"3a\" is highly comparable to doxorubicin regarding cell cycle arrest at G2/M, the pre-G0 phases and early and late apoptosis induction and is comparable to Erlotinib regarding binding to EGFR active site. Therefore, the current study could suggest that compound \"3a\" is, hopefully, the most safe and active synthesized isatin sulfonamide derivative for HCC management.