A wide number of marketed drugs and drug candidates in cancer clinical development contain halogen substituents. The aim of the present study was to synthesize a series of halogen incorporated indole-coumarin hybrid schiff bases - N′-((2-(2-oxo-2H-chromen-3-yl)-1H-indol-3-yl)methylene)benzohydrazides and to investigate their apoptotic and anti-migratory potential in human breast adenocarcinoma cells as well as to examine their Bcl-2 and Bcl-xL protein binding ability via in silico docking. Hybrid 5g with a bromine atom in position-7 of coumarin ring displayed significant dose dependent cytotoxic activity with high selectivity to MCF-7 cells in MTT assay. Cell cycle progression analysis of 5g treated cells using flow cytometer exhibited a cell cycle arrest in the S phase and accumulation of cells in the subG1 phase. The apoptotic mode of cell death induced by 5g was further confirmed by Annexin-V staining assay. The wound healing assay revealed a profound impairment in the migration of MCF-7 cells presumably due to down-regulation of Bcl-2 and Bcl-xL proteins induced by 5g as observed in immunoblotting analysis. SAR studies of these hybrid molecules based on cell viability and docking were also probed. The most active pharmacophore 5g was found to bind favourably to Bcl-2 and Bcl-xL in docking simulation analysis suggesting it to be a probable small molecule Bcl-2/Bcl-xL inhibitor and a potential lead for breast cancer chemotherapy with apoptotic and anti-metastatic properties.

在癌症临床开发中大量上市的药物和候选药物都含有卤素取代基。本研究的目的是合成一系列掺入卤素的吲哚-香豆素杂化席夫碱-N'-（（2-（2-oxo-2 H -chromen-3-yl）-1 H -indol-3- y）亚甲基）苯并肼并研究它们在人乳腺癌细胞中的凋亡和抗迁移潜力，以及通过计算机对接研究其Bcl-2和Bcl-xL蛋白的结合能力。在MTT分析中，香豆素环7位具有溴原子的杂化5g显示出显着的剂量依赖性细胞毒性活性，并且对MCF-7细胞具有高选择性。5g的细胞周期进程分析使用流式细胞仪处理的细胞在S期表现出细胞周期停滞，在subG1期表现出细胞蓄积。Annexin-V染色法进一步证实了5g诱导的细胞死亡的凋亡模式。伤口愈合试验表明，MCF-7细胞的迁移受到了严重损害，这可能是由于免疫印迹分析中观察到的5g诱导的Bcl-2和Bcl-xL蛋白下调所致。还探索了基于细胞活力和对接的这些杂合分子的SAR研究。最活跃的药效团5g 被发现在对接模拟分析中与Bcl-2和Bcl-xL具有良好的结合，表明它是可能的小分子Bcl-2 / Bcl-xL抑制剂，是具有凋亡和抗转移特性的乳腺癌化疗的潜在先导。