High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of BioMedicine, Tianjin, 300457, PR China; College of Pharmacy, Nankai University, Tianjin, 300353, PR China.
College of Veterinary Medicine, Hebei Agricultural University, Baoding, 071000, PR China.
Eur J Med Chem. 2019 Dec 1;183:111692. doi: 10.1016/j.ejmech.2019.111692. Epub 2019 Sep 11.
A novel series of phenothiazine derivatives containing diethanolamine, methoxyethylamine, flavonoids, and a nitric oxide (NO) donor was designed and synthesized for the treatment of breast cancer. Phenothiazine derivatives (l) did not noticeably inhibit the growth of SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells, whereas phenothiazine derivatives (ll) containing the NO donor were more potent or had comparable inhibitory activity to trifluoperazine (TFP) and thioridazine against SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells. Compounds 20a-c and 21a-c showed the strongest activity in SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells, and more potent inhibitory activity than TFP against KG1a cells (IC = 1.63, 2.93, 1.14, 1.78, 2.20, and 1.20 vs. 4.58 μM). Compounds 20a and 21a had lower toxicity than compounds 20b-c and 21b-c, and inhibited colony formation in MCF-7 cells, decreased the formation of mammospheres in SUM159 cells, and inhibited the migration of MDA-MB-231 cells. Compounds 20a and 21a could inhibited pNF-κB-p65 as shown by dual-luciferase reporter assays and western blotting in MDA-MB-231 cells.
设计并合成了一系列新型含二乙醇胺、甲氧基乙胺、黄酮和一氧化氮（NO）供体的吩噻嗪衍生物，用于治疗乳腺癌。吩噻嗪衍生物（l）对 SUM159、MDA-MB-231、MCF-7 和 SKBR-3 细胞的生长没有明显抑制作用，而含 NO 供体的吩噻嗪衍生物（ll）对 SUM159、MDA-MB-231、MCF-7 和 SKBR-3 细胞的抑制活性更强或与三氟拉嗪（TFP）和噻吨嗪相当。化合物 20a-c 和 21a-c 在 SUM159、MDA-MB-231、MCF-7 和 SKBR-3 细胞中表现出最强的活性，对 KG1a 细胞的抑制活性比 TFP 更强（IC=1.63、2.93、1.14、1.78、2.20 和 1.20 vs. 4.58 μM）。化合物 20a 和 21a 的毒性低于化合物 20b-c 和 21b-c，并且抑制 MCF-7 细胞集落形成，减少 SUM159 细胞中类球体的形成，抑制 MDA-MB-231 细胞迁移。化合物 20a 和 21a 可以通过 MDA-MB-231 细胞中的双荧光素酶报告基因检测和 Western blot 显示抑制 pNF-κB-p65。
