Design, synthesis and evaluation of novel phenothiazine derivatives as inhibitors of breast cancer stem cells
- Eur J Med Chem. 2019 Dec 1:183:111692. doi: 10.1016/j.ejmech.2019.111692.
- 1. 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.
- 2. College of Veterinary Medicine, Hebei Agricultural University, Baoding, 071000, PR China.
- 3. High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of BioMedicine, Tianjin, 300457, PR China. Electronic address: [email protected].
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 (IC50 = 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.