2. Academic Validation
  3. Design, synthesis and evaluation of novel phenothiazine derivatives as inhibitors of breast cancer stem cells

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.
Yuan Gao 1,  Tong-Yan Sun 1,  Wen-Fei Bai 2,  Cui-Gai Bai 3
Affiliations

Affiliations

  • 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: baicuigai@tjab.org.
PMID: 31541872 DOI: 10.1016/j.ejmech.2019.111692
Abstract

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.

Keywords

Breast cancer stem cells; Cell migration; NO-Donor; Phenothiazine; pNF-κB-p65.

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