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Design, synthesis and evaluation of novel phenothiazine derivatives as inhibitors of breast cancer stem cells
- Source :
- European Journal of Medicinal Chemistry. 183:111692
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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.
- Subjects :
- Antineoplastic Agents
Trifluoperazine
Thioridazine
Pharmacology
01 natural sciences
Nitric oxide
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Phenothiazines
Phenothiazine
Drug Discovery
medicine
Humans
skin and connective tissue diseases
Cell Proliferation
030304 developmental biology
0303 health sciences
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Organic Chemistry
Cell migration
General Medicine
0104 chemical sciences
Blot
chemistry
Drug Design
Toxicity
Drug Screening Assays, Antitumor
Stem cell
medicine.drug
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 183
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....afa0022fc58a354aa2c40b00df371106