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Identification of novel indole based heterocycles as selective estrogen receptor modulator
- Source :
- Bioorganic Chemistry. 79:72-88
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- In the present study, we have designed and synthesized indole derivatives by coalescing the indole nucleus with chromene carbonitrile and dihydropyridine nucleus. Two compounds 5c and 6d were selected from series I and II after sequential combinatorial library generation, docking, absorption, distribution, metabolism and excretion (ADME) filtering, anti-proliferative activity, cytotoxicity, and ER-α competitor assay kit by utilizing estrogen receptor-α (ER-α) dominant T47D BC cells line and PBMCs (Peripheral Blood Mononuclear Cells). Cell imaging experiment suggested that both the compounds successfully cross cellular biomembrane and accumulate in nuclear, cytoplasmic and plasma membrane region. Semiquantitative RT-PCR and Western blotting experiments further supported that both compounds reduced the expression of mRNA and receptor protein of ER-α, thereby preventing downstream transactivation and signaling pathway in T47D cells line. Current findings imply that 5c and 6d represent novel ER-α antagonists and may be used in the development of chemotherapy for the management of BC.
- Subjects :
- Selective Estrogen Receptor Modulators
0301 basic medicine
Indoles
Cell
Down-Regulation
Estrogen receptor
01 natural sciences
Biochemistry
03 medical and health sciences
Transactivation
Cell Line, Tumor
Drug Discovery
medicine
Humans
Benzopyrans
RNA, Messenger
Receptor
Molecular Biology
ADME
Indole test
Binding Sites
010405 organic chemistry
Chemistry
Organic Chemistry
Estrogen Receptor alpha
0104 chemical sciences
Molecular Docking Simulation
030104 developmental biology
medicine.anatomical_structure
Selective estrogen receptor modulator
Drug Design
Acridines
Signal transduction
Subjects
Details
- ISSN :
- 00452068
- Volume :
- 79
- Database :
- OpenAIRE
- Journal :
- Bioorganic Chemistry
- Accession number :
- edsair.doi.dedup.....cc1baf814124ab50d79f129ca6cef47f