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Design, synthesis and biological evaluation of novel indole-benzimidazole hybrids targeting estrogen receptor alpha (ER-α)
- Source :
- European Journal of Medicinal Chemistry. 146:206-219
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- In the course of efforts to develop novel selective estrogen receptor modulators (SERMs), indole-benzimidazole hybrids were designed and synthesised by fusing the indole nucleus with benzimidazole. All the compounds were first inspected for anti-proliferative activity using ER-α responsive T47D breast cancer cell lines and ER-α binding assay. From this study, two representative bromo substituted compounds 5f and 8f were found to be most active and thus were escalated for gene expression studies for targeting ER-α. Cell imaging experiment clearly suggest that compounds were able to cross cell membrane and accumulate thus causing cytotoxicity. RT-PCR and Western blotting experiments further supported that both compounds altered the expression of mRNA and receptor protein of ER-α, thereby preventing the further transactivation and signalling pathway in T47D cells lines. Structural investigation from induced fit simulation study suggest that compound 5f and 8f bind in antagonistic conformation similar to bazedoxifene by extensive hydrogen bonding and Van der Waals forces. All these results strongly indicate that compound 5f and 8f represents a novel potent ER-α antagonist properties and will proved promising in the discovery of SERM for the management of breast cancer.
- Subjects :
- Models, Molecular
0301 basic medicine
Benzimidazole
Indoles
Cell Survival
Cell
Antineoplastic Agents
Crystallography, X-Ray
01 natural sciences
Structure-Activity Relationship
03 medical and health sciences
Transactivation
chemistry.chemical_compound
Drug Discovery
Tumor Cells, Cultured
medicine
Humans
Cytotoxicity
Receptor
Cell Proliferation
Pharmacology
Indole test
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Chemistry
Organic Chemistry
Estrogen Receptor alpha
General Medicine
0104 chemical sciences
030104 developmental biology
medicine.anatomical_structure
Biochemistry
Selective estrogen receptor modulator
Drug Design
Benzimidazoles
Drug Screening Assays, Antitumor
Estrogen receptor alpha
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 146
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....2c0f797900be22afed8bbd1a68c188a9