scholarly journals Synthesis and evaluation of coumate analogues as estrogen receptor inhibitors for breast cancer therapy

2019 ◽  
Vol 10 (3) ◽  
pp. 2218-2224
Author(s):  
Selvaraj Jubie ◽  
Basheer A ◽  
Neetu Yadav ◽  
Ashish Wadhwani ◽  
Mohammed Afzal Azam
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Therapy ◽  
Schiff Bases ◽  
Cell Biology ◽  
Breast Cancer Therapy ◽  
Human Estrogen Receptor ◽  
Ic50 Values ◽  
Mcf 7 ◽  
Positive Breast Cancer

A sulphatase inhibitor 667 COUMATE is in clinical trials for estrogen-positive breast cancer therapy for postmenopausal women, while there are a number of similar sulphatase inbitors are under development. Schiff's bases are versatile pharmacophores in which the N atom involves in hydrogen bonding with active cell centers interfering in normal cell biology. A library of novel coumate analogues with Schiff bases were designed, and structural based drug design was performed with human estrogen receptor (PDB ID: 2IOG) (Already reported). Based on the in-silico outcomes, seven coumate-schiff bases were synthesized. The compounds were obtained in good yield. The novelty had been ascertained by sci finder software. The synthesized molecules were consistent with their assigned spectra such as IR, Mass and NMR spectral data which confirmed their formation. The cytotoxicity study was performed by MTT assay for all the synthesized compounds. Most of the compounds have good IC50 values (below 100 µg/ml).Two of the synthesized compounds COU-2 and COU-5 have shown good IC50 values such as 19µg/ml and 39µg/ml, respectively. They suppressed the proliferation of estrogen receptor overexpressed MCF-7 cells.

scholarly journals Design of Novel Selective Estrogen Receptor Inhibitors using Molecular Docking and Protein-Ligand Interaction Fingerprint Studies

2021 ◽  
pp. 470-483
Author(s):  
Galla Rajitha ◽  
Murthi Vidya Rani ◽  
Umakanth Naik Vankadoth ◽  
Amineni Umamaheswari
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Molecular Docking ◽  
Cancer Therapy ◽  
Binding Affinity ◽  
Docking Studies ◽  
Fingerprint Analysis ◽  
Breast Cancer Therapy ◽  
Ligand Interaction ◽  
Human Estrogen Receptor

Aims: The genomic and non-genomic actions of human estrogen receptor α (hERα) play a crucial role in breast epithelial cell proliferation and survival, as well as mammary tumorigenesis. hERα has been proved as a potential target for breast cancer therapy over the last 3 decades. Hence designing novel inhibitors targeting hERα can be a valuable approach in breast cancer therapy. Study Design:  In the present study, the goal is to identify novel hERα inhibitors through molecular docking, AI based virtual screening and interaction fingerprint analysis. Place and Duration of Study: Department of Bioinformatics, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India in between July 2021-sep 2021. Methodology: Molecular docking studies were performed using the human estrogen receptor alpha ligand-binding domain in complex with 4-hydroxytamoxifen (PDB: 3ERT) against existing compounds from literature. The best docked existing compound and co-crystal ligand were subjected to shape screening against 28 million compounds and resulted compounds constituted the hERα inhibitor dataset which was subjected to rigid receptor docking. Further, interaction fingerprint analysis was applied as complimentary method to docking for comparing the similarity of predicted binding poses of proposed leads with that of reference binding pose. Results: Co-crystal ligand (4-OHT) and E99 exhibited better binding affinity among existing ligand set. Rigid receptor docking studies resulted in four lead compounds possessing better docking scores than 4-OHT and E99. Moreover, leads showed favorable absorption, distribution, metabolism, excretion and toxicity properties within the range of 95% FDA approved drugs. Proposed leads showed interactions with binding site residues of hERα similar to that of 4-OHT with better binding affinity. The ability of obtained leads to retrieve actives was validated using receiver operative characteristic (ROC) curve. Conclusion: From above results, it has been observed that the proposed leads have potential to act as novel hERα inhibitors.

Translational cell study exploring the role of estrogen receptor β expression as a predictive and/or prognostic factor in breast cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22185-e22185
Author(s):  
S. Saji ◽  
N. Honma ◽  
M. Hirose ◽  
S. Hayashi ◽  
K. Kuroi
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cell Line ◽  
Cancer Patients ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
Her 2 ◽  
Mcf 7 ◽  
Cell Study ◽  
Positive Breast Cancer

e22185 Background: We have reported that positive expression of Estrogen receptor β (ERβ) was associated with better prognosis in the early breast cancer patients treated with adjuvant tamoxifen monotherapy (J Clin Oncol. 2008). In addition, this was also true in the ERα-negative/PR-negative/Her-2 negative patients. We explored the biological impact of ERβ in breast cancer cell lines to determine whether these observations were due to its prognostic power or predictive power of response to the therapy. Methods: Since MCF-7 cell was ERβ-negative ERα-positive cell line, we established two stable clones of MCF-7 by introducing ERβ expression vector (β-clone 1, β-clone 2) as the model of ERβ-positive ERα-positive breast cancer. MDA-MB 231 cell was used as ERβ-positive triple-negative cell line. These cells were subjected to proliferation, expression and functional analysis. Results: In western blotting, both β-clone 1 and clone 2 showed decreased expression of PR and Her-2 than parent MCF-7, although there were no differences in ERα expression. Expression of ERβ decreased estradiol (E2) induced proliferation ability and rate of cells in S-phase cycle. PPT (ERα-specific agonist) and DPN (ERβ-specific agonist) did not show any difference in response, and IC 50 for 4 OH-tamoxifen and fulvestrant did not differ among MCF-7, β-clone 1 and clone 2 (0.05–0.1 μM). Whereas, cell death due to deprivation of E2 from 1nM to 1pM was more frequently observed in ERβ-expressing clones than in parent MCF-7 cell. These cell deaths did not involve standard apoptosis pathway with caspase-3/7 activation and PARP cleavage. E2, DPN and PPT did not affect the proliferation of ERβ-positive triple negative MDA-MB 231 cell, and IC 50 for 4-OH tamoxifen was too high (8 μM) to be achieved in clinical pharmacological dose. Conclusions: From our cell study, better prognosis of ERβ-positive breast cancer patient who treated with adjuvant tamoxifen is mainly due to its own favorable biological behavior. However, this prognostic impact may include the favorable response to the treatment, when we use estrogen-deprivation therapy such as aromatase inhibitors (AIs). Additional clinical study in AI users would be required to address this issue. No significant financial relationships to disclose.

Enhanced noscapine delivery using estrogen-receptor-targeted nanoparticles for breast cancer therapy

2014 ◽  
pp. 1
Author(s):  
Jitender Madan ◽  
Sushma R. Gundala ◽  
Yoganjaneyulu Kasetti ◽  
Prasad V. Bharatam ◽  
Ritu Aneja ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Therapy ◽  
Breast Cancer Therapy ◽  
Targeted Nanoparticles
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