دورية أكاديمية
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Design, synthesis, in silico and biological evaluation of new indole based oxadiazole derivatives targeting estrogen receptor alpha.

التفاصيل البيبلوغرافية
العنوان: Design, synthesis, in silico and biological evaluation of new indole based oxadiazole derivatives targeting estrogen receptor alpha.
المؤلفون: Kaur K; Department of Pharmaceutical Sciences and Natural Products. Central University of Punjab, Ghudda, Bathinda (Pb) 151401, India., Verma H; Department of Zoology, Central University of Punjab, Ghudda, Bathinda (Pb) 151401, India., Gangwar P; Department of Zoology, Central University of Punjab, Ghudda, Bathinda (Pb) 151401, India., Jangid K; Department of Chemistry, Central University of Punjab, Ghudda, Bathinda (Pb) 151401, India., Dhiman M; Department of Microbiology, Central University of Punjab, Ghudda, Bathinda (Pb) 151401, India., Kumar V; Department of Chemistry, Central University of Punjab, Ghudda, Bathinda (Pb) 151401, India., Jaitak V; Department of Pharmaceutical Sciences and Natural Products. Central University of Punjab, Ghudda, Bathinda (Pb) 151401, India. Electronic address: vikasjaitak@gmail.com.
المصدر: Bioorganic chemistry [Bioorg Chem] 2024 Jun; Vol. 147, pp. 107341. Date of Electronic Publication: 2024 Apr 05.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Amsterdam : Elsevier
Original Publication: New York, London, Academic Press.
مواضيع طبية MeSH: Estrogen Receptor alpha*/metabolism , Estrogen Receptor alpha*/antagonists & inhibitors , Indoles*/chemistry , Indoles*/pharmacology , Indoles*/chemical synthesis , Oxadiazoles*/chemistry , Oxadiazoles*/pharmacology , Oxadiazoles*/chemical synthesis , Drug Design* , Antineoplastic Agents*/pharmacology , Antineoplastic Agents*/chemical synthesis , Antineoplastic Agents*/chemistry , Cell Proliferation*/drug effects , Drug Screening Assays, Antitumor* , Dose-Response Relationship, Drug*, Humans ; Structure-Activity Relationship ; Molecular Structure ; Molecular Docking Simulation ; Cell Line, Tumor
مستخلص: A series of new indole-oxadiazole derivatives was designed and synthesized to develop potential anti-breast cancer agents. The compounds exhibited significant inhibitory activity with IC 50 values ranging from 1.78 to 19.74 μM against ER-positive human breast cancer (BC) cell lines T-47D and MCF-7. Among them, compounds (5a, 5c, 5e-5h, 5j-5o) displayed superior activity against ER-α dominant (ratio of ER-α/ER-β is 9/1) T-47D cells compared to the standard drug bazedoxifene (IC 50  = 12.78 ± 0.92 μM). Compounds 5c and 5o exhibited remarkable anti-proliferative activity with IC 50 values of 3.24 ± 0.46 and 1.72 ± 1.67 μM against T-47D cells, respectively. Further, compound 5o manifested 1589-fold higher ER-α binding affinity (213.4 pM) relative to bazedoxifene (339.2 nM) in a competitive ER-α binding assay, while compound 5c showed a binding affinity of 446.6 nM. The Western blot analysis proved that both compounds influenced the ER-α protein's expression, impeding its subsequent transactivation and signalling pathway within T-47D cells. Additionally, a molecular docking study suggests that compounds 5c and 5o bind in such a fashion that induces conformational changes in the protein, culminating in their antagonistic effect. Also, pharmacokinetic profiles showed that all compounds have drug-like properties. Further, molecular dynamic (MD) simulations and density functional theory (DFT) analysis confirmed the stability, conformational behaviour, reactivity, and biological feasibility of compounds 5c and 5o. In conclusion, based on our findings, compounds 5c and 5o, which exhibit significant ER-α antagonistic activity, can act as potential lead compounds for developing anti-breast cancer agents.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
فهرسة مساهمة: Keywords: Anti-cancer; Breast Cancer; Estrogen receptor; Indole; Oxadiazole; Western blot
المشرفين على المادة: 0 (ESR1 protein, human)
تواريخ الأحداث: Date Created: 20240409 Date Completed: 20240516 Latest Revision: 20240516
رمز التحديث: 20240517
DOI: 10.1016/j.bioorg.2024.107341
PMID: 38593531
قاعدة البيانات: MEDLINE
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