دورية أكاديمية
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Discovery of 4'-trifluoromethylchalcones as novel, potent and selective hCYP1B1 inhibitors without concomitant AhR activation.

التفاصيل البيبلوغرافية
العنوان: Discovery of 4'-trifluoromethylchalcones as novel, potent and selective hCYP1B1 inhibitors without concomitant AhR activation.
المؤلفون: Wu Y; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China., Shi JH; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China., Zhu GH; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China., Xiong Y; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China., Gong JH; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China., Wei HZ; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China., Guo ZB; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China., Dai ZR; Ministry of Education, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100193, China. Electronic address: athenadai219@163.com., Sun XB; Ministry of Education, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100193, China., Ge GB; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: geguangbo@shutcm.edu.cn.
المصدر: European journal of medicinal chemistry [Eur J Med Chem] 2023 Oct 05; Vol. 258, pp. 115552. Date of Electronic Publication: 2023 Jun 08.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
مواضيع طبية MeSH: Chalcones*/pharmacology , Chalcones*/chemistry, Humans ; Cytochrome P-450 Enzyme System/metabolism ; Structure-Activity Relationship ; Molecular Docking Simulation
مستخلص: Human cytochrome P450 1B1 (hCYP1B1), an extrahepatic cytochrome P450 enzyme over-expressed in various tumors, has been validated as a promising target for preventing and treating cancers. Herein, two series of chalcone derivatives were synthesized to discover potent hCYP1B1 inhibitors without AhR agonist effect. Structure-activity relationship (SAR) studies demonstrated that 4'-trifluoromethyl on the B-ring strongly enhanced the anti-hCYP1B1 effects, identifying A9 as a promising lead compound. Further SAR analysis on A9 derivatives (modified A-ring of 4'-trifluoromethylchalcone) showed that introducing 2-methoxyl improved the anti-hCYP1B1 effect and selectivity, while introducing a methoxyl at the C-4 site was beneficial for avoiding AhR activation. Ultimately, five 4'-trifluoromethyl chalcones were identified as potent hCYP1B1 inhibitors (IC 50  < 10 nM), while B18 exhibits the most potent anti-hCYP1B1 effect (IC 50  = 3.6 nM), suitable metabolic stability and good cell-permeability. B18 also acted as an AhR antagonist and could down-regulate hCYP1B1 in living systems. Mechanistic studies showed that B18 potently inhibited hCYP1B1 in a competitive inhibition manner (K i  = 3.92 nM), while docking simulations revealed that B18 could tightly bind to the catalytic cavity of hCYP1B1 mainly via hydrophobic and hydrogen-bonding interactions. Furthermore, B18 could potently inhibit hCYP1B1 in living cells and showed remarkable anti-migration ability on MFC-7 cells. Taken together, this study deciphered the SARs of chalcones as hCYP1B1 inhibitors and provided several potent hCYP1B1 inhibitors as promising candidates for the development of more efficacious anti-migration 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 © 2023 Elsevier Masson SAS. All rights reserved.)
فهرسة مساهمة: Keywords: 4′-trifluoromethylchalcone; AhR antagonist; Anti-migration agent; Structure-activity relationships (SARs); hCYP1B1
المشرفين على المادة: 0 (Chalcones)
9035-51-2 (Cytochrome P-450 Enzyme System)
تواريخ الأحداث: Date Created: 20230614 Date Completed: 20230719 Latest Revision: 20230719
رمز التحديث: 20230719
DOI: 10.1016/j.ejmech.2023.115552
PMID: 37315474
قاعدة البيانات: MEDLINE
الوصف
تدمد:1768-3254
DOI:10.1016/j.ejmech.2023.115552