{"title":"In Vitro Evaluation of Endocrine-Related Adverse Effects of 5-Fluoroindole Derived Melatonin Analogues with Antioxidant Activity","authors":"Elif Ince-Erguc, Hanifa Fatullayev, Bita Entezari, Betül Tekiner, Sibel Süzen, Hande Gurer-Orhan","doi":"10.1002/cbdv.202402050","DOIUrl":null,"url":null,"abstract":"<p>Melatonin (MLT) is a natural indolic hormone with well documented antioxidant properties, but it can also modulate the estrogen signaling pathway by inhibiting the aromatase enzyme and estrogen receptor modulating activity. This dual activity raises concerns about potential endocrine-related adverse effects when using MLT and its analogues as therapeutic agents in the prevention and treatment of oxidative stress related diseases. In this study, 34 novel 5-fluoroindole derivatives of MLT were synthesized and evaluated for their antioxidant, estrogen receptor modulatory, and aromatase inhibitory activities.Three compounds (4c, 5c, and 6c) demonstrated significant antioxidant activity, with compound 4c showing the highest efficacy in reducing intracellular reactive oxygen species (ROS) by 65 % in CHO-K1 cells and displaying DPPH radical scavenging comparable to the standard antioxidant, BHT. However, these same compounds also exhibited antiestrogenic effects in the E-Screen assay, with IC<sub>50</sub> values of 3.36×10<sup>−5</sup> M, 1.31×10<sup>−7</sup> M, and 1.9×10<sup>−7</sup> M, respectively, and inhibited aromatase activity by up to 29 % in a direct enzymatic assay. These findings indicate that, while the compounds have potent antioxidant properties, their significant antiestrogenic and aromatase inhibitory activities may pose risks for unintended endocrine related effects. Further studies are needed to better understand the implications of these activities in vivo and to balance the benefits and risks of such compounds in therapeutic applications.</p>","PeriodicalId":9878,"journal":{"name":"Chemistry & Biodiversity","volume":"22 3","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemistry & Biodiversity","FirstCategoryId":"92","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cbdv.202402050","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Melatonin (MLT) is a natural indolic hormone with well documented antioxidant properties, but it can also modulate the estrogen signaling pathway by inhibiting the aromatase enzyme and estrogen receptor modulating activity. This dual activity raises concerns about potential endocrine-related adverse effects when using MLT and its analogues as therapeutic agents in the prevention and treatment of oxidative stress related diseases. In this study, 34 novel 5-fluoroindole derivatives of MLT were synthesized and evaluated for their antioxidant, estrogen receptor modulatory, and aromatase inhibitory activities.Three compounds (4c, 5c, and 6c) demonstrated significant antioxidant activity, with compound 4c showing the highest efficacy in reducing intracellular reactive oxygen species (ROS) by 65 % in CHO-K1 cells and displaying DPPH radical scavenging comparable to the standard antioxidant, BHT. However, these same compounds also exhibited antiestrogenic effects in the E-Screen assay, with IC50 values of 3.36×10−5 M, 1.31×10−7 M, and 1.9×10−7 M, respectively, and inhibited aromatase activity by up to 29 % in a direct enzymatic assay. These findings indicate that, while the compounds have potent antioxidant properties, their significant antiestrogenic and aromatase inhibitory activities may pose risks for unintended endocrine related effects. Further studies are needed to better understand the implications of these activities in vivo and to balance the benefits and risks of such compounds in therapeutic applications.
期刊介绍:
Chemistry & Biodiversity serves as a high-quality publishing forum covering a wide range of biorelevant topics for a truly international audience. This journal publishes both field-specific and interdisciplinary contributions on all aspects of biologically relevant chemistry research in the form of full-length original papers, short communications, invited reviews, and commentaries. It covers all research fields straddling the border between the chemical and biological sciences, with the ultimate goal of broadening our understanding of how nature works at a molecular level.
Since 2017, Chemistry & Biodiversity is published in an online-only format.