In Vitro Evaluation of Endocrine-Related Adverse Effects of 5-Fluoroindole Derived Melatonin Analogues with Antioxidant Activity

IF 2.3 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Elif Ince-Erguc, Hanifa Fatullayev, Bita Entezari, Betül Tekiner, Sibel Süzen, Hande Gurer-Orhan
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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.

Abstract Image

体外评估具有抗氧化活性的 5-氟吲哚衍生褪黑素类似物与内分泌相关的不良反应。
褪黑素(MLT)是一种天然吲哚类激素,其抗氧化活性已通过各种机制得到报道。MLT 通过抑制芳香化酶与雌激素信号通路相互作用,有人认为这些新化合物可能因其选择性雌激素调节剂活性而产生与内分泌相关的不良反应。在这项研究中,我们研究了 MLT 类似物 5-氯吲哚衍生物的芳香化酶抑制和雌激素受体激动剂/拮抗剂效应以及可能的抗氧化活性,以作为预防和治疗氧化应激相关疾病的潜在候选药物。在测试的 34 种化合物中,有三种化合物通过自由基清除活性和减少细胞内活性氧的形成而显示出抗氧化作用。 它们还显示出不同效力的抗雌激素和/或芳香化酶抑制活性,这应被视为 MLT 及其类似物的潜在非靶向效应。
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来源期刊
Chemistry & Biodiversity
Chemistry & Biodiversity 环境科学-化学综合
CiteScore
3.40
自引率
10.30%
发文量
475
审稿时长
2.6 months
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.
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