Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome

Article

Author: Enriz, Ricardo D ; Staels, Bart ; González-Navarro, Herminia ; Martínez-Solsona, María ; Zibar, Khamis ; García, Ainhoa ; Clarisse, Dorien ; Villarroel-Vicente, Carlos ; Schiel, María Ayelén ; Cabedo, Nuria ; Hennuyer, Nathalie ; Cortes, Diego ; Vila, Laura ; De Bosscher, Karolien

Peroxisome proliferator-activated receptors (PPARs) represent highly valuable therapeutic targets for the treatment of type 2 diabetes (T2D) and hypertriglyceridemia, both closely linked to the development of metabolic syndrome (MetS). Herein, we have synthesised two series of prenylated quinolines either at the 2- or 3-position, and their tetrahydroquinolines (THQs) using the Friedländer cyclodehydration, followed by the Grignard reaction and subsequent Johnson-Claisen rearrangement. All the synthesised compounds were evaluated in vitro for activity at each of the human PPAR, their cytotoxicity, their capacity to activate the PPAR target gene PDK4 and their anti-inflammatory effects. The compounds with a seven‑carbon prenylated side chain at the 2-position, such as THQ 5a and 6a (series a), displayed similar pan-PPAR agonism to the 2-prenylated benzopyran analogue BP-2. The compounds with a six‑carbon prenylated side chain at the 3-position, such as 5b and 6b (series b), had stronger selectivity for PPARα activation. The luciferase assays of the PPRE-driven gene PDK4 showed that THQ 5a, 5b, and quinoline 8a increased the transactivation of the PDK4-Luc + reporter, which confirmed their potential capacity to promote lipid metabolism. THQs 5a, 5b, and quinoline 8b repressed the transactivation of the TNFα-dependent NF-κB-Luc + reporter and efficiently down-regulated the transcription of several TNFα-induced pro-inflammatory genes. Furthermore, THQ 5a improves total cholesterol, non-HDL-c, HOMA-IR index and lipid metabolism in ob/ob mice, without increasing liver enzymes. Our results suggest that THQ 5a is a promising lead compound in the development of agents for treating metabolic disorders (T2D and dyslipidaemias), which may prevent further cardiovascular comorbidities associated with MetS.

01 Jun 2025·Journal of Hazardous Materials

Organobromine compounds in aquatic environments: Embryotoxicity linked to lipophilicity and molecular structure

Article

Author: Yan, Zhi ; Shi, Zhenzhen ; Hou, Zhihao ; Jiang, Yanqiu ; Li, Ke ; Lu, Zhen ; Wang, Derui

Organobromine compounds, prevalent in marine environments due to both anthropogenic activities and natural processes, have been shown to exhibit significant toxicity toward aquatic organisms. This study investigates the embryotoxicity and teratogenic effects of six bromophenol compounds using zebrafish (Danio rerio) embryos as a model. The compounds exhibited varying degrees of toxicity, with BP-6 and BP-5 showing the lowest LC₅₀ values. The study identified distinct embryonic malformations, including venous sinus edema, pericardial cysts, and craniofacial malformations. A correlation was observed between the toxicity of the bromophenols and their lipophilicity, with higher lipophilicity compounds demonstrating greater toxicity. Mechanistic insights into the toxicity of bromophenols were further explored through transcriptomic analysis, which identified significant effects on retinol metabolism, modulation of myocardial contraction via Ca²⁺/Na⁺ ion flux, stimulation of nonspecific immune responses, and suppression of primary bile acid synthesis. BP-2 exposure significantly altered calcium signaling and bile acid biosynthesis, indicating a potential mechanism for its enhanced toxicity. These findings underscore the need for further investigation into the environmental and health impacts of bromophenols, particularly as they accumulate in marine ecosystems and the food chain.

01 Jun 2025·The Journal of Steroid Biochemistry and Molecular Biology

Benzophenone UV-filters: Inhibition on human and rat 17β-hydroxysteroid dehydrogenase 1 - insights from 3D-QSAR and docking studies

Article

Author: Gong, Chaochao ; Zhu, Yang ; Wang, Shaowei ; Lu, Han ; Tang, Yunbing ; Chen, Zhuoqi ; Ying, Yingfen ; Ge, Ren-Shan

Benzophenone (BP) UV-filters have been extensively used for the prevention of UV-induced adverse effects in personal care products. Their potential to interfere with steroidogenesis in the female reproductive system remains uncertain. 17β-Hydroxysteroid dehydrogenase 1 (17β-HSD1) facilitates the conversion of estrone to estradiol, playing a key role in estrogen activation. This study delves into the effects of eleven BPs on human and rat 17β-HSD1, while also analysing the 3D-quntitative structure-activity relationship (3D-QSAR) and the underlying mechanisms. The inhibitory potency of inhibiting human placental 17β-HSD1 was found to be in the order of BP-2 (IC₅₀, 11.42 μM) > BP-1 (14.17 μM) > BP-4 (49.05 μM) > BP-6 (63.49 μM) = BP-8 (63.46 μM) > others. BP-1 and BP-2 markedly inhibited estradiol secretion by human placental BeWo cells at ≥ 1 μM. In contrast, the inhibitory strength of suppressing rat ovarian 17β-HSD1 activity was found to be in the order of BP-2 (IC₅₀, 13.33 μM) > BP-1 (15.09 μM) > BP-4 (22.68 μM) > BP-12 (31.12 μM) > BP-3 (97.11 μM) > BP (119.99 μM) > others. Mode action analysis revealed that these BP compounds acted as mixed inhibitors of both human and rat 17β-HSD1. The introduction of a 4-hydroxyl substitution in the benzene ring was found to markedly increase the inhibitory potency against human and rat 17β-HSD1. BP-1 and BP-2 demonstrated the ability to penetrate human BeWo cells and inhibit estradiol secretion at ≥ 1 μM. Docking analysis revealed that the 2-hydroxyl group of BP-1 and BP-2 forms a hydrogen bond with catalytic residue Ser142 of human 17β-HSD1. 3D-QSAR pharmacophore analysis showed that there are hydrophobic regions and hydrogen bond donor can interact with BPs. In conclusion, this study establishes that BP-2 is the most potent inhibitors of human 17β-HSD1 among the BPs under investigation, highlighting a significant difference in the structure-activity relationship.

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