Interaction of 7-Alkoxycoumarins with the Aryl Hydrocarbon Receptor

Abstract

The aryl hydrocarbon receptor (AhR) is a transcription factor activated by a vast array of natural and synthetic ligands. It plays a pivotal role in numerous physiological and pathological responses, such as cell proliferation and differentiation, induction of xenobiotic metabolizing enzymes, response to environmental toxins, and several others. In this study, we investigated the ability of some natural compounds (oxyprenylated ferulic acid and umbelliferone derivatives) and their semisynthetic analogues (e.g., differently substituted 7-alkoxycoumarins) to activate AhR, using a reporter luciferase assay. Among them, we found that 7-isopentenyloxycoumarin was the best AhR activator. Boropinic acid, 7-but-2'-enyloxycoumarin, 7-(2',2'-dimethyl-n-propyloxy)coumarin, 7-benzyloxycoumarin, and 7-(3'-hydroxymethyl-3'-methylallyloxy)coumarin were also active, although to a lesser extent. All the compounds were also analyzed for their ability to inhibit AhR activation, using a reference ligand, 6-formylindolo[3,2-b]carbazole. Data recorded in the present investigation pointed out the importance of a 3,3-dimethylallyloxy side chain attached to the coumarin ring core as a key moiety for AhR activation.

Oxyprenylated Phenylpropanoids Bind to MT1 Melatonin Receptors and Inhibit Breast Cancer Cell Proliferation and Migration

“…It is noteworthy that 1 – 11 have been purified by a simple acid–base workup followed by crystallization ( n -hexane) from every reaction in very good yields (>92%) and purity (>97.6% assessed by HPLC) without the need of any SiO 2 gel based chromatographic step. 1 H and 13 C NMR data for all samples exactly matched those reported in the literature for the same compounds …”

“…Plants have been used therapeutically for treating a variety of diseases ranging from neurodegenerative diseases to cancer. , The biochemical mechanisms within plants produce secondary metabolites, which are used as host defense mechanisms against herbivores, bacteria, and other invading pathogens . Unlike primary metabolites, secondary metabolites are not involved in a plant’s growth, development, or reproduction; however, these secondary metabolites (e.g., alkaloids, terpenoids, glycosides, polyketides, phenylpropanoids, and others) have been used for medicinal purposes for centuries to treat diseases such as cancer, leukemia, diabetes, anemia, and inflammation. , Oxyprenylated compounds, a class of secondary metabolites produced during the prenylation of an alkaloid or a phenylpropanoid, have demonstrated efficacy against cancer, inflammation, microbes, and fungi possibly through their antioxidant, receptor, or transporter-mediated properties. − As of 2007, about 300 oxyprenylated derivatives have been isolated from plants; some of these derivatives as well as their semisynthetic analogues show promise as anticancer, anti-inflammatory, antimicrobial, and antifungal therapies …”

“…In this study, oxyprenylated ferulic acid and coumarin derivatives (compounds 1 – 11 ) were chosen for study because these compounds demonstrate similar neuroprotective and anticancer actions to melatonin ,− and they display similar structural similarities to melatonin (specifically in their ring structures; graphical abstract). For most of these compounds, their mechanisms of action are unknown; however, some of the oxyprenylated derivatives, (e.g., 2 and 6 ) have been shown to activate the aryl hydrocarbon receptor, promoting mammary gland differentiation while inhibiting breast cancer (BC) cell proliferation and migration. − In addition, 6 demonstrated growth inhibitory effects in human cancer cell lines (HeLa and HT-29) and neuroprotective effects in astrocytes and neurons perhaps through the activation of the aryl hydrocarbon receptor …”

7-Isopentenyloxycoumarin: What Is New across the Last Decade

“…A straightforward biomimetic synthesis of 7-isopentenyloxycoumarin is also available and consists of a single step of a Williamson's reaction between umbelliferone and 3,3-dimethylallyl bromide in refluxing acetone promoted by dry K 2 CO 3 as the base [8].…”

“…As a confirmation, the effect of pre-treatment of Melan-a cells with the ER-β antagonist Faslodex ® 1 µM was abolished by 7-isopentenyloxycoumarin, which induced a 2-fold increase in melanin biosynthesis in the same cell line with respect to controls. Furthermore, an involvement of the aryl hydrocarbon receptor could be hypothesized [8].…”