Interaction of 7-Alkoxycoumarins with the Aryl Hydrocarbon Receptor

Note pubs.acs.org/jnp

Interaction of 7‑Alkoxycoumarins with the Aryl Hydrocarbon Receptor Marco Gargaro,† Francesco Epifano,*,‡ Serena Fiorito,‡ Vito Alessandro Taddeo,‡ Salvatore Genovese,‡ Matteo Pirro,§ Antonella Turco,† Paolo Puccetti,† Carsten B. Schmidt-Weber,# and Francesca Fallarino*,† †

Department of Experimental Medicine, University of Perugia, Polo Unico Sant’Andrea delle Fratte, Piazzale Gambuli, 06132, Perugia, Italy ‡ Department of Pharmacy, University “G. D’Annunzio” of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy § Department of Medicine, Piazzale Gambuli, University of Perugia, Perugia, Italy # Zentrum für Allergie und Umwelt (ZAUM), Technische Universität und Helmholtz Zentrum, München, Germany 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.

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of cytochrome P450 genes; however with the identification of endogenous, dietary, and microbial AhR ligands, AhR is recognized as a pleiotropic factor.7 Alternative modes of AhR activation have also been described, and they include nongenomic pathways.8 In general, the functionality of AhR is largely influenced by three main factors: the nature of the ligand, local tissue microenvironment (e.g., cytokines, microbiota, drugs, food, and environmental-derived metabolites), and the presence of specific coactivators in the cell. AhR has a high degree of ligand promiscuity. Endogenous agonists include tryptophan catabolites (e.g., indole-3-carbaldehyde, indole[3,2b]carbazole, 6-formylindole[3,2b]carbazole [FICZ], L-kynurenine, and kynurenic acid),9 metabolites of gut microflora (e.g., 7ketocholoesterol, bilirubin, and tetrahydropyrroles), xenobiotics (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxine, TCDD, and polychlorinated hydrocarbons),10 plant-derived tryptophan degradation products (e.g., isatin, indigo dye, and indirubin), carotenoids, and flavonoids (e.g., quercetin and galangin).11 Here our study aimed at getting further insights into the pharmacological target of naturally occurring oxyprenylated secondary metabolites and their semisynthetic derivatives. Most AhR ligands contain a large planar moiety with a single or a polycyclic aromatic core bearing one or more small polar

he transcription factor aryl hydrocarbon receptor (AhR) is a cytosolic sensor of small synthetic xenobiotic molecules and natural compounds, acting as AhR ligands. Specifically, AhR is a ligand-activated transcription factor acting as a heterodimeric transcriptional modulator.1 Its presence has been revealed in several animal species and in humans, and only in recent years have its functions begun to be characterized. Although AhR activity was originally investigated in toxicology, because of its ability to bind to environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), recently it has attracted enormous attention, and it is now well recognized to play pivotal roles in several physiological conditions. Accordingly, studies in AhR-null mice indicate that AhR deficiency impairs specific physiological processes, such as the development of selected immune system cell types and protection against bacterial infections.2,3 Moreover, AhR has been reported to be involved in numerous signaling pathways, involved in the maintenance of cell homeostasis, such as gene regulation, cell proliferation and differentiation, cell migration, immune responses, cytokine secretion, and several others.4−6 AhR agonists are able to promote binding of a heterodimeric form of the receptor, namely, the AhR/AhR nuclear translocator (ARNT) complex, at promoter recognition sequences of target genes.1 This process promotes transcription of specific genes also by recruiting specific histone acetyltransferase function. Historically, AhR function was restricted to regulation © 2017 American Chemical Society and American Society of Pharmacognosy

Received: February 28, 2017 Published: May 19, 2017 1939

DOI: 10.1021/acs.jnatprod.7b00173 J. Nat. Prod. 2017, 80, 1939−1943

Journal of Natural Products

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Scheme 1a

functional groups. This feature is also a specific characteristic of hydroxylated and methoxylated coumarins, having a 2benzopyrone moiety, and also of hydroxylated and methoxylated coumaric acid derivatives, having a benzene ring linked to a terpenyl side chain. Due to these structural similarities, we decided to investigate whether some selected oxyprenylated phenylpropanoids and their derivatives could modulate AhR functions. The chemical structures of both natural and semisynthetic products investigated in this study are illustrated below.

a Reagents and conditions: (a) alkyl bromide (1.0 equiv), K2CO3 (1.5 equiv), acetone, 80 °C, 1 h, b) basic workup.

chemicals were also assayed in vitro for their capacity to block AhR, using the prototypical AhR agonist FICZ.20 Specifically, AhR reporter cells were grown and treated with the reference ligand FICZ (10 nM) alone or in combination with different compounds used at three different concentrations (1, 10, and 100 μM). Among the tested molecules only two, namely, 7-npropyloxycoumarin (7) and 7-(3′-hydroxymethyl-3′methylallyloxy)coumarin (14), resulted in a significant decrease of FICZ-induced luciferase activity (Figure 2); all the other derivatives, when tested at the three different concentrations, did not significantly decrease FICZ agonist activity (data not shown). Interestingly, the fact that 14 was also able to activate AhR when used alone (Figure 1 and Figure 2) suggests that this molecule may behave as a partial AhR agonist. Among the 15 natural and semisynthetic compounds tested only 7-isopentenyloxycoumarin (4) provided a “clear” response, being able to activate AhR in a concentrationdependent manner. A similar but largely less pronounced effect was given by boropinic acid (2), which shares with 4 a 3,3dimethylallyloxy side chain. The elongation from 5 carbon atoms to 10 atoms (geranyl) totally abolished the effect. Neither 4′-geranyloxyferulic acid (1) nor auraptene (3) was able to activate AhR. Furthermore, any kind of structural replacement of the isopentenyloxy chain failed to evoke a response similar to the one obtained with compound 4. Degradation of the 3,3-dimethylallyl moiety to a skeleton with one to three carbon atom as in compounds 5, 6, 7, and 9 led to no effect. Compounds with four carbon atoms [e.g., 11 and 12] in the side chain retained some activity, but only at the highest concentration tested (100 μM). Deletion of a methyl group from the side chain as in 8 gave the same result as for 11 and 12. Reduction of the carbon−carbon double bond as in 10 totally abolished activity, unless two methyl groups were present, as in 12, for which a small effect was recorded at 100 μM. Increasing the unsaturation degree in the side chain as in 13 or partially oxidating it as in 14 provided a pattern of activity similar to compound 12. Finally, it is noteworthy to underline how the parent nonalkylated coumarin, umbelliferone (15), induced no appreciable effect. Very few reports on the biological activity of 7-isopentenyloxycoumarin have been reported in the literature. This secondary metabolite was shown to be a growth inhibitory agent of two human cancer cell lines (HeLa and HT-29) in vitro and an inhibitor of skin cancer, induced by dimethylbenz[a]anthracene in an in vivo animal model.22 Increasing epidemiological and experimental animal data provide substantial support for an abnormal AhR function in tumor cells, implying that AhR may be a novel druginterfering target. Interestingly, AhR was found to be overexpressed or implicated in key pathological pathways in the two cancer cell lines listed above.23,24 In addition, 7-isopentenyloxycoumarin was also reported to have neuroprotective effects against N-methyl-D-aspartateinduced cell death in astrocytes and neurons in vitro.14 It has been shown that AhR is also able to attenuate neuronal

The main natural sources of 4′-geranyloxyferulic acid (1), boropinic acid (2), auraptene (3), and 7-isopentenyloxycoumarin (4) have been described previously.12−15 7-Methoxycoumarin (5) is widespread in the plant kingdom and can be extracted from several species,16 7-(2-methyl)butoxycoumarin (10) has been isolated from the essential oil of Stenachaenium megapotamicum Spreng. Baker (Asteraceae) and from the aerial parts of Peucedanum hispanicum (Boiss.) Endl. (Apiaceae),17,18 and finally 7-(3′-hydroxymethyl-3′-methylallyloxy)coumarin (14) has been obtained from the resinous exudates of Haplopappus multifolius Phil ex Reiche (Rutaceae).19 All other coumarins (6−9 and 11−13) are of semisynthetic origin. 4′Geranyloxyferulic acid (1) and boropinic acid (2) have been synthesized from commercially available ferulic acid in very good overall yields (92% and 95%, respectively) and purity (>97.8% assessed by HPLC and elemental analysis) following the well-validated route previously reported in the literature. Briefly, ferulic acid was converted into the corresponding methyl ester by treatment with a solution of concentrated H2SO4 in refluxing MeOH for 12 h and purification by acid− base workup. The ester was then alkylated with 3,3dimethylallyl or geranyl bromide in acetone at 80 °C for 1 h followed by basic hydrolysis for one additional hour at the same temperature and purification by acid−base workup and crystallization (n-hexane). Coumarins have been synthesized in excellent yields (92−99%) and purity (>98.4%) from umbelliferone (15) by alkylation with the respective alkyl bromide in acetone and in the presence of dry K2CO3 as the base at 80 °C for 1 h (Scheme 1). Umbelliferone (15) has been used as a reference compound in our tests to assess the effect of alkylation on the activity on AhR. All the synthesized chemicals were then assayed in vitro for their capacity to interact with AhR, using as prototypical AhR reference ligand FICZ.20 Cells were grown and treated with the different compounds at three different concentrations (1, 10, and 100 μM), while the reference ligand was used at 1 μM. Luciferase activity was measured as previously described.21 The results are shown in Figure 1. In addition, all synthesized 1940

DOI: 10.1021/acs.jnatprod.7b00173 J. Nat. Prod. 2017, 80, 1939−1943

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Figure 1. Effects of coumarin and ferulic acid derivatives in the AhR luciferase reporter assay. Data are represented as mean ± SD, with *P < 0.05, **P < 0.01, ***P < 0.001.

activation and that linear coumarins functionalized with a 3,3dimethylallyloxy side chain may, like flavonoids and many other natural products, represent an additional class of AhR ligands. The linearity in the concentration−response effect provided by 7-isopentenyloxycoumarin (4), but not by other coumarins, together with the results showing that boropinic acid (2) can also activate AhR, led us to hypothesize that this coumarin may tightly interact with specific amino acid residues of AhR. To underline the importance of the presence of a terpenyl chain for the pharmacological activity and ligand-binding capacity, it has been recently reported that 6-(1,1-dimethylallyl)naringenin has a marked stronger capacity to interact with estrogen receptors than parent naringenin.27 Thus, further investigations are warranted on assessing the ability of natural coumarins (e.g., linear, furano, and pyranocoumarins) widely represented in nature as secondary plant, fungal, and bacterial metabolites28 to bind and activate AhR. An additional area of investigation is the identification of specific amino acid residues required for AhR interaction with the natural compounds and their semisynthetic analogues investigated in this study. Docking studies may reveal important details of the interaction between coumarins and AhR. Finally, the results reported herein may inspire the evaluation of oxyprenylated natural products as alternative candidate compounds capable of modulating AhR activity in specific biological settings.

Figure 2. Effects of 7-n-propyloxycoumarin (7) and 7-(3′-hydroxymethyl-3′-methylallyloxy)coumarin (14) in the AhR luciferase reporter assay. Reference ligand FICZ was used at 10 nM. Data are represented as mean ± SD, with *P < 0.05, ***P < 0.01.

excitotoxicity.25 Thus, the capacity of 7-isopentenyloxycoumarin (4) to act as an agonist of AhR described herein may in part account for its previously reported pharmacological properties. Ligand binding induces an AhR conformational change, thereby exposing a nuclear translocation site, initiating the socalled canonical AhR pathway.26 AhR translocates to the nucleus and binds to its dimerization partner ARNT; then the AhR−ARNT complex initiates transcription of genes contained in their promoter’s xenobiotic responsive elements. These genes include those encoding members of the cytochrome P450 family 1 such as CYP1A1, CYP1A2, and CYP1B1.26 This mechanism may contribute to the metabolism of toxic compounds and natural products present in food. In addition to the canonical pathway, the receptor can activate alternative signaling routes, intercepting other intracellular communication pathways. On the basis of these data, future studies should address the AhR-specific transcriptional program initiated by natural compounds such as 7-isopentenyloxycoumarin. We have recently demonstrated that different AhR ligands preferentially bind distinct conformations of the AhReach having a distinct set of crucial fingerprint residuesthus initiating different pathways of downstream signaling and transcriptional events.21 Overall, the evidence presented here enforces the concept that large planar moieties containing an aromatic ring are among the best pharmacophores for AhR

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EXPERIMENTAL SECTION

General Experimental Procedures. The same general synthetic procedures as already reported were followed.29 6-Formylindolo[3,2b]carbazole was purchased from Biomol (Plymouth Meeting, PA, USA). 4′-Geranyoxyferulic acid, 1. Analytical data were in full agreement with those previously reported for the same compound.29 Anal. Calcd for C20H26O4: C 72.70, H 7.93, O 19.37. Found: C 72.64, H 7.94, O 19.40. Boropinic Acid, 2. Analytical data were in full agreement with those previously reported for the same compound.29 Anal. Calcd for C15H18O4: C 68.68, H 6.92, O 24.40. Found: C 68.60, H 6.96, O 24.35. Auraptene, 3. Analytical data were in full agreement with those previously reported for the same compound.29 Anal. Calcd for C19H22O3: C 76.48, H 7.43, O 16.09. Found: C 76.44, H 7.40, O 16.04. 1941

DOI: 10.1021/acs.jnatprod.7b00173 J. Nat. Prod. 2017, 80, 1939−1943

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7-Isopentenyloxycoumarin, 4. Analytical data were in full agreement with those previously reported for the same compound.29 Anal. Calcd for C14H14O3: C 73.03, H 6.13, O 20.85. Found: C 72.98, H 6.16, O 20.81. 7-Methoxycoumarin, 5. Analytical data were in full agreement with those previously reported for the same compound.30 Anal. Calcd for C10H8O3: C 68.18, H 4.58, O 27.25. Found: C 68.22, H 4.56, O 27.21. 7-Ethoxycoumarin, 6. Analytical data were in full agreement with those previously reported for the same compound.31,32 Anal. Calcd for C11H10O3: C 69.46, H 5.30, O 25.24. Found: C 69.49, H 5.25, O 25.20. 7-nPropoxycoumarin, 7. Analytical data were in full agreement with those previously reported for the same compound.31,32 Anal. Calcd for C12H12O3: C 70.57, H 5.92, O 23.50. Found: C 70.51, H 5.91, O 23.48. 7-(2′-Butenyloxy)coumarin, 8. Analytical data were in full agreement with those previously reported for the same compound.33 Anal. Calcd for C13H12O3: C 72.21, H 5.59, O 22.20. Found: C 72.17, H 5.55, O 22.23. 7-Allyloxycoumarin, 9. Analytical data were in full agreement with those previously reported for the same compound.34 Anal. Calcd for C12H10O3: C 71.28, H 4.98, O 23.74. Found: C 71.33, H 4.96, O 23.79. 7-(3′-Methyl)-nbutyloxy)coumarin, 10. Analytical data were in full agreement with those previously reported for the same compound.35 Anal. Calcd for C14H16O3: C 72.39, H 6.94, O 20.66. Found: C 72.36, H 6.89, O 20.61. 7-(2′-Pentinyloxy)coumarin, 11. Analytical data were in full agreement with those previously reported for the same compound.31,32 Anal. Calcd for C14H12O3: C 73.67, H 5.30, O 21.03. Found: C 73.66, H 5.26, O 21.08. 7-(2′,2′-Dimethyl)-n-opropoxycoumarin, 12. Analytical data were in full agreement with those obtained from a commercial sample. Anal. Calcd for C14H16O3: C 72.39, H 6.94, O 20.66;. Found: C 72.32, H 6.91, O 20.69. 7-Benzyloxycoumarin, 13. Analytical data were in full agreement with those previously reported for the same compound.32,36 Anal. Calcd for C16H12O3: C 76.18, H 4.79, O 19.03. Found: C 76.24, H 4.77, O 19.00. 7-(3′-Hydroxymethyl-3′-methylallyloxy)coumarin, 14. Analytical data were in full agreement with those previously reported for the same compound.19 Anal. Calcd for C14H14O4: C 68.28, H 5.73, O 25.99. Found: C 68.23, H 5.76, O 25.92. Pharmacology. For assessing the capability of the synthesized natural compounds or their semisynthetic analogues to activate AhR, we used mouse hepatoma (H1L1.1c2) cells, containing the stably integrated AhR xenobiotic responsive element driven by a firefly luciferase reporter plasmid, pGudLuc6.1.37

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Grant GGP14042 to F.F. and AIRC Investigator Grant 16851 to P.P.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (F. Epifano). Tel: +3908713554654. Fax: +3908713554912. *E-mail: [email protected] (F. Fallarino). Tel: +395858242. ORCID

Francesco Epifano: 0000-0002-0381-7812 Francesca Fallarino: 0000-0002-8501-2136 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors from Chieti thank the University “Gabriele d’Annunzio” of Chieti-Pescara−Fondi FAR 2016 for financial support. This study was also supported by Telethon Research 1942

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DOI: 10.1021/acs.jnatprod.7b00173 J. Nat. Prod. 2017, 80, 1939−1943