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Communication

Geobarrettin D, a Rare Herbipoline-Containing 6-Bromoindole Alkaloid from Geodia barretti

by
Xiaxia Di
1,2,†,
Ingibjorg Hardardottir
2,3,
Jona Freysdottir
2,3,
Dongdong Wang
4,
Kirk R. Gustafson
4,
Sesselja Omarsdottir
1,* and
Tadeusz F. Molinski
5,*
1
Faculty of Pharmaceutical Sciences, University of Iceland, Hagi, Hofsvallagata 53, IS-107 Reykjavik, Iceland
2
Department of Immunology, Landspitali—The National University Hospital of Iceland, IS-101 Reykjavik, Iceland
3
Faculty of Medicine, Biomedical Center, University of Iceland, Vatnsmyrarvegur 16, IS-101 Reykjavik, Iceland
4
Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
5
Department of Chemistry and Biochemistry, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92093, USA
*
Authors to whom correspondence should be addressed.
†
Current address: Departments of Biochemistry and Biomedical Sciences & Chemistry and Chemical Biology, M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada.
Molecules 2023, 28(7), 2937; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28072937
Submission received: 8 February 2023 / Revised: 25 February 2023 / Accepted: 26 February 2023 / Published: 24 March 2023
(This article belongs to the Special Issue Bioactive Compounds from Natural Sources II)
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Abstract

:
Geobarrettin D (1), a new bromoindole alkaloid, was isolated from the marine sponge Geodia barretti collected from Icelandic waters. Its structure was elucidated by 1D, and 2D NMR (including 1H-15N HSQC, 1H-15N HMBC spectra), as well as HRESIMS data. Geobarrettin D (1) is a new 6-bromoindole featuring an unusual purinium herbipoline moiety. Geobarrettin D (1) decreased secretion of the pro-inflammatory cytokine IL-12p40 by human monocyte derived dendritic cells, without affecting secretion of the anti-inflammatory cytokine IL-10. Thus, compound 1 shows anti-inflammatory activity.

1. Introduction

The indole nucleus is an important element of many natural and synthetic molecules possessing significant biological activities. Indole has been termed a “privileged structure” in drug discovery and a common starting point for drug development or lead optimization [1,2]. Marine indole alkaloids comprise a large and complex class of natural products; most marine-derived indole metabolites are halogenated by bromine [2,3,4]. The presence of halogen substituents on the indole ring profoundly influences biological activity [2,3]. Interestingly, the Br substituent generally resides at C-5, less commonly at C-6, or at both C-5 and C-6 [4]. Additional modifications of the bromoindole core include C-substitutions by O, C (often prenyl) and N groups, pyrimidyl, 2-aminopyrimidyl groups or more complex polycyclic ring systems [5,6,7,8,9,10,11]. Bromoindoles have been reported to have anti-inflammatory, antibacterial, antifungal, antitumor, antioxidant, antifouling, and antiplasmodial activities [1,3,4,12,13].
The marine sponge Geodia barretti is the source of bromoindole alkaloids [14,15,16,17,18] and several N-methylated nucleosides [19]. In our previous study, three new 6-bromoindole derivatives were isolated from G. barretti collected in Icelandic waters [20]; of these, geobarrettins B and C exhibited anti-inflammatory activity [20]. As part of our ongoing investigation to find novel anti-inflammatory compounds, we report, here, the bromoindole geobarrettin D (1) (Figure 1, as the TFA salt) with potential anti-inflammatory effect measured by decreased pro-inflammatory cytokine secretion of human monocyte-derived dendritic cells (DCs).

2. Results

The lyophilized sponge G. barretti was extracted with CH2Cl2/MeOH (v/v 1:1). After removal of solvent, the resulting crude extract was resuspended in MeOH/H2O (9:1) and solvent-partitioned into five fractions of increasing polarity (hexane, CHCl3, CH2Cl2, n-BuOH, and H2O) using a modified Kupchan method [21,22]. The CHCl3 and CH2Cl2 fractions were combined and purified by RP C18 HPLC to afford the 6-bromoindole derivative, geobarrettin D (1, Figure 1).

2.1. Structural Elucidation

The HRMS of geobarrettin D (1) exhibited molecular ion isotopomers m/z 458.1343/460.1316 ([M]+) in a 1:1 ratio, indicating the presence of one Br and a molecular formula C20H2579BrN7O, corresponding to 12 degrees of unsaturation. The 13C NMR data (Table 1, see Supplementary Materials) showed 18 signals which were matched to the C content of the molecular formula, including five methyls (δC 54.8 (×3), 36.2, and 32.1), one sp3 methylene (δC 69.3), one aliphatic methine (δC 45.4), five aromatic methines (δC 140.1, 125.9, 124.2, 120.8, and 115.9), four quaternary aromatic carbons (δC 139.1, 125.2, 117.0, and 113.4), four quaternary heteroatom-bonded sp2 carbons (δC 155.0, 154.9, 151.0, and 110.0) (Table 1). The most intense MS peak at m/z 399.0603/401.0585 ([M-N(CH3)3]+) (Figure S10) was derived from a neutral loss of trimethylamine (–N(CH3)3). IR bands (3254, 1182, and 1131 cm−1) implied the presence of OH and/or NH functionalities. The 1H NMR data of 1 in CD3OD (Table 1) exhibited signals due to five aromatic protons, five N-methyl groups, [δH 4.11(3H, s, 11-Me), 3.91(3H, s, 12-Me), and 3.27 (9H, s, 1″-NMe)], a methine proton, and a methylene group. Three aromatic signals at δH 7.65 (1H, d, J = 8.5 Hz, H-4′), 7.60 (1H, d, J = 1.6 Hz, H-7′) and 7.24 (1H, dd, J = 8.5, 1.6 Hz, H-5′) indicated the presence of a 1,2,4-trisubstituted benzene ring. The 1H NMR spectrum, recorded in D2O/H2O (1:9), showed the presence of a downfield exchangeable proton (δH 10.60), which is diagnostic of an NH proton in an indole ring, and confirmed by a weak coupling (J = 2.0 Hz) to the isolated aromatic proton at δH 7.53 in the pyrrole ring. Correlations observed in the HMBC spectrum (Figure 2) allowed the definement of the substitution pattern and NMR assignments of the indole: H-4′ to C-3′, C-6′, and C-7a′, from H-5′ to C-3a′ and C-7′, and from H-7′ to C-5′ and C-3a′. H-2′ also showed a correlation to C-3′, C-3a′, and C-7a′. The NH exchangeable proton H-1′ showed correlations to C-2′, C-3′, C-3a′, and C-7a′. The indole assignment was supported by the presence of several bands in the UV-vis spectrum (λmax 228, 261, and 287 nm).
Br-substitution at C-6′ was deduced by a comparison of the chemical shifts of the aromatic carbons of related 6-bromoindole alkaloids [16,18,23]. Thus, geobarrettin D (1) was defined as a 3-substituted 6-bromoindole alkaloid. The 1H-1H COSY correlations from H-3″ (δH 6.05 (1H, t, J = 6.3 Hz)) to H-2″ (δH 4.07 (1H, dd, J = 13.7, 5.9 Hz); 4.15 (1H, dd, J = 13.7, 6.8 Hz)) and HMBC correlations of (CH3)3-N (δH 3.30 (9H, s))/C-2″ (δC 69.3), H-2″/C-3″ (δC 45.4) and H-3″/C-2″ indicated the presence of 2,2-disubstituted N,N,N-trimethylethanaminium group; further support of the connectivity of 6-bromo-indol-3-yl moiety and the N,N,N-trimethylethanaminium group were provided by additional HMBC correlations: H-3″/C-3′ (δC 113.4), H-3″/C-2′ (δC 125.9), H-3″/C-3a′ (δC 125.2), and H-2″/C-3′ (Figure 2).
The balance of the molecular formula C20H2579BrN7O of geobarrettin D (1), C7N5H8O, after accounting for the 6-bromoindole and 2,2-disubstituted N,N,N-trimethylethanaminium moieties, required another six degrees of unsaturation. The HMBC cross-peak H-3″/C-2 (δC 154.9) revealed that the C7N5H8O unit was connected to C-3″ through a C-N bond, which explains the downfield chemical shift of C-3″ (δC 45.4). Analysis of the 13C NMR data revealed the seven remaining carbons as non-protonated sp2 carbons with chemical shifts of δC 155.0, 154.9, 151.0, 140.1, 110.0 and two sp3 carbons δC 36.2, 32.1 (Table 1). The 1H NMR chemical shift of the non-exchangeable δH 9.01 lacked an expected cross-peak in the HSQC spectrum, but strong symmetric ‘satellite peaks’ appearing in the HMBC, centered on δC 140.1, were due to 1JCH ‘breakthrough’ (1JH8-C8 = 220 Hz) [24,25]: the large magnitude is consistent with a five-membered heterocycle [26]. Long-range correlations were also seen from H-8 [δH 8.81 (1H, s, H-8)] to two N-methyl groups (δC 36.2 and 32.1 ppm) in addition to C-4 and C-5 (δC 151.0 and 110.0, respectively). These data are reconciled by an N,N-dimethyl imidazole ring.
H-detected 15N-heteronuclear 2D NMR experiments (1H−15N HSQC and 1H-15N HMBC in D2O/H2O, 1:9) were also recorded. The correlations from H-8 [δH 8.81 (1H, s, H-8)] to N-9 (δN 157.3), N-7 (δN 156.4), from CH3-12 (δH 3.91 (3H, s)) to N-9, from CH3-11 (δH 4.11 (3H, s)) to N-7 in 1H−15N HMBC and 1H−13C HMBC spectra further supported a N,N-dimethyl imidazolinium ring. The latter partial structures, together with the last two degrees of unsaturation, were assembled with the remaining quaternary C and three N atoms to complete an N-quaternized guanininium nucleobase. This hypothesis was supported by the H-8/C-6 4JCH correlation and the downfield chemical shift of C-4, and comparisons of 13C shifts of 1 with published data for similar purine bases, e.g., herbipoline (7,9-dimethyl-2-(N-amino)guaninium) [25,27,28,29,30] with the same C-2″–N-10 bond. The NMR data are in good agreement with other natural alkylpuriniums: 7,9-dimethyl-2-(N-methyl)guaninium chloride [25] and N,N-dimethyl-1,3-dimethylherbipoline [30].
Although 1 is chiral, the weak optical activity ([α]23D +2 (c 0.4, MeOH)) suggests a near-racemic mixture.

2.2. Anti-Inflammatory Activity

When DCs were matured and activated in the presence of geobarrettin D (1), secretion of the pro-inflammatory cytokine IL-12p40 was diminished by 48%, whereas secretion of the anti-inflammatory cytokine IL-10 was not affected (Figure 3). On balance, these results indicate an overall anti-inflammatory effect of geobarrettin D (1).

3. Discussion

Marine sponges have proven to be a rich source of naturally occurring modified nucleosides: these exist as free bases, nucleotides, and within polynucleotides [31,32]. The first natural purinium salt found in nature, herbipoline, was isolated from the sponge Geodia gigas [32]. Subsequently, several related herbipoline salts were characterized from tropical marine sponges: l-methylherbipoline from Jaspis sp. [25]], 1-methylherbipoline salts of halisulfate-1 and suvanine from Coscinoderma mathewsi [27] and suvanine (N,N-dimethyl-1,3-dimethylherbipoline salt) from Coscinoderma sp. [30]. A literature survey revealed that 1 is the first herbipoline-containing indole [32], and a rare bis-quaternized alkaloid.
Most natural product alkaloids are derived from the aromatic amino acids including tryptophan, tyrosine and phenylalanine. Compound 1 is likely biosynthetically derived from 6-bromotryptamine—an alkaloid known from other marine invertebrates [33]—through a fusion of an oxidized tryptamine intermediate and a guanine equivalent (Figure 4) through a 1,4-conjugate addition, followed by extensive methylation reactions involving S-adenosylmethionine (SAM). Oxidation and conjugate addition is necessary and sufficient to explain formation of many C–C and C–heteroatom bonds in alkaloids [34], including 1. For example, one of us (T.F.M) recently reported two cyclic guanidines, aiolochroiamides A and B, whose formation may also be rationalized by an oxidation–conjugate addition mechanism [35]. It is likely that the oxidation reaction is enzyme-mediated as spontaneous autoxidation seems unlikely, however the subsequent conjugate addition may be spontaneous given the low specific rotation (and therefore enantiomeric excess) observed for 1. As with other complex highly-methylated quaternized alkaloids, the ordering of N-methylation and condensation reactions is uncertain. Further biosynthetic studies are necessary for understanding the biosynthesis of 1, but these are beyond the scope of this study.
Purines have found antiviral, antibiotic, and anticancer activities [27,31,36,37], and have the potential to regulate myocardial oxygen supply and cardiac blood flow [38]. In addition, evidence supports their role in biological evolution, differentiation, and ecological processes [31]. Purines are also involved in various inflammatory responses which underscores the significant attention given to purine natural products and their synthetic mimetics for the development of anti-inflammatory agents [20,39,40].
The anti-inflammatory properties of compound 1 were investigated in an in vitro model of human monocyte-derived DCs [20]. DCs matured and activated in the presence of compound 1 secreted less IL-12p40 than DCs cultured without 1, whereas 1 had no effect on their secretion of IL-10. The pro-inflammatory cytokine IL-12p40 (one of the two chains that form the structures of IL-12 and IL-23 cytokines) is a major determinant of the differentiation of naïve T cells into Th1 or Th17 phenotypes [41], whereas the anti-inflammatory cytokine IL-10 drives polarization of naïve T cells into a T regulatory phenotype [42]. Thus, suppression of IL-12p40 secretion by DCs in the presence of 1 indicates that geobarrettin D (1) has anti-inflammatory activity.

4. Materials and Methods

4.1. General Procedures

The UV spectrum was recorded on a NanoVueTM spectrophotometer (GE Healthcare Life Sciences, Little Chalfont, UK) with a 0.2 mm path length. Optical rotation was measured on a P-2000 polarimeter (Jasco, Oklahoma City, OK, USA), with a quartz cell (10 mm path length). The infrared spectrum was measured on a Spectrum Two TM FTIR spectrometer (Perkin Elmer®, Waltham, MA, USA) of samples as thin films. NMR spectra were recorded on a Bruker Avance 600 spectrometer (Billerica, MA, USA) (1H and 13C frequencies: 600.13 MHz and 150.76 MHz, respectively) in CD3OD and D2O/H2O (1:9). The residual solvent signals were used as internal references: δH 3.30/δC 49.0 ppm (CD3OD) and δH 4.79 (D2O). For 1H-15N 2D NMR spectroscopy, the nominal 15N standard was liquid ammonia, NH3 (l) (δ = 0 ppm). Samples (1.6–6.0 mg) were introduced into Shigemi tubes and their 2D NMR spectra measured as illustrated by the following 1H{13C} heteronuclear HSQC and HMBC spectra using modifications of the Bruker pulse sequences hsqcedetgpsisp2.4 and hmbcgplpndqf, respectively: Spectra were acquired at near ambient temperature (T = 300.0 K) in the specified solvent with an rf pulse calibrated to 1H π/2 = 8.75 µs, with appropriate gradient field strengths, and dwell times corresponding to 1H (F2) and 13C (F1) spectral widths of 8417.5 Hz and 33112.6 Hz and centered at δH 7.01 and δC 110.4 ppm, respectively. Accumulated scans (n = 8 for HMBC and n = 32 for HSQC) for each T1 increment were averaged between a relaxation delay, D1 =1.5 s. The acquired matrix (1H and 13C, 1024 × 256 increments for HMBC, and 672 × 256 for HSQC) was zero-filled in each dimension to a final size of 2048 × 1024, and processed, after standard apodizations, by Fourier transform.The high-resolution mass spectrum was measured on an Acquity UPLC I-Class System coupled to Xevo G2-XS QTof Mass Spectrometer (Waters®, Milford, MA, USA) using Acquity UPLC® HSS T3 column (High Strength Silica C18, 1.8 µm, 2.1 × 100 mm, Waters®, (Milford, MA, USA) operating at 60 °C). The MS and MSn spectra were recorded in positive mode and data were acquired using MassLynx® Software (version 4.1, Waters Crop., Milford, MA, USA). VLC chromatography on C18 adsorbent (LiChroprep RP-18, 40–63 μm, Merck Inc., Darmstadt, Germany) and Dionex 3000 HPLC system armed with a G1310A isopump, a G1322A degasser, a G1314A VWD detector (210 nm), a 250 × 21.2 mm Phenomenex Luna C18(2) column (5 μm), and a 250 × 4.6 mm Phenomenex Gemini-NX C18 column (5 μm) were conducted for separation and purification of pure compounds.

4.2. Animal Materials

In short, the sponge material Geodia barretti was collected in Iceland, identified by. Hans Tore Rapp, University of Bergen (Norway), and deposited at University of Iceland. For a complete description of the samples, see Xiaxia Di et al. [20].

4.3. Extraction and Isolation

Frozen sponge was cut into approximately 1 cm3 pieces and freeze-dried. The dried tissue was extracted with a mixture of CH2Cl2:CH3OH (v/v, 1:1) for 3 times (2 L, each for 24 h) at room temperature. The combined CH2Cl2-MeOH extracts were dried under reduced pressure then the residue (1.8 g) was suspended in MeOH:H2O (v/v, 9:1) and subjected to a modified Kupchan partition, as previously described [21,22], to yield five fractions: hexane (fraction A), chloroform (fraction B), dichloromethane (fraction C), n-butanol (fraction D), and H2O (fraction E). Using a VLC RP-18 CC (MeOH-H2O, 10:90→100:0) technique, the mixture of the fractions B and C was separated into nice fractions (F2.1−F2.9). Fraction F2.2 (75.0 mg) was purified by preparative HPLC (28:72:0.1 CH3CN-H2O-TFA, 8.0 mL/min) and then re-chromatographed by semi-preparative HPLC (CH3CN-H2O-TFA, 31:69:0.1) to give geobarrettin D (1) (3.3 mg).
Geobarrettin D (1): Light yellowish oil; [α]23D +2 (c 0.4, MeOH); UV (MeOH) λmax (log ε) nm: 212 (3.90), 228 (4.04), 261 (3.81), 287 (3.65); IR νmax cm−1: 3255, 1679, 1607, 1478, 1444, 1385, 1203, 1131; For 1H and 13C NMR data, see Table 1; HRESIMS m/z 458.1343 [M]+ (C20H25ON7Br, 458.1298).

4.4. Maturation and Activation of DCs

DCs were differentiated from human monocytes as previously described [20]. Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood obtained from healthy human donors (approval #06-068-V1 by National Bioethics Committee of Iceland (Visindasidanefnd) from 15th of December 2015) by density centrifugation using Histopaque-1077 (Sigma-Aldrich, Munich, Germany). Then CD14+ monocytes were isolated from the PBMCs using magnetic cell sorting and CD14 Microbeads (Miltenyi Biotech, Bergisch Gladbach, Germany). The CD14+ monocytes were cultured at 5 × 105 cells/mL in RPMI 1640 medium, supplemented with 10% fetal calf serum and 5% penicillin/streptomycin (all from Gibco®, Thermo Fisher Scientific, UK) in 48 well tissue culture plates for seven days. In order to differentiate CD14+ monocytes into immature DCs, IL-4 at 12.5 ng/mL and GM-CSF at 25 ng/mL (both from R&D Systems, Bio-Techne, Abingdon, England) were added to the cells. After seven days the monocytes had differentiated into immature DCs which were harvested and cultured for 24 h in 48 well tissue culture plates at 2.5 × 105 cells/mL. The immature DCs were matured and activated by culturing them with IL-1β at 10 ng/mL, TNF-α at 50 ng/mL (both from R&D Systems), and lipopolysaccharide (LPS) at 500 ng/mL (Sigma-Aldrich, Munich, Germany). Geobarrettin D (1) was dissolved in DMSO and added to the DCs at 10 µg/mL at the same time as the cytokines and LPS. DMSO was used as a control. After 24 h the mature and activated DCs were harvested and the concentrations of IL-12p40 and IL-10 in the supernatants were measured by sandwich ELISA using DuoSets from R&D Systems according to the manufacturer’s protocol. The results are expressed as a secretion index (SI). Data are presented as the mean values ± SEM, n = 3. As the data were not normally distributed, Mann–Whitney U test was used to determine statistical differences between the groups (SigmaStat 3.1, Systat Software, San Jose, CA, USA) and p < 0.05 was considered as statistically significant.

5. Conclusions

Geobarrettin D (1) is a newly detected bromoindole alkaloid possessing an unusual brominated and fused-herbipoline-dimethylguaninium heterocycle. Geobarrettin D (1) decreased DC secretion of the pro-inflammatory cytokine IL-12p40, indicating its potential as an anti-inflammatory agent.

Supplementary Materials

The following are available online at https://0-www-mdpi-com.brum.beds.ac.uk/article/10.3390/molecules28072937/s1, Figure S1. 1H NMR spectrum of geobarrettin D (1), recorded in CD3OD, 600 MHz; Figure S2. 13C NMR spectrum of geobarrettin D (1), recorded in CD3OD, 150 MHz; Figure S3. DEPT-135 NMR spectrum of geobarrettin D (1); Figure S4. HSQC spectrum of geobarrettin D (1); Figure S5. HMBC spectrum of geobarrettin D (1); Figure S6. COSY spectrum of geobarrettin D (1); Figure S7. 1H NMR spectrum of geobarrettin D (1), recorded in D2O/H2O 10/90, 600 MHz; Figure S8. 1H-15N HSQC spectrum of geobarrettin D (1), recorded in D2O/H2O 10/90; Figure S9. 1H-15N HMBC spectrum of geobarrettin D (1), recorded in D2O/H2O 10/90; Figure S10. ESI spectrum of geobarrettin D (1); Figure S11. IR spectrum of geobarrettin D (1).

Author Contributions

Methodology and formal analysis, X.D., I.H., J.F., T.F.M., D.W., K.R.G. and S.O.; Writing—original draft preparation, X.D.; Writing—review and editing, I.H., J.F., T.F.M., D.W. and S.O.; Supervision, I.H., J.F., S.O. and T.F.M.; Funding Acquisition, I.H., J.F., S.O. and T.F.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by University of Iceland Research Fund (Doctoral Grant and Project Grant), grant numbers not available, AVS R&D Fund of Ministry of Fisheries and Agriculture in Iceland, grant number R 029-14, the Landspitali University Hospital Research Fund (grant number not available), and the National Institutes of Health (AI100776, AT009783, to T.F.M.).

Institutional Review Board Statement

The study was authorized by the National Bioethics Committee of Iceland (Visindasidanefnd), approval #06-068-V1 from 15 December 2015.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors would like to thank Hans Tore Rapp at the University of Bergen for the identification of the animal material and Caroline Rouger and Deniz Tasdemir at GEOMAR Helmholtz Center for Ocean Research for NMR spectrometry. The parts of the results for the manuscript are the doctoral thesis “Searching for immunomodulatory compounds from Icelandic marine invertebrates” of the author Xiaxia Di.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Sample Availability

Samples of the compound geobarrettin (1) are available from the authors.

References

  1. De Sa Alves, F.R.; Barreiro, E.J.; Fraga, C.A. From nature to drug discovery: The indole scaffold as a ‘privileged structure’. Mini Rev. Med. Chem. 2009, 9, 782–793. [Google Scholar] [CrossRef] [PubMed]
  2. Netz, N.; Opatz, T. Marine indole alkaloids. Mar. Drugs 2015, 13, 4814–4914. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Gul, W.; Hamann, M.T. Indole alkaloid marine natural products: An established source of cancer drug leads with considerable promise for the control of parasitic, neurological and other diseases. Life Sci. 2005, 78, 442–453. [Google Scholar] [CrossRef] [PubMed]
  4. Pauletti, P.M.; Cintra, L.S.; Braguine, C.G.; da Silva Filho, A.A.; Silva, M.L.; Cunha, W.R.; Januario, A.H. Halogenated indole alkaloids from marine invertebrates. Mar. Drugs 2010, 8, 1526–1549. [Google Scholar] [CrossRef] [Green Version]
  5. Franco, L.H.; Joffe, E.B.D.; Puricelli, L.; Tatian, M.; Seldes, A.M.; Palermo, J.A. Indole alkaloids from the tunicate Aplidium meridianum. J. Nat. Prod. 1998, 61, 1130–1132. [Google Scholar] [CrossRef]
  6. Walker, S.R.; Carter, E.J.; Huff, B.C.; Morris, J.C. Variolins and related alkaloids. Chem. Rev. 2009, 109, 3080–3098. [Google Scholar] [CrossRef]
  7. Butler, M.S.; Capon, R.J.; Lu, C.C. Psammopemmins (A-C), novel brominated 4-hydroxyindole alkaloids from an antarctic Sponge, Psammopemma sp. Aust. J. Chem. 1992, 45, 1871–1877. [Google Scholar] [CrossRef]
  8. Reyes, F.; Fernandez, R.; Rodriguez, A.; Francesch, A.; Taboada, S.; Avila, C.; Cuevas, C. Aplicyanins A-F, new cytotoxic bromoindole derivatives from the marine tunicate Aplidium cyaneum. Tetrahedron 2008, 64, 5119–5123. [Google Scholar] [CrossRef]
  9. Bialonska, D.; Zjawiony, J.K. Aplysinopsins-marine indole alkaloids: Chemistry, bioactivity and ecological significance. Mar. Drugs 2009, 7, 166–183. [Google Scholar] [CrossRef] [Green Version]
  10. Anthoni, U.; Bock, K.; Chevolot, L.; Larsen, C.; Nielsen, P.H.; Christophersen, C. Marine alkaloids. 13. Chartellamide A and B, halogenated β-lactam indole-imidazole alkaloids from the marine bryozoan Chartella papyracea. J. Org. Chem. 1987, 52, 5638–5639. [Google Scholar] [CrossRef]
  11. Gribble, G.W. The diversity of naturally occurring organobromine compounds. Chem. Soc. Rev. 1999, 28, 335–346. [Google Scholar] [CrossRef]
  12. Frederich, M.; Tits, M.; Angenot, L. Potential antimalarial activity of indole alkaloids. Trans. R. Soc. Trop. Med. Hyg. 2008, 102, 11–19. [Google Scholar] [CrossRef]
  13. Woolner, V.H.; Jones, C.M.; Field, J.J.; Fadzilah, N.H.; Munkacsi, A.B.; Miller, J.H.; Keyzers, R.A.; Northcote, P.T. Polyhalogenated indoles from the red alga Rhodophyllis membranacea: The first isolation of bromo-chloro-iodo secondary metabolites. J. Nat. Prod. 2016, 79, 463–469. [Google Scholar] [CrossRef]
  14. Lidgren, G.; Bohlin, L. Studies of Swedish marine organisms VII. A novel biologically active indole alkaloid from the sponge Geodia barretti. Tetrahedron Lett. 1986, 27, 3283–3284. [Google Scholar] [CrossRef]
  15. Solter, S.; Dieckmann, R.; Blumenberg, M.; Francke, W. Barettin, revisited? Tetrahedron Lett. 2002, 43, 3385–3386. [Google Scholar] [CrossRef]
  16. Sjogren, M.; Goransson, U.; Johnson, A.L.; Dahlstrom, M.; Andersson, R.; Bergman, J.; Jonsson, P.R.; Bohlin, L. Antifouling activity of brominated cyclopeptides from the marine sponge Geodia barretti. J. Nat. Prod. 2004, 67, 368–372. [Google Scholar] [CrossRef]
  17. Hedner, E.; Sjogren, M.; Hodzic, S.; Andersson, R.; Goransson, U.; Jonsson, P.R.; Bohlin, L. Antifouling activity of a dibrominated cyclopeptide from the marine sponge Geodia barretti. J. Nat. Prod. 2008, 71, 330–333. [Google Scholar] [CrossRef]
  18. Olsen, E.K.; Hansen, E.; Moodie, L.W.; Isaksson, J.; Sepcic, K.; Cergolj, M.; Svenson, J.; Andersen, J.H. Marine AChE inhibitors isolated from Geodia barretti: Natural compounds and their synthetic analogs. Org. Biomol. Chem. 2016, 14, 1629–1640. [Google Scholar] [CrossRef]
  19. Lidgren, G.; Bohlin, L.; Christophersen, C. Studies of Swedish marine organisms, part X. biologically active compounds from the marine sponge Geodia barretti. J. Nat. Prod. 1988, 51, 1277–1280. [Google Scholar] [CrossRef]
  20. Di, X.; Rouger, C.; Hardardottir, I.; Freysdottir, J.; Molinski, T.F.; Tasdemir, D.; Omarsdottir, S. 6-Bromoindole derivatives from the Icelandic marine sponge Geodia barretti: Isolation and anti-inflammatory activity. Mar. Drugs 2018, 16, 437. [Google Scholar] [CrossRef] [Green Version]
  21. Kupchan, S.M.; Tsou, G.; Sigel, C.W. Datiscacin, a novel cytotoxic cucurbitacin 20-acetate from Datisca glomerata. J. Org. Chem. 1973, 38, 1420–1421. [Google Scholar] [CrossRef] [PubMed]
  22. VanWagenen, B.C.; Larsen, R.; Cardellina, J.H.; Randazzo, D.; Lidert, Z.C.; Swithenbank, C. Ulosantoin, a potent insecticide from the sponge Ulosa ruetzleri. J. Org. Chem. 1993, 58, 335–337. [Google Scholar] [CrossRef]
  23. Di, X.; Wang, S.; Oskarsson, J.T.; Rouger, C.; Tasdemir, D.; Hardardottir, I.; Freysdottir, J.; Wang, X.; Molinski, T.F.; Omarsdottir, S. Bromotryptamine and imidazole alkaloids with anti-inflammatory activity from the bryozoan Flustra foliacea. J. Nat. Prod. 2020, 83, 2854–2866. [Google Scholar] [CrossRef] [PubMed]
  24. Takahashi, H.; Kurimoto, S.-i.; Kobayashi, J.i.; Kubota, T. Ishigadine A, a new canthin-6-one alkaloid from an Okinawan marine sponge Hyrtios sp. Tetrahedron Lett. 2018, 59, 4500–4502. [Google Scholar] [CrossRef]
  25. Yagi, H.; Matsunaga, S.; Fusetani, N. Isolation of 1-methylherbipoline, a purine base, from a marine sponge, Jaspis sp. J. Nat. Prod. 1994, 57, 837–838. [Google Scholar] [CrossRef]
  26. BourguetKondracki, M.L.; Martin, M.T.; Guyot, M. A new β-carboline alkaloid isolated from the marine sponge Hyrtios erecta. Tetrahedron Lett. 1996, 37, 3457–3460. [Google Scholar] [CrossRef]
  27. Kimura, J.; Ishizuka, E.; Nakao, Y.; Yoshida, W.Y.; Scheuer, P.J.; Kelly-Borges, M. Isolation of 1-methylherbipoline salts of halisulfate-1 and of suvanine as serine protease inhibitors from a marine sponge, Coscinoderma mathewsi. J. Nat. Prod. 1998, 61, 248–250. [Google Scholar] [CrossRef]
  28. Davis, F.A.; Zhang, Y.; Anilkumar, G. Asymmetric synthesis of the quinolizidine alkaloid (–)-epimyrtine with intramolecular Mannich cyclization and N-sulfinyl δ-amino β-ketoesters. J. Org. Chem. 2003, 68, 8061–8064. [Google Scholar] [CrossRef]
  29. Januar, L.A.; Molinski, T.F. Acremolin from Acremonium strictum is N2,3-Etheno-2’-isopropyl-1-methylguanine, not a 1H-Azirine. Synthesis and Structural Revision. Org. Lett. 2013, 15, 2370–2373. [Google Scholar] [CrossRef] [Green Version]
  30. Kim, C.K.; Song, I.H.; Park, H.Y.; Lee, Y.J.; Lee, H.S.; Sim, C.J.; Oh, D.C.; Oh, K.B.; Shin, J. Suvanine sesterterpenes and deacyl irciniasulfonic acids from a tropical Coscinoderma sp. sponge. J. Nat. Prod. 2014, 77, 1396–1403. [Google Scholar] [CrossRef]
  31. Rosemeyer, H. The chemodiversity of purine as a constituent of natural products. Chem. Biodivers. 2004, 1, 361–401. [Google Scholar] [CrossRef] [PubMed]
  32. Garcia, P.A.; Valles, E.; Diez, D.; Castro, M.A. Marine alkylpurines: A promising group of bioactive marine natural products. Mar. Drugs 2018, 16, 6. [Google Scholar] [CrossRef] [Green Version]
  33. Searle, P.A.; Molinski, T.F. Five new alkaloids from the tropical ascidian, Lissoclinum sp. lissoclinotoxin A is chiral. J. Org. Chem. 1994, 59, 6600–6605. [Google Scholar] [CrossRef]
  34. Miyanaga, A. Michael additions in polyketide biosynthesis. Nat. Prod. Rep. 2019, 36, 531–547. [Google Scholar] [CrossRef]
  35. Salib, M.N.; Hendra, R.; Molinski, T.F. Bioactive bromotyrosine alkaloids from the Bahamian marine sponge Aiolochroia crassa. Dimerization and Oxidative Motifs. J. Org. Chem. 2022, 87, 12831–12843. [Google Scholar] [CrossRef]
  36. Cafieri, F.; Fattorusso, E.; Mangoni, A.; Taglialatela-Scafati, O. Longamide and 3, 7-dimethylisoguanine, two novel alkaloids from the marine sponge Agelas longissima. Tetrahedron Lett. 1995, 36, 7893–7896. [Google Scholar] [CrossRef]
  37. Chehade, C.C.; Dias, R.L.; Berlinck, R.G.; Ferreira, A.G.; Costa, L.V.; Rangel, M.; Malpezzi, E.L.; de Freitas, J.C.; Hajdu, E. 1,3-Dimethylisoguanine, a new purine from the marine sponge Amphimedon viridis. J. Nat. Prod. 1997, 60, 729–731. [Google Scholar] [CrossRef]
  38. Tang, Z.; Ye, W.; Chen, H.; Kuang, X.; Guo, J.; Xiang, M.; Peng, C.; Chen, X.; Liu, H. Role of purines in regulation of metabolic reprogramming. Purinergic Signal. 2019, 15, 423–438. [Google Scholar] [CrossRef]
  39. Wang, Y.; Yang, X.; Zheng, X.; Li, J.; Ye, C.; Song, X. Theacrine, a purine alkaloid with anti-inflammatory and analgesic activities. Fitoterapia 2010, 81, 627–631. [Google Scholar] [CrossRef]
  40. Da Rocha Lapa, F.; da Silva, M.D.; de Almeida Cabrini, D.; Santos, A.R. Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy: Evidence for the role of adenosine A2 receptors. Purinergic Signal. 2012, 8, 693–704. [Google Scholar] [CrossRef] [Green Version]
  41. Lim, H.X.; Hong, H.J.; Jung, M.Y.; Cho, D.; Kim, T.S. Principal role of IL-12p40 in the decreased Th1 and Th17 responses driven by dendritic cells of mice lacking IL-12 and IL-18. Cytokine 2013, 63, 179–186. [Google Scholar] [CrossRef] [PubMed]
  42. Hsu, P.; Santner-Nanan, B.; Hu, M.; Skarratt, K.; Lee, C.H.; Stormon, M.; Wong, M.; Fuller, S.J.; Nanan, R. IL-10 potentiates differentiation of human induced regulatory T cells via STAT3 and Foxo1. J. Immunol. 2015, 195, 3665–3674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Molecules 28 02937 g001 550
Figure 1. Structure of geobarrettin D (1).
Figure 1. Structure of geobarrettin D (1).
Molecules 28 02937 g001
Molecules 28 02937 g002 550
Figure 2. Key 1H-13C HMBC and 1H-15N HMBC correlations for compound 1.
Figure 2. Key 1H-13C HMBC and 1H-15N HMBC correlations for compound 1.
Molecules 28 02937 g002
Molecules 28 02937 g003 550
Figure 3. The effect of geobarrettin D (1) on DC secretion of IL-12p40 and IL-10. DCs were matured and activated with IL-1β, TNF-α and LPS for 24 h in the absence (solvent control (CT)) or presence of geobarrettin D (1) at 10 μg/mL. The concentrations of IL-12p40 and IL-10 in the supernatants were determined by ELISA. The data are presented as SI, i.e., the concentration of each cytokine in the supernatant of cells cultured in the presence of compound 1 divided by the concentration of the cytokine in the supernatant of cells cultured without compound 1. The results are shown as mean ± SEM, n = 3. Different from CT: * p ˂ 0.05.
Figure 3. The effect of geobarrettin D (1) on DC secretion of IL-12p40 and IL-10. DCs were matured and activated with IL-1β, TNF-α and LPS for 24 h in the absence (solvent control (CT)) or presence of geobarrettin D (1) at 10 μg/mL. The concentrations of IL-12p40 and IL-10 in the supernatants were determined by ELISA. The data are presented as SI, i.e., the concentration of each cytokine in the supernatant of cells cultured in the presence of compound 1 divided by the concentration of the cytokine in the supernatant of cells cultured without compound 1. The results are shown as mean ± SEM, n = 3. Different from CT: * p ˂ 0.05.
Molecules 28 02937 g003
Molecules 28 02937 g004 550
Figure 4. Putative biosynthesis of geobarrettin D (1).
Figure 4. Putative biosynthesis of geobarrettin D (1).
Molecules 28 02937 g004
Table
Table 1. 1H NMR (600 MHz) and 13C NMR (150 MHz) spectroscopic data for geobarrettin D (1).
Table 1. 1H NMR (600 MHz) and 13C NMR (150 MHz) spectroscopic data for geobarrettin D (1).
No.δH aδH bδC aδN b1H-13C HMBC a1H-15N HMBC b
N-1′ 10.60 (1H, d, 2.0) 131.3
2′7.57 (1H, s)7.53 (1H, d, 2.0)125.9 C-1″, 3′, 5′, 3a′, 7a′
3′ 113.4
3a′ 125.2
4′7.65 (1H, d, 8.5)7.12 (1H, d, 8.5)120.8 C-3′, 6′, 3a′, 7a′
5′7.24 (1H, dd, 8.5, 1.6)7.45 (1H, dd, 8.5, 1.6)124.2 C-7′, 3a′
6′ 117.0
7′7.60 (1H, d, 1.5)7.61 (1H, d, 1.5)115.9 C-6′, 5′, 3a′
7a′--139.1
N-1″ 47.9 c
2″4.07 (1H, dd, 13.7, 5.9)4.15 (1H, dd, J = 13.7, 6.8 Hz)4.07 (2H, m)69.3 C-2″, 3′, -N(CH3)3N-10
3″6.05 (1H, t, 6.3)6.05 (1H, t, 6.3)45.4 C-1″, 3′, 3a′, 2′, N-10
1″-NMe3.30 (9H, s)3.27 (9H, s)54.8 C-2″, 1″N-3″
N-1
2 154.9
N-3
4 151.0
5 110.0
6 155.0
N-7 156.4 c
89.01 (1H, s)8.81 (1H, s)140.1 C-11, 4, 5N-7, 9
N-9 157.3 c
N-10 96.3 c
114.11 (3H, s)3.84 (3H, s)36.2 C-5, 8N-7
123.91 (3H, s)3.92 (3H, s)32.1 C-4, 8N-9
a Recorded in CD3OD. b Recorded in D2O/H2O (1/9). c 15N δ obtained by indirect detection from 1H-15N HMBC cross peaks.
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MDPI and ACS Style

Di, X.; Hardardottir, I.; Freysdottir, J.; Wang, D.; Gustafson, K.R.; Omarsdottir, S.; Molinski, T.F. Geobarrettin D, a Rare Herbipoline-Containing 6-Bromoindole Alkaloid from Geodia barretti. Molecules 2023, 28, 2937. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28072937

AMA Style

Di X, Hardardottir I, Freysdottir J, Wang D, Gustafson KR, Omarsdottir S, Molinski TF. Geobarrettin D, a Rare Herbipoline-Containing 6-Bromoindole Alkaloid from Geodia barretti. Molecules. 2023; 28(7):2937. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28072937

Chicago/Turabian Style

Di, Xiaxia, Ingibjorg Hardardottir, Jona Freysdottir, Dongdong Wang, Kirk R. Gustafson, Sesselja Omarsdottir, and Tadeusz F. Molinski. 2023. "Geobarrettin D, a Rare Herbipoline-Containing 6-Bromoindole Alkaloid from Geodia barretti" Molecules 28, no. 7: 2937. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28072937

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