Sporothriolide-Related Compounds from the ... - ACS Publications

Note Cite This: J. Nat. Prod. 2017, 80, 2850-2854

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Sporothriolide-Related Compounds from the Fungus Hypoxylon monticulosum CLL-205 Isolated from a Sphaerocladina Sponge from the Tahiti Coast Charlotte Leman-Loubière,† Géraldine Le Goff,† Pascal Retailleau,† Cécile Debitus,‡ and Jamal Ouazzani*,† †

Centre National de la Recherche Scientifique, Institut de Chimie des Substances Naturelles ICSN, Avenue de la Terrasse, 91198 Gif-sur-Yvette, Cedex, France ‡ LEMAR, IRD, CNRS, IFREMER, Université de Bretagne Occidentale, IUEM, Technopole Brest-Iroise, Rue Dumont d’Urville, 29280 Plouzané, France S Supporting Information *

ABSTRACT: Two sporothriolide-related compounds were obtained from an extract of the fungus Hypoxylon monticulosum CLL205, isolated from a Sphaerocladina sponge collected from the Tahiti coast. Compound 2 is a deoxy analogue of sporothric acid (4). Compound 3 is a newly reported unusual scaffold combining sporothriolide (1) and trienylfuranol A (5) moieties, through a Diels−Alderase-type reaction. Various experimental and analytical arguments supported the biocatalytic origin of compound 3. The structures of the isolated compounds were elucidated using 1D and 2D NMR, HRMS, and IR data. The structure and the absolute configuration of 3 were unambiguously confirmed by a single-crystal X-ray diffraction analysis.

Hypoxylon is an ascomycete belonging to the fungal Xylariaceae family with more than 130 species reported so far.1 Hypoxylon colonizes various marine and terrestrial habitats and produces a large variety of bioactive compounds including sporothriolide (1).1−4 Sporothriolide belongs to the furofurandiones family of natural compounds, first published in 1994.2 This compound exhibits antifungal activity and benefits from substantial synthetic efforts.5−8 In this study, we report the complete structural characterization of deoxysporothric acid (2) and a new sporothriolide scaffold derivative, 3. The fungus Hypoxylon monticulosum CLL-205 was isolated from a Sphaerocladina sponge collected in the cave of Ti-Pari Tahiti (France).9 The strain was identified on the basis of an ITS gene sequence analysis. H. monticulosum CLL-205 was cultivated in potato dextrose broth (PDB) for 5 days. Ethyl acetate extraction gives 300 mg/L of extract. The extract was fractionated by flash chromatography and semipreparative HPLC, yielding sporothriolide (1) and compounds 2 and 3.

CHCl3) confirmed that the absolute configuration was the same as previously reported for sporothriolide (1).2 Compound 2 was obtained as a white powder. Its molecular formula, C13H20O4, was deduced by HRESIMS with m/z 241.1436 [M + H]+. The 1H and 13C NMR spectra of compound 2 closely resemble the NMR data of the previously described sporothric acid (4).3 The main difference between 1 H NMR data of 4 and 2 was the presence of two nonequivalent protons at δH 2.56 (H-5a) and 2.01 (H-5b), instead of a CH group with a proton at δH 4.30.3 This observation, together with the comparison of molecular formulas, suggested the lack of a hydroxy group in 2 compared to 4.3 Moreover, the 13C NMR data of 2 and 4 were also very similar except for the C-5 at δC 35.7 in compound 2. This is supported by COSY correlations between H-5 and H-6 (δH 4.43)/H-2 (δH 3.68) together with HMBC correlations between H-5/H-2 and C-1, H-2 and C-4/C-13 and between H-2/H-5 and C-3 (Figure 1). The relative configuration of compound 2 was established on the basis of an ROE correlation between H-6 and H-2. The two protons are in the cis configuration as in sporothric acid (4) (Figure 1). This supported the hypothesis that the absolute configuration of compound 2 could be 2R, 6R, corresponding to 2-[(2R,6R)-6hexyl-2-oxotetrahydrofuran-3-yl]acrylic acid.

Sporothriolide (1) was identified based on HRESIMS and NMR data. Both 1H and 13C NMR data were identical to those reported by Krohn et al.2 Moreover, an [α]D −154 (c 0.5, © 2017 American Chemical Society and American Society of Pharmacognosy

Received: August 21, 2017 Published: October 18, 2017 2850

DOI: 10.1021/acs.jnatprod.7b00714 J. Nat. Prod. 2017, 80, 2850−2854

Journal of Natural Products

Note

presence of two lactonic ester groups. The absorption band at 1059 cm−1 was assigned to the C−C−O stretching vibration of a secondary alcohol. The 13C NMR revealed the presence of 24 carbons attributed by 1H−13C EDT-HSQC to two methyl carbons (δC 21.7 and 14.2), eight aliphatic methylene groups (δC 42.6, 31.7, 29.1, 28.9, 25.5, 22.5, 22.7, and 20.9), 11 methine groups including five oxygen-bond methines at δC 83.3 (C-20), 81.2 (C-6), 78.2 (C-5), 74.8 (C-21), and 74.3 (C-23), four methines involved in double bonds at δC 131.6 (H-18), 131.5 (H-19), 129.4 (C-15), and 124.0 (C-16), and two lactonic ester groups at δC 177.0 (C-4) and 171.8 (C-1), and a spiro carbon at δC 51.0 (C-3). The nJ1H−13C connectivities given by an HMBC NMR experiment are listed in Table 1. The 1H NMR spectrum of compound 3 revealed the presence of a triplet corresponding to a methyl group at δH 0.89 (H-12) and five CH2 signals typical of a hexyl side chain. We observed two oxygenated CH groups at δH 5.10 (H-5) and 4.45 (H-6) and one CH group at δH 3.32 (H-2). The COSY correlations between H-2 and H-5, H-5 and H-6, and H-6 and H-7 together with HMBC correlations between H-5 and C-1 and between H-2 and C-1/C-3/C-4 enabled us to form the bisγ-lactone ring. All of these structural components are similar to those of sporothriolide 1. Contrary to 1, 13C NMR data of 3 indicated the presence of a spiro carbon at δC 51.0 (C-3). The C-3 carbon is part of a sixmembered ring deduced from the sequential COSY correla-

Figure 1. Key COSY, HMBC, and NOESY correlations for compound 2.

Compound 3 was obtained as a white powder. The molecular formula C24H34O6 was deduced by HRESIMS with ions at m/z 419.2423 [M + H]+ and 441.2250 [M + Na]+. The molecular formula indicates eight degrees of unsaturation. Based on the following spectroscopic data, these degrees of unsaturation corresponded to two γ-lactones, two double bonds, one six-membered-ring moiety, and one tetrahydrofuran moiety. Characteristic IR bands at 1770 cm−1 suggested the Table 1. NMR Spectroscopic Data of Compounds 2 and 3 compound 2

a

position

δC, type

1 2 3 4 5

176.1, C 44.8, CH 135.8, C 169.8, C 35.7, CH2

6 7

79.3, CH 35.5, CH2

8 9 10 11 12 13

25.3, CH2 29.1, CH2 31.8, CH2 22.7, CH2 14.2, CH3 131.4, CH2

compound 3

δH mult (J in Hz)

HMBCb

3.68, dd (8.9, 12.0)

1, 3, 4, 5, 13

2.56, m 2.01, q (10.5) 4.43, m 1.82, m 1.65, m 1.48, m 1.33, m 1.28, m 1.30, m 0.89, t (6.9) 6.54, s 5.95, s

δC, type

1, 3

171.8, C 50.6, CH 51.0, C 177.0, C 78.2, CH

8 5, 6, 8, 9

81.2 CH 28.9, CH2

7, 10 8, 10 7, 8, 9 10, 12 11 2, 3, 4, 5

25.5, 29.1, 31.7, 22.7, 14.2, 20.9,

CH2 CH2 CH2 CH2 CH3 CH2

14

22.5, CH2

15 16 17

129.4, CH 124.0, CH 45.5, CH

18 19 20 21 22

131.6, CH 131.5, CH 83.3, CH 74.8, CH 42.6, CH2

23 24

74.3, CH 21.7 CH3

δH mult (J in Hz) 3.32, d (5.3)

HMBCb 1, 3, 4, 17

5.10, dd (3.5, 5.3)

1, 4, 6

4.45, m 1.91, m 1.82, m 1.45, m 1.37, m 1.30, m 1.30, m 0.89, t (6.8) 2.00, m

5, 8 6, 8, 9

2.62, m 2.27, m 5.94, m (11.0) 5.63, m (11.0) 2.76, br t (5.8)

15, 16

5.64, m (15.6) 5.64, m (15.6) 4.16, t (4.8) 4.30, m 2.39, m 1.55, m 3.94, sext (6.3) 1.34, d (6.2)

6, 9 8, 10 9, 11 12 10, 11 3, 4, 15, 17

13, 14, 17 3, 14, 17, 18 3, 13, 15, 16, 18, 19 16, 17, 20 17, 20 19, 21, 23 20, 23 20, 21, 23, 24

22, 23

Data acquired in CDCl3 at 500 MHz for 1H NMR and 125 MHz for 13C. bHMBC correlations are from the proton(s) to the indicated carbon(s). 2851



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tions from H-13 to H-17 through H-14/H-15/H-16 and the key HMBC correlations between H-13 and C-3 and from H-2 to C-17 (Figure 2). The coupling constant of 15.6 Hz between

Figure 4. Proposed biogenetic pathway to compound 3.

despite intensive analytical efforts and daily sampling, we did not detect free trienylfuranol A. Furthermore, compound 3 was detected directly and after lyophilization of the cultivation broth, by HPLC-MS analysis; the HPLC profile is similar to the one that was obtained after the extraction process. During the cultivation step the temperature was 27 °C and the pH monitoring indicated values around 6. These conditions are not consistent with chemical Diels−Alder catalysis and support a Diels−Alderase-catalyzed condensation. Sporothriolide (1) was reported as an antifungal compound but was inactive on Gram+ B. subtilis and Gram− E. coli bacteria. The compound was also reported as noncytotoxic on HCT-116, CHO-K1, and U-2 OS cancer cell lines.3 In the context of our continuing efforts to identify potential bioactive agents, we submitted compounds 1−3 to a series of bioassays, including antibiotic activity and cytotoxicity against HCT-116 (human colon carcinoma), PC-3 (prostate cancer cell lines), and MCF-7 (breast cancer cell line). We also investigated the inhibition of two cosmeceutical enzyme targets, elastase and hyaluronidase.15,16 For the three compounds, no antibacterial activity was detected against B. subtilis, M. luteus, and E. coli. Compound 3 was not cytotoxic, and compound 2 exhibited an IC50 of 18 μM on the HCT-116 cell line. Sporothriolide (1) exhibited IC50 values of 7.1 μM for HCT-116, 6.4 μM for PC-3, and 4 μM for the MCF-7 cell line. These results are different from those reported in the literature, in which 1 was reported as noncytotoxic.3 Compound 3 inhibits hyaluronidase with an IC50 of 300 μM on the order of the positive control glycyrrhizin (IC50 = 320 μM). Due to the emerging role of hyaluronidases in cancer therapy, compound 3 deserves further biological investigation.17,18

Figure 2. Key COSY, HMBC, and NOESY correlations for compound 3.

H-18 and H-19 indicated an E configuration for the C-18/C-19 double bond. The double bond was connected to the sixmembered ring through C-17, according to the COSY correlation between H-17 and H-18. The HMBC correlations between H-18 and C-16 and between H-17 and C18/C-19 confirmed this connection (Figure 2). The tetrahydrofuran moiety was deduced from the COSYbased spin system from H-20 to H-24 signals. The ring closure was based on the HMBC correlation between H-20 and C-23. The chemical shifts of C-20 (δC 83.3) and C-23 (δC 74.3) showed that both were connected to an oxygen atom. Finally, the chemical shift of C-21 (δC 74.8) suggested the presence of a hydroxy. The heterocycle was linked to the C-18/C-19 double bond using the COSY correlation between H-20 and H-19 and the HMBC correlation between H-20 and C-19. The structure and absolute configuration of 3 were unambiguously confirmed by a single-crystal X-ray diffraction experiment (Figure 3). Compound 3 was named sporochartine A.

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations [α]D were measured using an Anton Paar MCP-300 polarimeter. IR spectra were obtained using a PerkinElmer BX FT-IR spectrometer. Melting points were measured using a Buchi B540 melting point apparatus. NMR experiments were performed using a Bruker Avance 500 MHz spectrometer. All the spectra were acquired in CDCl3 (δH 7.26; δC 77.23) at room temperature. High-resolution mass spectra were obtained on a Waters LCT Premier XE spectrometer equipped with an ESI-TOF (electrospray-time-of-flight) by direct infusion of the purified compounds. Preparative HPLC was performed using Waters modules consisting of an autosampler 717, a pump 600, a photodiode array detector 2996, and an evaporative light-scattering detector ELSD 2420. Redisep prepacked silica gel columns were used for flash chromatography using a Combiflash-Companion chromatogram (Serlabo). All other chemicals and solvents were purchased from SDS (France). Animal Material. The Sphaerocladina sponge was collected on December 17, 2015, from the coast of Tahiti (9°45.421′ S, 139°08.275′ W) at 20 m depth. Identification was performed by Andrzej Pisera and collaborators.19

Figure 3. Single-crystal X-ray structure of 3.

Based on the structure of sporothriolide (1) and the recently reported structure of trienylfuranol A (5) isolated from a different Hypoxylon species,12 we suggest a hypothetical biogenetic pathway to compound 3 involving a “spiro” Diels−Alderase reaction (Figure 4).13,14 The formation of compound 3 through a purely chemical interaction between sporothriolide 1 and trienylfuranol A (5) is unlikely. Thus, 2852



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structure factors along with the observed one. The final R1 factors for all data (respectively better than 2σ(I)) went down from 0.181 to 0.136 (respectively from 0.126 to 0.078). Finally the assignment of the absolute configuration constituted a challenging goal to pursue because of the weak anomalous signal (less than half of the unique reflections are above 2σ(I)), which led to a meaningless Flack parameter. The 2077 Friedel opposites (91% of coverage) were, however, kept unmerged to perform a Bijvoet analysis using likelihood methods. Given the enantiopurity of this natural product, the presence of the (1S,2S,3a′S,6′R,6a′R)-6′-hexyl-2-((E)-2-((2S,3S,5R)-3-hydroxy5-methyltetrahydrofuran-2-yl)vinyl)-6′,6a′-dihydro-2′H-spiro[cyclohexane-1,3′-furo[3,4-b]furan]-3-ene-2′,4′(3a′H)-dione inside the crystal (and also in the bulk) was likely. Indeed, the calculated probability that the structure was inverted was smaller than 1 × 10−6, and the value of the absolute structure parameter y, −0.06(17), also seemed unambiguous. Crystallographic data for compound 3 have been deposited with the Cambridge Crystallographic Data Centre under the following deposit number: CCDC 1562128. Copies of these data can be obtained free of charge on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44) 1223-336033; e-mail: deposit@ ccdc.cam.uk). Cytotoxicity Assays. A tetrazolium dye [3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide; MTT]-based colorimetric assay was used to measure the inhibition on the proliferation of the tumor cell lines HCT-116 (human colon carcinoma), PC-3 (prostate cancer cell line), and MCF-7 (breast cancer cell line). The tested compounds were formulated in DMSO and added to the cells such that the final DMSO concentration ranged from 1% to 3%. Cells were grown in DMEM medium supplemented with 10% fetal calf serum (Invitrogen), in the presence of penicillin, streptomycin, and fungizone, plated in 96well microplates. After 24 h of growth, cells were treated with target compounds from 100 μM to 10 nM. After 72 h, MTS reagent (Promega) was added, and the absorbance was monitored (490 nm) to measure the inhibition of cell proliferation compared to untreated cells. IC50 determination experiments were performed in separate duplicate experiments.

Fungal Strain Identification and Cultivation. Hypoxylon monticulosum CLL205 was isolated from a Sphaerocladina sponge and grown at 27 °C on PDB medium (DIFCO). The ITS rDNA gene amplification and sequencing were performed, and the sequence was submitted to the NCBI/BLAST database (GenBank). The primers used for PCR amplification were ITS1 F: CTT GGT CAT TTA GAG GAA GTA A (Tm: 55 °C) and ITS4: TCC TCC GCT TAT TGA TATGC (Tm: 53 °C). The GenBank accession number for the Hypoxylon monticulosum CLL205 sequence is SUB2477083 25758633.seq KY744359. Hypoxylon monticulosum CLL205 was cultivated in a 2 L Erlenmeyer flask containing 1 L of PDB medium (DIFCO) over 5 days in a rotary shaker at 27 °C and 130 rpm. Compound Isolation. The culture broth was exhaustively extracted with EtOAc (3 × 500 mL). The solvent was concentrated to dryness in vacuo. The extract (300 mg) was submitted to flash chromatography on a Combiflash Companion using a Redisep 12 g silica column, eluting with a heptane−EtOAc mixture. The fractions containing sporothriolide (1) and compounds 2 and 3 were further purified by preparative reversed-phase HPLC (Sunfire Prep C18 5 μm, 10 × 250 mm) eluting with an isocratic H2O−CH3CN (4/6) mixture supplemented with 0.1% formic acid. After concentration in vacuo, sporothriolide (30 mg) was obtained as white needles, while compounds 2 (8 mg) and 3 (13 mg) were obtained as white powders. Sporothriolide (1): white needles; [α]25D −154 (c 0.5, CHCl3) (lit. −144 (c 3.3, CHCl3 );3 NMR data, Table S28 (Supporting Information); HRESIMS m/z 239.1271 [M + H]+ (calcd for C13H18O4, 239.1283). Deoxysporothric acid (2): white powder; [α]25D +18 (c 0.37, CHCl3); IR νmax 2956, 2927, 2858, 1756, 1700, 1630, 1204, 1189 cm−1; NMR data, Table 1; HRESIMS m/z 241.1436 [M + H]+ (calcd for C13H20O4, 241.1440). Sporochartine A (3): white needles, mp 86.5−87.9 °C; [α]25D −57 (c 0.5, CHCl3); IR νmax 3521, 2929, 2859, 1770, 1452, 1304, 1175, 1059 cm−1; NMR data, Table 1; HRESIMS m/z 419.2433 [M + H]+ (calcd for C15H26N3O2, 419.2433). X-ray Structure Determination of Compound 3. The crystal structure presented herein was solved from a colorless needle-like single crystal, isolated in Paratone oil from the bulk of 3, crystallized by slow evaporation in butanol. It was then mounted on a nylon loop for data collection under a low-temperature nitrogen flow of 193(2) K. Xray diffraction data were recorded using a Rigaku MM007 HF copper rotating-anode generator, equipped with Osmic confocal optics and a Rapid II curved image plate, to enhance as much as possible the weak crystal diffraction. A total of 83 images of 10-degree oscillations and 72 s exposures per degree were measured according to a ω-scan profile data strategy, derived by the CrystalClear SM Expert software package. Intensities were reduced and merged after empirical absorption correction as well as correction for Lorentz and polarization effects, using CrystalClear. The structure was solved by new intrinsic phasing methods (SHELXT) and refined on F2 by means of full-matrix leastsquares methods (SHELXL-2016/6). Four disagreeable unique reflections due to beamstop shading were discarded. All non-hydrogen atoms were refined anisotropically, whereas hydrogen atoms were first located in Fourier differences but then refined using a riding model. The ORTEP drawing was made using ORTEP-III as implemented within PLATON. Compound 3 crystallizes in the Sohncke space group P21 with one molecule in the asymmetric unit, adopting a Vshaped conformation stabilized by an intramolecular hydrogen bond between the hydroxy group of the tetrahydrofuran and one carbonyl group of the central heterotricycle (d O26···O18, 3.081(8) Å). This molecular conformation allows a crystalline arrangement around the 2fold screw axis at a central position in the unit cell 0, 1/2, 0, with direction [0, 1, 0], creating infinitely large solvent channels running along the b crystallographic axis that can host solvent molecules (see Figure S28 made with Mercury10). The SQUEEZE procedure of Spek and van der Sluis11 was therefore used to model extra electron density that was too diffuse: 76 e/cell were indicated, this being potentially related to the floating presence of 1.8 molecules of butanol per unit cell. This was included in the formula, formula weight, calculated density, μ, and F(000) in the deposited cif file, as well as the modified

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.7b00714. Detailed experimental procedures; physicochemical properties; 1D and 2D NMR, MS, and IR spectra of the reported compounds, and X-ray data for compound 3, protocols for antibacterial, elastase, and hyaluronidase essays (PDF) Crystallographic data for compound 3 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*Tel: +33 1 69 82 30 01. Fax: +33 1 69 07 72 47. E-mail: jamal. [email protected]. ORCID

Jamal Ouazzani: 0000-0003-4483-6638 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the TASCMAR project, funded by the European Union’s Horizon 2020 Research & Innovation Programme under grant agreement no. 634674. The authors are grateful to the CIBI Platform of CNRS-ICSN for cytotoxicity assays (J. Bignon & H. Levaique). We thank the 2853



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French and French-Polynesian governments for their support in the sponge survey from French Polynesia (project Biopolyval), IRD for funding the R/V Alis fieldtrip, L. Hertrich (Tahiti Iti Diving) for his help in the exploration of the cave, and A. Pisera (Polish Academy of Sciences, Institute of Paleaobiology) for the sponge identification.19

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REFERENCES

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Sporothriolide-Related Compounds from the ... - ACS Publications

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