Note pubs.acs.org/jnp

Cytotoxic Alkylated Hydroquinone, Phenol, and Cyclohexenone Derivatives from Aspergillus violaceofuscus Gasperini Yusuke Myobatake,†,∥ Kenji Takemoto,†,∥ Shinji Kamisuki,† Natsuki Inoue,‡ Ayato Takasaki,† Toshifumi Takeuchi,† Yoshiyuki Mizushina,§,⊥ and Fumio Sugawara*,† †

Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba 278-8510, Japan Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan § Laboratory of Food & Nutritional Sciences, Faculty of Nutrition, Kobe Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan ⊥ Cooperative Research Center of Life Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Hyogo 650-8586, Japan ‡

S Supporting Information *

ABSTRACT: New alkylated hydroquinones violaceoid A (1), violaceoid B (2), and violaceoid C (3), an alkylated phenol violaceoid D (4), and a cyclohexenoid violaceoid E (5) were isolated from a culture broth of Aspergillus violaceofuscus Gasperini isolated from moss. The structures were identified by interpretation of spectroscopic data (1D and 2D NMR, MS, and IR). Two known compounds, the cyclohexenoid 6 and eupenoxide (7), were also isolated. Compound 6 was isolated for the first time as a natural product and named violaceoid F. Isolated compounds were tested for cytotoxic activity against five human cancer cell lines and a mouse macrophage cell line. Violaceoid A was the most potent of the seven compounds against all cell lines. Violaceoid C and D exhibited cytotoxicity against the leukemia cell lines with LD50 values 5.9−8.3 μM, while violaceoid F was found to be cytotoxic against HCT116 and RAW264.7 with LD50 values of 6.4 and 6.5 μM, respectively. These results demonstrate that violaceoid derivatives are a new class of cytotoxic hydroquinones with a hydroxymethyl and a linear alkyl substituent.

B

activity relationship using the hydroquinone, phenol, and cyclohexanoid derivatives are presented. Repeated separation of a culture extract from A. violaceofuscus Gasperini using silica gel or reverse-phase C18 column chromatography yielded compounds 1−7. The molecular formula of C14H20O3 for compound 1 was determined by HRESIMS. The IR spectrum showed the presence of a hydroxy group (3404 and 3209 cm−1). The 1H and 13C NMR spectra established the presence of a disubstituted hydroquinone, as shown in Table 1. HMBC correlations from H-7 (δ 4.72) to C1 (δ 125.9), C-2 (δ 127.6), and C-6 (δ 150.6) suggested that a hydroxymethyl group was connected at C-1 of hydroquinone. Two proton resonances at δ 6.45 (H-1′) and 6.06 (H-2′) with the coupling constant (J1′−2′ = 16.1 Hz) indicated the presence of E-olefin, and consecutive 1H−1H COSY correlations from H-1′ to H-7′ revealed the presence of a 1-heptenyl side chain. The HMBC spectrum showing the correlations from H-1′ to C-1, C-2, and C-3 (δ 148.8) supported the location of the 1heptenyl side chain at C-2 of hydroquinone; thus, the structure of compound 1 was determined (Figure 1), and it was named violaceoid A.

ioactive secondary metabolites derived from fungi have yielded some of the most important natural products for the pharmaceutical industry,1 including antibiotics (e.g., penicillin),2 immunosuppressants (e.g., cyclosporin A),3 and cholesterol-lowering agents (e.g., compactin).4 The hypothesis that there are 5.1 million species of fungi on the Earth, of which only about 99 000 have been reported in the literature, implies that more than 98% of fungal species are still unknown.5 Both their biodiversity and their ability to produce unique compounds make fungi a most attractive source to screen for novel bioactive secondary metabolites for drug discovery. In the past, we have focused on fungi isolated from seaweed, mosses, and other plants and isolated new and known compounds to construct a natural products library. Screening our library for bioactive compounds resulted in the discovery of DNA polymerase inhibitors,6 cytotoxins,7 a neuroprotective compound,8 and antihepatitis C virus agents.9 In this study, we report the isolation, structural elucidation, and biological activities of new alkylated hydroquinones violaceoid A (1), violaceoid B (2), and violaceoid C (3), an alkylated phenol violaceoid D (4), and a cyclohexenoid violaceoid E (5). Two known compounds, violaceoid F (6) and eupenoxide (7), are also described. Isolated metabolites were evaluated for their cytotoxicity against six cell lines, and preliminary structure− © 2014 American Chemical Society and American Society of Pharmacognosy

Received: December 7, 2013 Published: May 1, 2014 1236

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Table 1. 1H (400 MHz) and 13C (100 MHz) NMR Spectroscopic Data for Compounds 1−5 1a position

δC, type

1 2 3

125.9, C 127.6, C 148.8, C

4

116.3, CH 115.0, CH 150.6, C 58.5, CH2 124.6, CH 137.9, CH 34.9, CH2 30.3, CH2 32.7, CH2 23.6, CH2 14.4, CH3

5 6 7 1′ 2′ 3′ 4′ 5′ 6′ 7′ a

δH (J in Hz)

2a δC, type

δH (J in Hz)

125.1, C 130.4, C 150.05, C 6.60, d (8.7) 6.54, d (8.7)

4.72, s

117.5, CH 115.8, CH 150.14, C 56.6, CH2

6.57, d (8.7) 6.59, d (8.7)

38.2, CH2 27.2, CH2

1.55, m

30.3, CH2

1.33, m

1.37, m

33.1, CH2

1.33, m

1.37, m

23.7, CH2

1.33, m

0.93, t (7.1)

14.4, CH3

0.89, t (6.8)

72.0, CH

δC, type

4b

δH (J in Hz)

126.6, C 130.7, C 149.2, C

4.71, d (11.7) 4.68, d (11.7) 5.15, dd (9.0, 4.6) 1.89, m 1.71, m

6.45, dt (16.1, 1.5) 6.06, dt (16.1, 6.9) 2.24, tdd (6.9, 6.9, 1.5) 1.51, m

3a

116.1, CH 114.0, CH 150.4, C 57.7, CH2 27.2, CH2 31.7, CH2 31.1, CH2 30.4, CH2 33.1, CH2 23.7, CH2 14.5, CH3

6.57, d (8.6) 6.49, d (8.6)

4.69, s 2.67, t (7.9) 1.50, m 1.37, m 1.37, m 1.31, m 1.31, m 0.90, t (6.8)

δC, type 123.2, C 142.8, C 118.1, CH 129.1, CH 115.8, CH 156.2, C 58.0, CH2 71.7, CH 37.9, CH2 26.1, CH2 29.2, CH2 31.7, CH2 22.6, CH2 14.1, CH3

δH (J in Hz)

6.89, d (7.9) 7.13, dd (7.9, 7.9) 6.75, d (7.9)

4.85, d (12.8) 4.75, d (12.8) 4.71, dd (7.6, 6.0) 1.74, m 1.65, m 1.36, m 1.27, m 1.27, m 1.27, m 1.27, m 0.87, t (6.9)

5a δC, type 133.7, C 152.1, C 68.6, CH 71.4, CH 41.5, CH2 198.9, C 54.5, CH2 127.9, CH 143.2, CH 35.0, CH2 29.8, CH2 32.6, CH2 23.6, CH2 14.4, CH3

δH (J in Hz)

4.53, brd (3.7) 4.17, ddd (3.9, 3.7, 3.3) a, 2.92, dd (16.7, 3.3) b, 2.47, ddd (16.7, 3.9, 1.0) 4.44, d (11.4) 4.38, d (11.4) 6.74, d (15.8) 6.57, dt (15.8, 7.0) 2.31, m 1.52, m 1.36, m 1.36, m 0.92, t (7.1)

In CD3OD. bIn CDCl3.

that 3 possessed a saturated heptyl side chain. Thus, the structure of compound 3 (violaceoid C) was determined (Figure 1). The molecular formula of C14H22O3 for compound 4 was determined by HRESIMS and was one oxygen atom less than compound 2. The 1H NMR spectrum of compound 4 was similar to that of 2, except for the presence of an additional aromatic proton at H-3 (δ 6.89) in 4. The 13C NMR, HMQC, and HMBC spectra revealed that methine carbon at C-3 (δ 118.1) was substituted for a carbon adjacent to the oxygen at C3 in compound 2 (Figure 2). The structure of compound 4 was determined (Figure 1), and it was named violaceoid D.

Figure 1. Structures of compounds 1−7.

The molecular formula of C14H22O4 for compound 2 was determined by HRESIMS. As shown in Table 1, the 1H and 13C NMR spectra suggested that the structure of compound 2 was similar to compound 1, except for C-1′ and C-2′ of their side chains. Two olefinic proton signals of H-1′ and H-2′ in compound 1 was replaced by those of H-1′ (δ 5.15) and H-2′ (δ 1.89 and δ 1.71) in compound 2, suggesting the presence of C-1′ alcohol, in agreement with the HRESIMS results, which identified an additional oxygen atom in the molecular formula. Thus, the structure of compound 2 (violaceoid B) was elucidated (Figure 1) and was further confirmed by DEPT, 1 H−1H COSY, HMQC, and HMBC experiments. The molecular formula of C14H22O3 for compound 3 was determined by HRESIMS and was found to differ from that of compound 1 by two hydrogen atoms. The 1H NMR spectrum of compound 3 was similar to that of 1, except for the presence of two aliphatic protons at H-1′ (δ 2.67) and H-2′ (δ 1.50) in 3 and the absence of the olefinic protons in 1. The data indicated

Figure 2. Key HMBC and 1H−1H COSY correlations of compounds 1 and 4.

The molecular formula of C14H22O4 for compound 5 was determined by HRESIMS. The IR spectrum indicated the presence of a hydroxyl (3371 cm−1) and a conjugated carbonyl (1658 cm−1) group. The 1H and 13C NMR spectra were similar to those of eupenoxide (7), except for the signals corresponding to the epoxy methine. The 1H−1H COSY correlations between H-3 (δ 4.53) and H-4 (δ 4.17) and 1237

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between H-4 and H-5 (δ 2.47 and δ 2.92) suggested that −CH(OH)−CH(OH)−CH2 − was the partial structure (Figure 3). The structure of compound 5 was further confirmed

rotation data of compound 7 were in complete agreement with those of (+)-eupenoxide,10 but not with those of 3′,4′dihydrophomoxide; therefore, 7 was identified as (+)-eupenoxide. Compounds 1−7 were evaluated for their in vitro cytotoxicity against five human cancer cell lines, including cervix (HeLa), breast (MCF-7), T cell leukemia (Jurkat), acute lymphoblastic leukemia (MOLT-4), and colon carcinoma (HCT116), and a mouse macrophage cell line (RAW264.7), according to a procedure described previously.14 The LD50 values determined are shown in Table 2. Compound 1 exhibited the strongest cytotoxicity of the seven compounds against all cell lines tested. The inhibitory effects of compounds 2−4, which lack the olefin group on the side chain, were weaker than that of 1, suggesting the conjugated double bond of 1 is likely to be important for cytotoxicity. Interestingly, compound 3 and 4 strongly suppressed the proliferation of only two leukemia cell lines, Jurkat and MOLT-4, with LD50 values in the range of 5.9−8.3 μM; compound 2 did not suppress proliferation in these two cell lines. Compound 5 and eupenoxide (7) were found to be inactive against all cell lines (LD50 > 100 μM), whereas compound 6 exhibited significant cytotoxicity against HCT116 and RAW264.7 with LD50 values of 6.4 and 6.5 μM, respectively. These results suggested that α,β-unsaturated ketone and epoxy groups of 6 were important for cytotoxicity against these cell lines. Although many cytotoxic prenylated hydroquinones have been isolated from natural sources,15 to our knowledge, violaceoid derivatives are a new class of cytotoxic hydroquinones with a hydroxymethyl and a linear alkyl substituent.

Figure 3. Key HMBC, 1H−1H COSY, and NOESY correlations of compound 5.

by DEPT, HMQC, and HMBC experiments (Figure 3). The relative configuration of compound 5 was determined by 1 H−1H coupling constants and NOESY correlations. The gauche relationships of H-5a/H-4 and H-5b/H-4 were deduced from the coupling constants (J4,5a = 3.3 Hz and J4,5b = 3.9 Hz, respectively), indicating the orientation of H-4 is pseudoequatrial. The gauche relationship of H-4/H-3 was determined from the coupling constant (J3,4 = 3.7 Hz) and the NOE correlation between H-3 and H-5b, suggesting the orientation of H-3 is pseudoaxial (Figure 3). Thus, the structure of compound 5 was determined (Figure 1), and it was named violaceoid E. Due to the unstable nature and shortage of materials, the absolute configurations of violaceoid B, D, and E still remain to be determined. NMR and MS analysis suggested that compound 6 is an oxidative form of eupenoxide (7) and has a ketone group at C6. This compound was previously reported as an intermediate in the enantioselective total synthesis of eupenoxide, and the NMR, MS, and optical rotation data listed in the literature were in complete agreement with our data for 6.10 Thus, the structure of compound 6 was confirmed (Figure 1). Compound 6 was isolated for the first time as a natural product and named violaceoid F. NMR and MS spectroscopic analysis of major metabolite 7 revealed its structure, as shown in Figure 1. Previously, eupenoxide11,12 and its stereoisomer, 3′,4′-dihydrophomoxide12,13 were isolated from a natural source, and their absolute configurations were determined by comparison of spectroscopic data from synthetic samples.10 NMR, MS, and optical



EXPERIMENTAL SECTION General Experimental Procedures. Optical rotations were recorded on a JASCO P-1010 digital polarimeter at room temperature. UV spectra were obtained on a Hitachi U3210 spectrophotometer. Infrared spectra (IR) were recorded on a HORIBA FREEXACT-II FT-720 spectrometer and were reported as wave numbers (cm−1). 1H and 13C NMR spectra were recorded on a Bruker 400 MHz spectrometer (Avance DRX-400) using CDCl3 or methanol-d4 solution (with TMS for 1H NMR and CDCl3 or methanol-d4 for 13C NMR as an internal reference). Chemical shifts are expressed in δ (parts per million) relative to TMS or residual solvent resonance, and coupling constants (J) are expressed in hertz. Mass spectra (MS) were obtained on an Applied Biosystems mass spectrometer (APIQSTAR) pulsar (i) under conditions of high resolution, using poly(ethylene glycol) as the internal

Table 2. LD50 of Compounds on the Proliferation of Human Cancer Cell Lines and a Mouse Macrophage Cell Line LD50 value (μM)a compounds

HeLa

MCF-7

Jurkat

MOLT-4

HCT116

RAW264.7

1 2 3 4 5 6 7 Gemcitabine

24.6 ± 3.0 >100 77.6 ± 7.8 64.2 ± 6.9 >100 77.8 ± 8.6 >100 0.023 ± 0.0022

14.8 ± 1.7 >100 93.0 ± 9.9 >100 >100 75.0 ± 8.2 >100 0.004 ± 0.0004

3.1 ± 0.4 >100 8.2 ± 0.9 8.3 ± 0.9 >100 20.0 ± 2.2 >100 0.012 ± 0.0015

3.0 ± 0.3 >100 5.9 ± 0.6 6.2 ± 0.6 >100 11.2 ± 1.0 >100 0.008 ± 0.0010

5.8 ± 0.6 69.7 ± 6.8 61.8 ± 6.2 66.0 ± 6.9 >100 6.4 ± 0.7 >100 0.005 ± 0.0005

5.6 ± 0.7 55.4 ± 6.3 20.1 ± 2.3 26.2 ± 3.0 >100 6.5 ± 0.7 >100 0.005 ± 0.0006

The five human cancer cell lines and a mouse macrophage cell line, RAW264.7, were incubated with each compound for 24 h. Cell viability was determined using the WST-1 assay; data, mean ± SD (n = 5). a

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Cell Culture and Measurement of Cell Viability. Human cancer cell lines, including cervix (HeLa), breast (MCF-7), T cell leukemia (Jurkat), acute lymphoblastic leukemia (MOLT-4), and colon carcinoma (HCT116), and a mouse macrophage cell line, RAW264.7, were obtained from the American Type Culture Collection (Manassas, VA, U. S. A.). These cells were cultured in McCoy’s 5A medium supplemented with 10% fetal bovine serum, penicillin (100 units/mL), and streptomycin (100 μg/mL) at 37 °C in a humid atmosphere of 5% CO2/95% air. For the cell viability assay, cells were plated at 1 × 104 into each well of a 96-well microplate with various concentrations of the test compound and cultured for 24 h. Cell viability was determined using the WST-1 assay.14 Gemcitabine (2′,2′-difluoro-2′-deoxycytidine, dFdC),16 which is widely used to treat a variety of cancers, was used as a control.

standard. Analytical TLC was carried out on precoated silica gel 60 F254 plates (Merck, Germany). Isolation and Cultivation of Fungi. Wild mosses was collected in Arashiyama, Kyoto, Japan and suspended in sterilized H2O. The suspension was placed on potato dextrose agar (PDA) plates (Difco & BBL, NJ, U. S. A.), and the plates were incubated for 1−2 weeks at 37 °C. Fungi growing on this plate were transferred onto individual PDA plates and cultured. Cultures were repeated 2 to 5 times to obtain pure mycelium strains. The fungus producing the new compounds reported here was identified as Aspergillus violaceofuscus Gasperini (Aspergillus japonicus Saito) by Techno Suruga Laboratory Co., Ltd. (Shizuoka, Japan). The ITS-5.8S rDNA and calmodulin sequences of this strain showed 100% and 99.9% identity with A. violaceofuscus CBS 123.27 (GenBank accession number FJ491678) and A. violaceofuscus CCF4079 (GenBank accession number FR751423), respectively. Extraction and Purification of Compounds. The isolated fungal strain was cultured by transferring a small agar piece from the culture plate into four 2-L Erlenmeyer flasks containing potato dextrose broth (24 g) (Difco and BBL) in H2O (1 L). The culture (4 L) was grown under static conditions at room temperature and in the dark for 14 days. The culture broth was filtered through cheesecloth to remove fungal mycelia. The filtrate was extracted using CH2Cl2. The organic layer was evaporated in vacuo to obtain a crude extract (2.12 g). This crude extract was separated by silica gel column chromatography with CHCl3−MeOH (10:0−10:1) to give fractions 1−4. Fraction 1 was purified by silica gel column chromatography with toluene−EtOAc (10:1−4:1) to give compound 2 (40.6 mg) as a yellow solid and 6 (185.3 mg), and fraction 2 was purified by silica gel column chromatography with toluene−EtOAc (8:1−3:1) to give eupenoxide (7), compound 1 (15.5 mg) as a white solid, and compound 3 (25.8 mg) as a brown solid. Fraction 3 was separated by silica gel column chromatography with toluene−EtOAc (3:1−2:1) to give compound 4 (5.1 mg) as a colorless oil and fraction 3-2. Fraction 3-2 was purified by reverse-phase C18 column chromatography with MeOH−H 2 O (1:9−3:7) to give compound 5 (12.6 mg) as a colorless oil. Violaceoid A (1): white solid; UV (MeOH) λmax (log ε) 313 (3.59) nm; IR (film) νmax 3404, 3209, 2954, 2920, 2848, 1612, 1477, 1375, 1242 cm−1; HRESIMS m/z 259.1295 [M + Na]+, calcd for C14H20O3Na, 259.1304; 13C and 1H data, see Table 1. Violaceoid B (2): white solid; [α]22D +29.5 (c 0.078, CHCl3); UV (MeOH) λmax (log ε) 300 (3.03) nm; IR (film) νmax 3374, 2924, 2856, 1548, 1464, 1244 cm−1; HRESIMS m/z 277.1400 [M + Na]+, calcd for C14H22O4Na, 277.1410; 13C and 1H data, see Table 1. Violaceoid C (3): brown solid; UV (MeOH) λmax (log ε) 299 (3.57) nm; IR (film) νmax 3365, 2916, 2850, 1618, 1485, 1456, 1381, 1238 cm−1; HRESIMS m/z 261.1464 [M + Na]+, calcd for C14H22O3Na, 261.1461; 13C and 1H data, see Table 1. Violaceoid D (4): colorless oil; [α]23D +10.6 (c 0.24, CHCl3); UV (MeOH) λmax (log ε) 281 (3.08) nm; IR (film) νmax 3323, 2925, 2858, 1589, 1462, 1269 cm−1; HRESIMS m/z 261.1460 [M + Na]+, calcd for C14H22O3Na, 261.1461; 13C and 1H data, see Table 1. Violaceoid E (5): colorless oil; [α]24D −107.7 (c 0.56, CHCl3); UV (MeOH) λmax (log ε) 286 (4.29) nm; IR (film) νmax 3371, 2954, 2925, 2862, 1658, 1628, 1371, 1026 cm−1; HRESIMS m/z 277.1416 [M + Na]+, calcd for C14H22O4Na, 277.1410; 13C and 1H data, see Table 1.



ASSOCIATED CONTENT

S Supporting Information *

1

H and 13C NMR, DEPT, COSY, HMQC, and HMBC spectra for 1, 1H and 13C NMR spectra for 2−4, and 1H and 13C NMR and NOESY spectra for 5. This material is available free of charge via the Internet at http://pubs.acs.org.



AUTHOR INFORMATION

Corresponding Author

*Tel.: +81-4-7124-1501, ext. 3400. Fax: +81-4-7123-9767. Email: [email protected] Author Contributions ∥

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS S.K. acknowledges a Grant-in-Aid for Young Scientists (B) (No. 25750389) from MEXT (Ministry of Education, Culture, Sports, Science and Technology). Y.M. acknowledges Grant-inAids for Scientific Research (C) (No. 24580205) from MEXT.



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Cytotoxic alkylated hydroquinone, phenol, and cyclohexenone derivatives from Aspergillus violaceofuscus Gasperini.

New alkylated hydroquinones violaceoid A (1), violaceoid B (2), and violaceoid C (3), an alkylated phenol violaceoid D (4), and a cyclohexenoid violac...
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