Bioorganic & Medicinal Chemistry 22 (2014) 2442–2446

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Structural elucidation and synthesis of vialinin C, a new inhibitor of TNF-a production Yue Qi Ye a,b, Chiemi Negishi b, Yayoi Hongo a, Hiroyuki Koshino a, Jun-ichi Onose b, Naoki Abe b,⇑, Shunya Takahashi a,⇑ a b

RIKEN, Wako-shi, Saitama 351-0198, Japan Department of Nutritional Science, Faculty of Applied Bio-Science, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan

a r t i c l e

i n f o

Article history: Received 31 January 2014 Revised 24 February 2014 Accepted 28 February 2014 Available online 6 March 2014

a b s t r a c t A new inhibitor of TNF-a production (IC50 = 0.89 lM) named vialinin C (1) was isolated from dry fruiting bodies of an edible Chinese mushroom, Thelephora vialis. The structure of 1 was determined by high-resolution MS, NMR spectroscopic analysis, and confirmed by synthesis. Synthesis of ganbajunin B (5) obtained from the same origin was also described. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: TNF-a Vialinin C Vialinin A Vialinin B

1. Introduction In the course of our studies on naturally occurring bioactive compounds contained in edible Chinese mushrooms, we have isolated new p-terphenyl compounds, vialinin A (2)1 and vialinin B (4)2 along with known compounds, ganbajunin B (5),3 and cycloleucomelone4 from the dry fruiting bodies of Thelephora vialis, and demonstrated that 2 and 4 were a powerful inhibitor of a tumour necrosis factor (TNF)-a production in rat basophilic leukemia (RBL-2H3) cells: IC50 = 0.09 nM for 2 and 0.05 nM for 4 versus IC50 = 0.25 nM for FK-506.2,5 TNF-a is a potent multifunctional cytokine that mediates a variety of biological actions with a central role in the pathogenesis of many inflammatory diseases.6–8 Thus, inhibitors of TNF-a production in activated mast cells and basophiles are promising candidates for a new type of anti-allergic agent. Recently we developed an advanced analogue with a comparable inhibitory activity to that of 29, and conducted to an investigation to find 2 as a ubiquitin specific peptidase-5 inhibitor.10–12 Compound 213 was also reported as an anticancer active compound from Thelephora aurantiotincta together with a new analogue thelephantin O.14 We continued to search for new compounds, leading to the discovery of a new dibenzofuran compound named vialinin C (1) (Fig. 1). In this paper, we describe the isolation, structure elucidation and synthesis of 1. Evaluation ⇑ Corresponding authors. Tel.: +81 484679223; fax: +81 484624627 (S.T.). E-mail addresses: [email protected] (N. Abe), [email protected] (S. Takahashi). http://dx.doi.org/10.1016/j.bmc.2014.02.058 0968-0896/Ó 2014 Elsevier Ltd. All rights reserved.

of its inhibitory activity against TNF-a production and synthesis of 5 for confirmation of the structure are also discussed. 2. Results and discussion 2.1. Isolation and structure elucidation The dry fruiting bodies (250 g) of Thelephora vialis were extracted with 80% ethanol, and then filtered. After evaporation of the whole organic solvent, the remaining aqueous concentrate was adjusted to pH 3.0 and extracted with ethyl acetate: because polyphenolic p-terphenyl derivatives, such as vialinin A (2) containing many acidic phenols can be selectively extracted in acidic conditions. The crude extraction was successively subjected to a Sephadex LH-20 column chromatography, and then reversed phase HPLC to give compound 1 (10.5 mg). The molecular formula of 1 was established as C32H20O11 on the basis of high resolution negative ESIMS data. The IR spectrum of 1 showed the presence of hydroxyl and ester carbonyl groups. The UV spectrum closely resembled those of vialinin B (4) and ganbajunin B (5). The 1H NMR spectrum of 1 in acetone-d6 and DQF-COSY data revealed the presence of two aromatic singlet signals at 7.11 and 7.10 ppm for a tetra-substituted benzene ring, and six doublet signals with 8.8 Hz and each 2H integration values for three sets of p-substituted phenyl groups at 7.28 (H-20 /60 ) and 6.80 (H-30 /50 ), 7.73 (H-200 /600 ) and 6.77 (H-300 /500 ), and 7.99 (H-2000 /6000 ) and 6.91 (H-3000 /5000 ) ppm, respectively (Table 1). In the 13C-NMR spectrum,

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Figure 2. Summary of HMBC and NOE spectral data of 1.

Figure 1. Structures of vialinin C (1) and its related compounds.

Table 1 H NMRa and

1

a b c d

13

C NMRb data (d) for 1 in acetone-d6

Position

1

Hc

13

1 2 3 4 4a 5a 6 7 8 9 9a 9b 10 20 (60 ) 30 (50 ) 40 100 200 (600 ) 300 (500 ) 400 700 1000 2000 (6000 ) 3000 (5000 ) 4000 7000

— — — — — — 7.11 — — 7.10 — — — 7.28 6.80 — — 7.73 6.77 — — — 7.99 6.91 — —

138.4d 137.7d 122.0 130.1d 143.6d 151.9 99.1 147.5 143.0 107.3 115.0 119.5 124.6 132.7 115.7 157.6 121.1 132.9 115.9 162.9 164.8 120.8 133.2 116.4 163.3 164.3

s

s

d (8.8) d (8.8)

d (8.8) d (8.8)

d (8.8) d (8.8)

C

600 MHz. 150 MHz. Numbers in parentheses are J values. Interchangeable.

26 carbon signals were observed, and six carbon signals were overlapped and assigned to carbons of the p-substituted phenyl groups from HSQC data. There were 18 carbons with no attached protons, further structural information was analysed by HMBC experiments. Three bonds correlations were observed from the deshielded doublet signals at 7.73 (H-200 /600 ) and 7.99 (H-2000 /6000 ) ppm to ester carbonyl carbons at 164.8 (C-700 ) and 164.3 (C-7000 ) ppm together with the carbons with a hydroxyl group at 162.9 (C-400 ) and 163.4 (C-4000 ) ppm, respectively. Additional three-bond and two-bond correlations from H-300 /500 to C-100 (121.1 ppm) and C-400 , and H-3000 /5000 to C-1000 (120.8 ppm) and C-4000 confirmed the 13C NMR assignments and 1H and 13C NMR chemical shifts values suggested the presence of two p-hydroxybenzoyl groups.15 In the

negative mode ESIMS spectra, characteristic fragment ions at m/z 459 [MH120(C7H4O2)] and 339 [MH240(C14H8O4)] were observed and supported the presence of two p-hydroxybenzoate moieties. The remaining NMR signals were quite similar to the signals of the highly oxygenated dibenzofuran with the p-hydroxyphenyl group for the core terphenyl skeleton on 4,2 whose structure was confirmed by total synthesis.16 HMBC correlations from two singlet signals (H-6 and H-9) and signals of another p-hydroxyphenyl group (H-20 /60 and H-30 /50 ) are summarised in Fig. 2. The positions of two p-hydroxybenzoates were determined by 1D-DPFGSE (double-pulsed-field-gradient-spin-echo)NOE experiments.17,18 Sequential NOEs were observed as follows, between the p-hydroxyphenyl proton signal of the terphenyl portion at 7.28 (H-20 /60 ) ppm and the high-field shifted signal of the p-hydroxybenzoate at 7.73 (H-200 /600 ) ppm, and between H-200 /600 and H-2000 /6000 (7.99 ppm) corresponding to two p-hydroxybenzoates in ortho relationships, and from H-2000 /6000 to the singlet signal at 7.10 (H-9) ppm for the 1,2,4,5-tetrasubstituted benzene ring in the dibenzofuran portion (Fig. 2). On the basis of these spectral data, the structure of 1 was determined to be 1,2-bis(p-hydroxybenzoyloxy)-3-(4-hydroxyphenyl)dibenzofuran-4,7,8-triol, designate vialinin C, as shown in Fig. 1. Vialinin C (1) possesses the same dibenzofuran core structure of 4 with four phenolic hydroxyl groups. The difference between 4 and 1 is the acyl groups at the catechol portion at C-1 and C-2. From Thelephore terrestris dibenzofuran type p-terphenyl compounds terrestrins E-G with triacyl groups like 5 were isolated.13 Several dibenzofuran p-terphenyl derivatives with acetoxy or methoxy groups were also isolated as biologically active fungal metabolites.19–23 The structural feature with di-p-hydroxybenzoate moiety in the ortho relationship of 1 is similar to thelephantin G (3).15 2.2. Synthesis Our recent studies on natural p-terphenyls revealed that it was not easy to determine the structure, in particular, the position of the hydroxyl groups in these molecules, by NMR analyses only.15,24,25 Several papers have also appeared denoting different NMR data with regard to one natural product.3,26 For example, the 1H-NMR data of 5 isolated by us did not match with those reported in the literature.3 These results suggest that the proposed structure should be confirmed by total synthesis. Therefore, we planned to synthesise 1 and 5 from the key intermediate 616 in our total synthesis of 4 (Scheme 1). According to the method described in Ref. 16, an orthoester 7 was prepared from 6 synthesized by a sequential Suzuki–Miyaura coupling of three components. After hydrolysis of 7, the resulting catechol was submitted to esterification by lithium bis(trimethylsilylamide) (LHMDS) and p-benzyloxybenzoyl chloride,27 giving 8 in good yield (86%). Hydrogenolysis of this with Pd(OH)2 gave 1 (86%). The 1H and 13C NMR data of synthetic 1 were identical to those of natural 1. On the other hand, synthesis of 5 began with phenylacetylation of 6. Since the use of organic bases such

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leading to an useful information for designing new anti-allergic drugs. 2.4. Conclusion We isolated a new p-terphenyl named vialinin C (1) from the dry fruiting bodies of an edible Chinese mushroom, Thelephora vialis. Compound 1 showed weak inhibitory activity (IC50 = 0.89 lM) against TNF-a production from RBL-2H3 cells. The structures of 1 and ganbajunin B (5) were unambiguously established by the synthesis. 3. Experimental All reactions were carried out under an argon atmosphere, unless otherwise noted. Melting points are uncorrected. IR spectra were recorded with a JASCO VALOR-III spectrophotometer by ATR method. Proton (1H) and carbon (13C) NMR spectra were obtained using Varian NMR System 500 (500 MHz) or JEOL ECA-600 (600 MHz) spectrometer as solutions in CDCl3 unless otherwise noted. Chemical shifts are reported in ppm downfield from tetramethylsilane with the solvent resonance as the internal standard (dH 7.26 ppm or dC 77.0 ppm for CDCl3, dH 3.30 ppm or dC 49.0 ppm for CD3OD, and dH 2.04 ppm or dC 29.8 ppm for acetone-d6). ESI-MS spectra were obtained using JEOL JMS-T100LC Accu TOF mass spectrometer. Column chromatography was performed on Kanto silica gel 60 N (spherical, neutral; 40–100 lm). Merck precoated silica gel 60 F254 plates, 0.25 mm thickness, was used for analytical thin-layer chromatography. The solvent extracts were dried with magnesium sulfate, and the solutions were evaporated under diminished pressure at 35–40 °C. 3.1. Isolation of vialinin C (1)

Scheme 1. Reagents and conditions: (a) aq AcOH, 60 °C; (b) LHMDS, THF, 78 °C and then 4-BnOC6H4COCl, 78 °C ? rt, 86% (2 steps); (c) H2, Pd(OH)2, EtOAc, rt, 86% for 1, 30% for 5 (3 steps from 10); (d) n-BuLi, THF, 78 °C and then phenylacetyl chloride, 78 ? 0 °C, 88%; (e) Pb(OAc)4, benzene, 80 °C, 73%; (f) LHMDS, THF, 78 °C and then phenylacetyl chloride, 78 °C ? rt.

as pyridine and triethylamine for the acylation gave unsatisfactory results, 6 was treated with n-butyllithium at 78 °C and the resulting lithium alkoxide reacted with phenylacetyl chloride, affording phenylacetate 9 in high yield. Lead tetraacetate (LTA) oxidation of this proceeded smoothly to afford orthoacetate 10. Exposure of 10 to mild acidic conditions led to the removal of the acetal group, providing catechol 11 which was successively treated with LHMDS and phenylacetyl chloride to give 5 after hydrogenolysis in 30% overall yield. The low yield of 5 was due to the instability of 11 toward basic conditions employed. The 1H and 13C NMR data of synthetic 5 well matched those of the natural product isolated by us1 and the reported data by Radulovic´ et al.13 2.3. Biological activity The inhibitory activity of 1 against TNF-a production from RBL2H3 cells was evaluated. Compound 1 showed an IC50 value of 0.89 lM when the analogue compound vialinin B (4) showed 0.02 nM. On the other hand, the inhibitory activity of vialinin A (2) and its p-hydroxybenzoyl analogue, thelephantin G (3) was reported to be comparable (IC50 = 0.25 nM vs 3.5 nM).15 These results indicate that the p-terphenyl backbone as well as the type of two ester moieties was very important to the inhibitory activity, thus

The dry fruiting bodies (250 g) of Thelephora vialis were extracted with 5.0 L of 80% ethanol for 3 days at room temperature, and then the extracts were filtered. After evaporation in vacuo, the aqueous concentrate was adjusted to pH 3.0 and extracted with 1.5 L of ethyl acetate. The organic layer was concentrated and gave 26.1 g of the ethyl acetate extract. A part of the extract (10.0 g) was applied to a Sephadex LH-20 column, eluted with methanol: chloroform (6:4, v/v) and 8 fractions were obtained (Frs. 1–8). The fifth fraction was purified by a reverse-phase preparative HPLC (Shiseido Co. Ltd., CAPCELL PAK C18 UG120 15 mmu  250 mm) with 0.15% KH2PO4 (pH 3.5)/acetonitrile (7:3) at the flow rate of 8.8 mL/min, monitoring at 254 nm) to give 1 (10.5 mg) as a brownish amorphous powder; IR (ATR) 3306, 1697, 1604, 1589, 1249, 1226, 1160, 1066 cm1; UV kmax (e, methanol) 211 (50700), 263 (45200), 330 (20900) nm; ESIMS (neg.) m/z 579 [MH], 459 [MHC7H4O2], 339 [MH(C7H4O2)  2]; HRESIMS (neg.) m/z 579.0924 [MH], calcd for C32H19O11 579.0927. 3.2. 1,2-Bis((p-benzyloxy)benzoyloxy)-7,8-bis(benzyloxy)-4(benzyloxycarbonyloxy)-3-(4-(benzyloxy)phenyl)dibenzo furan (8) A solution of 7 (104.0 mg, 0.13 mmol) in acetic acid–water (20:1; 4.2 mL) was stirred at 50 °C for 3 h, concentrated, and coevaporated with toluene to give an amorphous solid, which was employed to the next step without further purification. To a stirred solution of the above solid in THF (4.0 mL) was added dropwise a 1.0 M solution of lithium bis(trimethylsilylamide) in tetrahydrofuran (0.29 mL, 0.29 mmol) at -78 °C. After 1 h, 4-benzyloxybenzoyl chloride (160.3 mg, 0.65 mmol) in THF (2 ml) was added at 78 °C and the resulting mixture was stirred at 78 °C for 30 min and at 0 °C ? rt for 1 h. After being quenched with

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saturated aqueous NH4Cl, the mixture was extracted with ethyl acetate. The combined organic layers were washed successively with water, saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was chromatographed on silica gel (n-hexane–ethyl acetate = 10:1 ? 5:1) to afford 8 (126.0 mg, 86%) as a white solid; IR (ZnSe) 3033, 1735, 1604, 1508, 1453, 1217, 1163 cm1; 1H NMR (500 MHz, CDCl3): d 8.14 (2H, d, J = 9.0 Hz), 7.85 (2H, d, J = 9.0 Hz), 7.48–7.15 (33H, m), 7.11 (1H, s), 7.03 (2H, d, J = 9.0 Hz), 6.87 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 5.26 (2H, s), 5.19 (2H, s), 5.13 (2H, s), 5.05 (2H, s), 4.98 (2H, s), 4.94 (2H, s); 13C NMR (125 MHz, CDCl3): d 164.0, 163.34, 163.25, 162.8, 158.4, 152.4, 152.0, 150.2, 146.1, 145.7, 136.8, 136.7, 136.45, 136.43, 136.0, 135.9, 134.7, 134.6, 132.6, 132.2, 131.2, 131.0, 128.7, 128.65, 128.61, 128.53, 128.49, 128.48, 128.37, 128.32, 128.2, 128.1, 128.0, 127.95, 127.7, 127.5, 127.18, 127.17, 127.15, 123.7, 121.0, 120.7, 119.6, 114.8, 114.5, 114.4, 114.3, 107.6, 98.5, 71.7, 71.3, 70.5, 70.2, 70.0, 69.8; HRESIMS m/z 1187.3655 [M+Na]+ (calcd for C75H56O13Na 1187.3619). 3.3. Preparation of vialinin C (1) To a stirred solution of 8 (51.0 mg, 43.8 lmol) in ethyl acetate– THF (1:1, 4.0 mL) was added palladium hydroxide (15.0 mg). The mixture was stirred vigorously under a hydrogen atmosphere at rt for 13.5 h, filtered through a filter paper under N2 atmosphere, and then concentrated. The residue was chromatographed on silica gel (dichloromethane–methanol = 10:1) to give 1 (21.9 mg, 86%) as a white solid; HRESIMS m/z 603.0891 [M+Na]+ (calcd for C32H20O11Na 603.0903). 3.4. 7,8-Bis(benzyloxy)-3-(4-(benzyloxy)phenyl)-1,2-methylene dioxy-4-(phenylacetyloxy)dibenzofuran (9) To a stirred solution of 6 (55.0 mg, 88.3 mmol) in THF (2.0 mL) was added dropwise a 1.59 M of n-butyllithium (0.07 mL, 111.3 mmol) in n-hexane at 78 °C. After 15 min, phenylacetyl chloride (0.02 mL, 115.1 mmol) was added and the mixture was stirred at 78 °C for 30 min and 0 °C for 1 h. After addition of ice-water, the resulting mixture was stirred for 30 min, and then extracted with ethyl acetate. The combined organic layers were washed successively with water, saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was chromatographed on silica gel (n-hexane–ethyl acetate = 20:1) to give 9 (57.3 mg, 88%) as a white solid; IR (ZnSe) 3032, 1751, 1456, 1296, 1253, 1187 cm1; 1H NMR (500 MHz, CDCl3): d 7.51–7.21 (23H, m), 7.10 (1H, s), 6.92 (2H, d, J = 8.8 Hz), 6.11 (2H, s), 5.23 (2H, s), 5.21 (2H, s), 5.09 (2H, s), 3.82 (2H, s); 13C NMR (125 MHz, CDCl3): d 169.4, 158.4, 152.1, 150.0, 146.0, 144.4, 140.7, 137.1, 137.0, 136.9, 136.7, 133.1, 130.9, 129.4, 128.63, 128.58, 128.52, 128.46, 128.03, 127.98, 127.88, 127.6, 127.5, 127.3, 127.1, 125.9, 123.7, 115.4, 114.6, 114.0, 108.8, 108.0, 102.1, 98.7, 72.4, 71.5, 70.0, 40.8; HRESIMS m/z 763.2282 [M+Na]+ (calcd for C48H36O8Na 763.2308). 3.5. 1,2-(Acetoxymethylenedioxy)-7,8-bis(benzyloxy)-4(phenylacetyloxy)-3-(4-(benzyloxy)phenyl)dibenzofuran (10) A mixture of 9 (122.3 mg, 0.17 mmol) and lead tetraacetate (146.4 mg, 0.33 mmol) in benzene (4.0 mL) was stirred at 80 °C for 5 h. After being cooled to rt, the reaction mixture was filtered through a pad of Celite, and concentrated. The residue was chromatographed on silica gel (n-hexane–ethyl acetate = 20:1 ? 10:1) to give 10 (96.8 mg, 73%) as an amorphous solid; IR (ZnSe) 3050, 1750, 1559, 1521, 1508, 1296, 1250 cm1; 1H NMR (500 MHz, CDCl3): d 8.03 (1H, s), 7.67–7.37 (24H, m), 7.07 (2H, d, J = 8.8 Hz), 5.37 (2H, s), 5.36 (2H, s), 5.24 (2H, s), 3.98 (2H, s), 2.27 (3H, s);

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13

C NMR (150 MHz, CDCl3): d 169.2, 168.9, 158.6, 152.1, 150.2, 146.2, 144.9, 138.1, 137.0, 136.8, 136.6, 134.2, 132.9, 130.9, 129.4, 128.63, 128.58, 128.54, 128.46, 128.1, 128.0, 127.9, 127.6, 127.5, 127.23, 127.19, 126.8, 123.0, 115.7, 114.7, 113.6, 113.5, 109.1, 107.9, 98.6, 72.3, 71.4, 69.9, 40.8, 21.1; HRESIMS m/z 821.2372 [M+Na]+ (calcd for C50H38O10Na 821.2363). 3.6. Preparation of Ganbajunin B (5) A solution of 10 (95.0 mg, 0.12 mmol) in acetic acid–water (16:1; 8.5 mL) was stirred at 50 °C for 3 h, concentrated, and coevaporated with toluene to give 11 as an amorphous solid, which was employed to the next step without further purification. To a stirred solution of the above solid in THF (4.0 mL) was added dropwise a 1.0 M solution of lithium bis(trimethylsilylamide) in tetrahydrofuran (0.30 mL, 0.30 mmol) with stirring at 78 °C. After 1 h, phenylacetyl chloride (0.08 ml, 0.60 mmol) was added at 78 °C and the resulting mixture was stirred at 78 °C for 30 min and at 0 °C ? rt for 14 h. After being quenched with saturated aqueous NH4Cl, the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed successively with water, saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was passed through a short column of silica gel (benzene–dichloromethane–n-hexane = 2:2:1) to afford an amorphous solid (74.8 mg) which was dissolved in ethyl acetate (6.0 ml). To this solution was added palladium hydroxide (15.0 mg). The mixture was stirred vigorously under a hydrogen atmosphere at rt for 14 h, filtered through a filter paper under N2 atmosphere, and then concentrated. The residue was purified by preparative TLC (dichloromethane–methanol = 20:1) under N2 atmosphere to give 5 (19.8 mg, 30%) as an amorphous solid; IR (ZnSe) 3364, 3031, 1735, 1100, 1071, 992 cm1; 1H NMR (500 MHz, CD3OD): d 7.44–7.39 (4H, m), 7.34–7.31 (1H, m), 7.24– 7.20 (6H, m), 7.08–7.04 (3H, m), 7.00 (1H, s), 6.91–6.89 (4H, m), 6.66 (2H, d, J = 8.5 Hz), 3.90 (2H, s), 3.74 (2H, s), 3.18 (2H, s); 13C NMR (150 MHz, CD3OD): d 170.74, 170.68, 170.1, 158.6, 152.7, 148.8, 147.2, 144.3, 137.2, 134.9, 134.6, 134.5, 134.4, 132.14, 132.12, 130.8, 130.3, 130.0, 129.5, 128.7, 128.4, 128.1, 123.5, 120.4, 116,2, 114.1, 107.6, 99.2, 41.4, 41.2, 40.8; HRESIMS m/z 717.1702 [M+Na]+ (calcd for C42H30O10Na 717.1737). Acknowledgments This work was supported by the Chemical Genomics Project (RIKEN) and in part by JSPS KAKENHI Grant Number 24580168. N.A. acknowledges the Advanced Research Project of Tokyo University of Agriculture. Supplementary data Supplementary data (NMR data of compounds 1, 5, and 8–10) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmc.2014.02.058. References and notes 1. Xie, C.; Koshino, H.; Esumi, Y.; Takahashi, S.; Yoshikawa, K.; Abe, N. Biosci. Biotechnol. Biochem. 2005, 69, 2326. 2. Xie, C.; Koshino, H.; Esumi, Y.; Onose, J.; Yoshikawa, K.; Abe, N. Bioorg. Med. Chem. Lett. 2006, 16, 5424. 3. Hu, L.; Gao, J. M.; Liu, J. K. Helv. Chim. Acta 2001, 84, 3342. 4. Jagers, E.; Hillen-Maske, E.; Steglich, W. Z. Naturforsch. 1987, 42b, 1349. 5. Onose, J.; Xie, C.; Ye, Y.-Q.; Takahashi, S.; Koshino, H.; Yasunaga, K.; Abe, N.; Yoshikawa, K. Biol. Pharm. Bull. 2008, 31, 831. 6. Vassalli, P. Annu. Rev. Immunol. 1992, 10, 411. 7. Sieper, J.; Braun, J. Expert Opin. Emerg. Drugs 2002, 2, 235. 8. Holgate, S. T. Cytokine 2004, 28, 152. 9. Ye, Y.-Q.; Onose, J.; Abe, N.; Koshino, H.; Takahashi, S. Bioorg. Med. Chem. Lett. 2012, 22, 2385.

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