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Six New Induced Sesquiterpenes from the Cultures of Ascomycete Daldinia Concentrica Xiang-Dong Qin, Hong-Jun Shao, Ze-Jun Dong, Ji-Kai Liu

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Six New Induced Sesquiterpenes from the Cultures of Ascomycete Daldinia Concentrica Xiang-Dong Qin, Hong-Jun Shao, Ze-Jun Dong, Ji-Kai Liu J. Antibiot. 61(9): 556–562, 2008 THE JOURNAL OF ORIGINAL ARTICLE ANTIBIOTICS Six New Induced Sesquiterpenes from the Cultures of Ascomycete Daldinia concentrica Xiang-Dong Qin, Hong-Jun Shao, Ze-Jun Dong, Ji-Kai Liu Received: April 23, 2008 / Accepted: August 19, 2008 © Japan Antibiotics Research Association Abstract Six new sesquiterpenes having the botryane production titers of desired compounds. This approach was carbon skeleton (1ϳ6), together with known compounds successfully used as a valuable tool to exploit natural (7ϳ10) were induced and isolated from the ascomycete products diversity in the past, for example, actinomycetes Daldinia concentrica (strain S 0318). Structures (Streptomyces sp.) and fungi (Aspergillus sp., elucidation was accomplished by NMR spectroscopic and Sphaeropsidales sp.) produce additional compounds after X-ray crystallographic studies. variation of the culture conditions [3ϳ5]. Previous investigation reported the isolation of induced Keywords Sesquiterpenes, Daldinia concentrica, daldinins A, B, and C with a new skeleton and four known ascomycete, induction, botryane compounds from the cultures of ascomycete Daldinia concentrica [6]. Following the OSMAC approach, the strain S 0318 (Daldinia concentrica) has been cultivated Introduction and further investigated. In the culture broth extract from Erlenmeyer flasks (color, transparent; size, 500 ml; media, Fungi or bacteria that produce secondary metabolites often 300 ml) instead of reagent bottles under same cultivation have the potential to produce various compounds from a conditions we detected additional metabolites by TLC and single strain. Variation of cultivation parameters to induce HPLC. Careful investigation on the culture of D. the production of formerly unknown compounds is one of concentrica strain (S 0318) led to the isolation of new the approach to increase the number of secondary compounds methyl-7a-acetoxydeacetylbotryoloate (1), 7a- metabolites from one single organism. This way of acetoxydeacetylbotryenedial (2), 7a-hydroxybotryenalol releasing nature’s chemical diversity was termed the (3), 7,8-dehydronorbotryal (4), 7a-acetoxydehydro- ‘OSMAC (One Strain-Many Compounds)’ approach [1, 2], botrydienal (5), and 7a-acetoxy-15-methoxy-10-O-methyl- which is based on the observation that individual strains are deacetyldihydrobotrydial (6) (Fig. 1), and known able to produce more metabolites than normally detected in compounds, 7a-hydroxy-10-O-methyldihydrobotrydial [7], a routine screening program. Small changes in the 7-hydroxy-16-O-methyldeacetyldihydrobotrydial-hydrate cultivation parameters (for example, culture vessel, media [9, 10], 7-hydroxydeacetyl-botryenalol [8], and 7a- composition, and addition of enzyme inhibitors) can hydroxydihydrobotrydial [7], by the alteration of culture completely shift the metabolic profile of various parameter (form of culture vessel). The fermentation, microorganisms. It is a very simple approach to the isolation and structure elucidation of these compounds are improvement of fermentations to obtain maximum reported here. J.-K. Liu (Corresponding author), H.-J. Shao, X.-D. Qin, Z.-J. Dong: State Key Laboratory of Phytochemistry and Plant Materials and Methods Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China, E-mail: General [email protected] NMR experiments were performed on a Bruker AM-400 or 557 Fig. 1 Structures of 1ϳ6. 1: methyl-7a-acetoxydeacetylbotryoloate, 2: 7a-acetoxydeacetylbotryenedial, 3: 7a-hydroxybotryenalol, 4: 7,8-dehydronorbotryal, 5: 7a-acetoxydehydrobotrydienal, 6: 7a-acetoxy-15-methoxy-10-O-methyl-deacetyldihydrobotrydial. a DRX-500 spectrometer with TMS as internal standard. Cultivation Mass spectra were recorded on a VG Auto Spec-3000 or an Strain S 0318 was grown on agar slants at 22°C until API QSTAR Pulsar 1 spectrometer. IR spectra were sporulation, and then stored at 4°C. The culture medium recorded on a Bruker Tensor 27 spectrometer with KBr consisted of potato (peel off) 200 g, glucose 20 g, KH2PO4 pellets. Optical rotations were measured on a Horiba SEPA- 3.0 g, MgSO4 1.5 g, citric acid 0.1 g and thiamin 300 polarimeter. Column chromatography was performed hydrochloride 10 mg in 1.0 liter of de-ionized water. The on silica gel (200ϳ300 mesh; Qingdao Marine Chemical fungus was grown in Erlenmeyer flasks (color, transparent; Ltd., Qingdao, People’s Republic of China) and Sephadex size, 500 ml; media, 300 ml). The pH was adjusted to 6.5 LH-20 (Amersham Biosciences, Sweden). TLC analysis before autoclaving. Fermentation was carried out on a was carried out on silica gel GF254 precoated plates rotary shaker at 22°C and 150 rpm for 10 days. (0.20ϳ0.25 mm; Qingdao) with detection by heating silica gel plates sprayed with 10% H2SO4 in EtOH. Extraction and Isolation The mycelium from 60 liters was filtered, and the filtrate Fungal Material was extracted five times with EtOAc (total 80 liters). The Strain (S 0318) was isolated from tissue culture of the EtOAc extract was evaporated in vacuo and the deep brown fruiting bodies of Daldinia concentrica collected at gum (80 g) was subjected to column chromatography (silica Laojunshan, Yunnan Province, P. R. China, in July 2003 gel) using a CHCl3/MeOH stepwise elution. Elution with and identified by Prof. Mu Zang, Kunming Institute of CHCl3/MeOH (98 : 2, v/v) produced 5 (11 mg). The Botany, Chinese Academy of Sciences. A voucher fraction (20 g) from CHCl3/MeOH (95 : 5) was further specimen (HKAS 40992) was deposited at the herbarium of purified by repeated chromatography over silica gel Kunming Institute of Botany, Chinese Academy of (petroleum ether/Me2CO from 20 : 1 to 10 : 1; Sciences. CHCl3/MeOH, from 30 : 1 to 10 : 1), and Sephadex LH-20 558 (CHCl3/MeOH, 1 : 1) to afford the pure 2 (21 mg), 3 309.1706 (calcd for C17H24O5, 309.1701). (35 mg), 4 (6 mg), 6 (27 mg), 8 (30 mg), 10 (43 mg). The fraction (24 g) eluted with CHCl3/MeOH (90 : 10) at the 7a-Hydroxybotryenalol (3) 21.6 ϩ first chromatography was further purified by repeated Colorless solid; m.p. 60°C; [a]D 162.4° (c 0.35 in chromatography over silica gel (CHCl3/MeOH, from 20 : 1 MeOH); IR (KBr) n max 3472, 2965, 2936, 2883, 1713, Ϫ1 to 5 : 1) to yield 1 (22 mg), 7 (78 mg), and 9 (8 mg). 1670, 1267, 1052, 1042 cm ; UV (MeOH) l max (log e) 252 (4.06) nm; 1H- and 13C-NMR data see Tables 1 and 3; Physico-chemical Properties EI-MS m/z (rel intensity) [MϪH]ϩ 309 (3), 280 (12), 250 Methyl-7a-acetoxydeacetylbotryoloate (1) (5), 220 (44), 205 (55), 200 (100), 187 (35), 173 (40), 159 13 ϩ Colorless needles; m.p. 186°C; [a]D 2.52° (c 0.53 in (38), 145 (18); Negative FAB-MS m/z (rel intensity) Ϫ Ϫ Ϫ Ϫ MeOH); IR (KBr) n max 3353, 2970, 2957, 1736, 1710, [M H] 309 (99); HR-TOF-MS m/z: [M H] 309.1700 Ϫ1 1241, 1036 cm ; UV (MeOH) l max (log e) 204 (2.66) nm; (calcd for C17H25O5, 309.1701). Ϫ ϩ EI-MS m/z (rel intensity) [M H2O] 340 (22), 309 (15), 280 (35), 265 (51), 250 (100), 235 (42), 210 (60), 185 (73), 7,8-Dehydronorbotryal (4) 1 13 24 Ϫ 153 (67), 109 (69), 95 (96), 83 (47); H- and C-NMR data Colorless crystal; m.p. 112°C; [a]D 148.7° (c 0.11 in see Tables 1 and 3; Positive FAB-MS m/z (rel intensity) MeOH); IR (KBr) n max 3396, 2957, 2930, 2867, 1653, ϩ ϩ ϩ ϩ Ϫ1 [M H] 359 (10); HR-ESI-MS m/z [M Na] 381.1885 1594, 1063 cm ; UV (MeOH) l max (log e) 294 (4.31) nm; 1 13 (calcd for C18H30O7Na, 381.1889). H- and C-NMR data see Tables 2 and 3; EI-MS m/z (rel intensity) [MϩH]ϩ 221 (3), 185 (21), 167 (25), 149 (100), 7a-Acetoxydeacetylbotryenedial (2) 69 (41); Positive TOF-MS m/z (rel intensity) [MϩH]ϩ 221; 20 ϩ ϩ ϩ Colorless crystal; m.p. 126°C; [a]D 211.9° (c 0.23 in HR-TOF-MS m/z [M H] 221.1541 (calcd for C14H20O2, MeOH); IR (KBr) n max 3427, 2980, 2958, 2933, 2879, 221.1541). Ϫ1 1714, 1676, 1264, 1052 cm ; UV (MeOH) l max (log e) 252 (3.96) nm; 1H- and 13C-NMR data see Tables 1 and 3; 7a-Acetoxydehydrobotrydienal (5) ϩ ϳ 26 Ϫ EI-MS m/z (rel intensity) [M] 308 (3), 293 (7), 266 (2), Colorless prisms; m.p. 162 163°C; [a]D 32.5° (c 0.24 248 (20), 220 (65), 205 (65), 191 (80), 177 (55), 159 (100), in MeOH); IR (KBr) n max 2729, 1728, 1683, 1591, 1374, Ϫ1 145 (30), 131 (27), 91 (32); Negative FAB-MS m/z (rel 1254 cm ; UV (MeOH) l max (log e) 204 (4.33), 268 intensity) [MϪH]Ϫ 307 (100); HR-TOF-MS m/z: [MϩH]ϩ (3.27), 278 (2.16), 322 (2.58) nm; 1H- and 13C-NMR data Table 1 1H-NMR data for 1ϳ3 No. 123 H-1 2.38 (1H, d, Jϭ12.3) H-2 2.00 (1H, m) 2.82 (1H, m, Jϭ3.8, 6.7) 2.87 (1H, m) H-3 a 1.09 (1H, m) a 1.31 (1H, m) a 1.40 (1H, ddd, Jϭ2.6, 9.4, 12.0) b 1.95 (1H, m) b 2.11 (1H, m) b 2.03 (1H, ddd, Jϭ2.6, 9.4, 12.0) H-4 3.88 (1H, dt, Jϭ4.7, 11.0) 3.70 (1H, ddd, Jϭ3.9, 9.3, 11.3) 4.90 (1H, m) H-5 1.59 (1H, d, Jϭ11.0) 2.42 (1H, d, Jϭ9.3) 2.44 (1H, d, J= 8.9) H-6 H-7 5.48 (1H, s) 4.79 (1H, s) 3.67 (1H, s) H-10 9.66 (1H, s) 10.24 (1H, s) H-11 0.91 (3H, d, Jϭ6.1) 1.02 (3H, d, Jϭ6.7) 1.07 (3H, d, Jϭ6.8) H-12 1.14 (3H, s) 1.01 (3H, s) 0.75 (3H, s) H-13 1.35 (3H, s) 1.30 (3H, s) 1.15 (3H, s) H-14 0.90 (3H, s) 1.28 (3H, s) 1.25 (3H, s) H-15 a 3.19 (1H, d, Jϭ11.9) 9.52 (1H, s) a 3.56 (1H, d, Jϭ10.7) b 3.44 (1H, d, Jϭ11.9) b 3.69 (1H, d, Jϭ10.7) H-16 3.73 (3H, s) H-17 2.11 (1H, s) 2.05 (3H, s) H-18 2.09 (3H, s) 559 Table 2 1H-NMR data for 4ϳ6 No.
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