中田, 智子

山田, 剛司

田路, さやか

Japanese

Osaka Medical and Pharmaceutical University Repository

53Bulletin of Osaka University of Pharmaceutical Sciences 3 (2009)—Articles—New Lanostane Triterpenoids, Inonotsutriols D, and E from Inonotus ObliquusTomoko NAKATA, Sayaka TAJI, Takeshi YAMADA, and Reiko TANAKA*Osaka University of Pharmaceutical Sciences, 4-20-1, Nasahara, Takatsuki, Osaka  569-1094, Japan(Received October 10, 2008; Accepted November 14, 2008)Two new lanostane-type triterpenoids, inonotsutriols D (1) and E (2), were isolated from the sclerotia of Inonotus obliquus (Pers.: Fr.) Pil. (Japanese name: kabanoanatake; Russian name: chaga).  Their structures were determined to be lanost-8-ene-3β,22R,24R-triol (1) and lanost-8-ene-3β,22R,24S-triol (2) on the basis of spectral data, including 2D NMR analysis.  In addition, major compounds inotodiol (3), trametenolic acid (4), 3β-hydroxylanosta-8,24-dien-21-al (5), and inonotsuoxide A (6) were evaluated for their cancer cell growth inhibitory activity using the murine P388 leukemia cell line.Key words——Inonotus obliquus; kabanoanatake; sclerotium; inonotsutriol D; inonotsutriol E; lanost-8-ene-3β,22R,24R-triol; lanost-8-ene-3β,22R,24S-triol; 2D NMR; murine P388 leukemia cell lineINTRODUCTIONInonotus obliquus (PERS.: Fr.) Pil. (= Fuscoporia obliqua (PERS.: Fr.) Aoshima), commonly known as kabanoanatake in Japan and chaga or tchaga in Russia, is a white-rot fungus belonging to the family Hymenochaetaceae Donk1 and is widely distributed in Europe, Asia, and North America2. The imperfect form of I. obliquus occurs parasitically on trunks, usually of Betula (birch), and more rarely on Ulmus, Alnus, and Fraxinus. Only after the tree dies is the perfect form with pores and basidia produced under the bark. I. obliquus is widely distributed in Betula platyphylla var. japonica (Japanese name: shirakaba) forests in Hokkaido, Japan3,4.Lanost-8-ene-3β,22R-diol (inotodiol) was isolated by Ludwiczak and Wrecino5. Kahlos et al. isolated 3β-hydroxylanosta-8,24-dien-21-oic acid (trametenolic acid) and 3β-hydroxylanosta-8,24-dien-21-al6, as well as 3β,22,25-trihydroxylanosta-8,23-diene7 and 3β,22-dihydroxylanosta-8,24-dien-7-one8. His group also reported that inotodiol exhibits significant anticancer activity against Walker 256 carcinosarcoma and MCF-7 human mammary adenocarcinoma in vitro and leukemia P388 in vivo9, and that 3β-hydroxylanosta-8,24-dien-21-al,  3β,21-dihydroxylanosta-8,24-d iene,  and t rametenol ic  acid have ant i f ungal activity10. Mizuno et al. reported the antitumor and hypoglycemic activities of polysaccharides from I. obliquus11. Babitskaya et al. reported melanin complex of I. obliquus has antioxidant and genoprotective effects12 and Burczyk et al. reported that the aqueous extract of I. obliquus inhibited growth of human cervical and uterine cancer cells (HeLa S313). Shin et al. isolated 3β-hydroxylanosta-8,24-diene-21,23-lactone, 21,24-cyclopentalanost-8-ene-3β,21,25-triol, and lanost-8-ene-3β,22,25-triol from the sclerotia of I. obliquus14,15.*e-mail: tanakar@gly.oups.ac.jp54I.  obliquus  has been found to possess the following activities: anti-cancer16,17,  anti-breast cancer18, anti-inflammatory and anti-nociceptive effects19,20,  anti-oxidant21,22,  anti-mutation23, anti-inflammatory24,25,  inhibition of oxidative DNA damage in human lymphocytes25, platelet aggregation inhibitory activity26, and blocker of IκBα kinase activation27. Recently, we reported the structures of new lanostane-type triterpenoids isolated from the sclerotia of I. obliquus: inonotsuoxides A and B (22R,25-epoxylanost-8-ene-3β,24S-diol and its 22S,25-epoxy epimer)28; inonotsulides A, B, and C ((20R,24S)-3β,25-dihydroxylanost-8-en-20,24-olide, its (20R,24R)-olide epimer, and (20R,24S)-3β,25-dihydroxylanosta-7,9(11)-dien-20,24-olide29); lanosta-8,23E-diene-3β,22R,25-triol and lanosta-7:9(11),23E-triene-3β,22R,25-triol30; and inonotsutriols A, B, and C ((20R,24S)-cyclopentalanost-8-ene-3β,21R,25-triol, its 24R-hydroxyl epimer, and (20R,24S)-cyclopentalanosta-7:9(11)-diene-3β,21R,25-triol31). In addition, the anti-tumor promoting activity of inotodiol28 and 3β-hydroxylanosta-8,24-dien-21-al30, which are abundant triterpene constituents in this sclerotium, has been reported.  Careful examination of the sclerotia of I. obliquus has led to the isolation of two new lanostane-type triterpenes named inonotsutriols D (1) and E (2). The 55Vol.3 (2009)structures of compounds 1 and 2 were determined on the basis of spectroscopic data, including 2D NMR spectra.  This report deals with the structure determination of inonotsutriols D (1) and E (2), and the P388 cancer cell growth inhibitory activity of abundant triterpenoids inotodiol (3), trametenolic acid (4), 3β-hydroxylanosta-8,24-dien-21-al (5), and inonotsuoxide A (6). Results and discussionThe sclerotia of I. obliquus were extracted with CHCl3 and the extract was separated by silica gel column chromatography, medium-pressure liquid ch romatography (MPLC), and h igh-pressure liquid chromatography (HPLC) to obtain two new triterpenes (1 and 2). The molecular formula of inonotsutriol D (1) was determined to be C30H50O3 (M+; m/z 458.3766, calcd 458.3760) by HREIMS. The IR spectrum showed the presence of hydroxyl groups (νmax 3399 cm-1). The 1H and 13C NMR spectra (CDCl3) of 1 (Table 1) exhibited signals assignable to six tertiary methyl groups; one secondary methyl group [δH 0.94 (3H, d, J = 6.7 Hz)]; nine sp3 methylenes; one terminal methylene [δH 4.84 (1H, dq, J = 3.8, 1.8 Hz), 5.01 (1H, quint, J = 1.2 Hz)]; six sp3 methines including three oxymethines [δH 3.24 (1H, dd, J = 11.7, 4.5 Hz); δC 79.0 (d)], [δH 3.96 (1H, dt, J = 9.2, 3.0 Hz); δC 74.6 (d)], [δH 4.26 (1H, dd, J = 9.2, 3.5 Hz); δC 76.5 (d)]; four sp3 quaternary carbons; and one tetrasubstituted double bond [δC 134.1 (s), 134.6 (s)]. Compound 1 showed the same carbon composition (C30H50O3) and fragment ion peaks similar to those of inonotsuoxides A and B28, and inonotsutriols A and B31. In addition, 1H and 13C NMR chemical shifts of rings A-D (C-1 – C-19) were in good agreement with those of inonotsuoxides A and B, inonotsutriols A and B, and inonotsulides A and B29 which have a common lanost-8-ene skeleton.  The planar structure of 1 was determined from HMBC and 1H-1H COSY spectra. The HMBC spectrum of 1 (Table 1, Fig. 1) indicated long-range correlations between Me-18 (δH 0.72) and C-12, C-13, C-14, and C-17; between Me-19 (δH 0.98) and C-1, C-5, C-9, and C-10; between Me-21 (δH 0.94) and C-17, C-20, and C-22; between Me-27 (δH 1.76) and C-24, C-25, and C-26; between H2-26 (δH 4.84, 5.01) and C-24, C-25, and C-27; between Me-28 (δH 1.00) and C-3, C-4, C-5, and C-29; between Me-29 (δH 0.81) and C-3, C-4, C-5, and C-28; and between Me-30 (δH 0.87) and C-8, C-13, C-14, and C-15. The chemical shifts in the 1H and 13C NMR spectra of 1 resembled those of inonotsuoxide A (6) except those of H-22, H-23α, H-23β, H-24, H2-26, and Me-27 signals and C-22, C-24, and C-27 signals. Partial structural units are shown by bold lines in the 1H-1H COSY spectrum (Fig. 1). Acetylation of 1 with Ac2O/pyridine gave triacetate (1a) (C36H56O6, m/z 584.4069, calcd. 584.4077) in which the acetoxymethine proton signal appeared at δH 4.49 (dd), δH 4.88 (dt), and δH 5.22 (dd). The results indicate that compound 1 is a side-chain-cleaved inonotsuoxide A, and its chemical name is suggested to be lanost-8-ene-3β,22,24-triol. The relative configuration at C-17 and C-20 was established as R and S, because of the observed NOEs from Me-18 to H-20β and from H-17α to Me-21 and Me-30, and the coupling constants of H-17 [δH 1.46 (ddd, J17,16α = 9.6 Hz, J17,16β = 7.3 Hz, J17,20 = 12.7 Hz)] and H-20 [δH 1.70 (1H, dqd, J20,17 = 12.7 Hz, J20,21 = 6.7 Hz,  J20,22 = 3.0 Hz)]. The absolute configuration at C-22 was determined to be R (Figs. 2 and 3) because of the significant NOEs for H-20β/H-22, Me-21/H-23α, H-22/H-23β and H-22/H-24, and the coupling constants of H-22 [δH 3.96 (1H, dt, J22,20, J22,23β = 3.0 Hz, J22,23α = 9.2 Hz)].  The configuration of H-24 was R due to the significant NOEs for H-24/56Table 1  NMR spectral data of inonotsutriol D (1) in CDCl357Vol.3 (2009)H-26B, Me-27, and the coupling constants of H-24 [δH 4.26 (1H, dd, J24,23α = 9.2 Hz, J24,23β = 3.5 Hz)].One of the hydroxyl groups was C-3β as shown by the chemical shift and the coupling constants [δH 3.24 (1H, dd, J3,2α = 4.5 Hz and J3,2β = 11.7 Hz.); δC 79.0 (d)]. Other NOEs were observed from Me-19 to H-2β, H-6β, Me-18, and Me-29; from H-5α to H-1α, H-3α, H-7α, nd Me-28; from H-6β to Me-19 and Me-29; from H-7α to H-5α and Me-30; from H-12α to Me-30; from H-11β to Me-19; and from Me-18 to H-20β and Me-21. Therefore, rings A, B, and C in 1 adopted chair/twist, chair/twist, and chair conformations (Fig. 2).  These Fig. 1  Selected 1H-1H COSY and HMBC correlations for innotsutriol D (1)Fig. 2  Partial conformation for innotsutriol D (1)58Table 2  NMR spectral data of inonotsutriol E (2) in CDCl359Vol.3 (2009)data suggested that inonotsutriol D (1) is lanost-8-ene-3β,24R,24R-triol. The minor compound inonotsutriol E (2) had the same molecular formula C30H50O3 (M+; m/z 458) as 1 by EIMS. The IR, 1H, and 13C NMR spectra (Table 2) resembled those of 1 except H-23α (δH 1.67), H-24 (δH 4.36), H-26A (δH 4.94), and H-26B (δH 5.11) in the 1H NMR spectrum and C-22 (δC 70.3), C-24 (δC 73.5), and C-27 (δC 19.3) in the 13C NMR spectrum. HMBC and 1H-1H COSY spectra of 2 closely resembled those of 1, therefore, it was revealed that compound 2 was the same lanost-8-ene-3β,22,24-triol of 1. The R configuration at C-22 in 2 was deduced from the chemical shift and the coupling constants [δH 3.98 (1H, ddd, J22,20β = 3.2 Hz, J22,23α = 10.2 Hz, J22,23β = 2.8 Hz)], and from NOEs from H-22 to H-16α, H-16β, H-17α, H-20β, and H-23β, which is the same as that of 1. On the other hand, the absolute configuration at C-24 was S because of the NOEs of H-24/H-23α, H-24/H-23β, and H-24/H-26B (Figs. 4 and 5), and the chemical shift and the coupling constants [δH 4.36 (1H, t, J24,23α, J24,23β= 4.8 Hz)].  These data deduced the structure of inonotsutriol E (2) as lanost-8-ene-3β,24R,24S-triol, which is the C-24 epimer of 1.  Cancer cell growth inhibitory activities of main triterpene constituents: inotodiol (3), trametenolic acid (4), 3β-hydroxylanos-8,24-dien-21-al (5), and inonotsuoxide A (6) were examined using the murine P388 leukemia cell line (Table 3).  Compounds 4-6 exhibited moderate cytotoxic activity, while inotodiol (3) was inactive.Fig. 3  Observed NOEs correlations of innotsutriol D (1)(graphical representation using Chem 3D)60Fig. 4  Partial conformation for innotsutriol E (2)Fig. 5  Observed NOEs correlations of innotsutriol E (2)(graphical representation using Chem 3D)61Vol.3 (2009)EXPERIMENTALGeneralMelting points were determined on a Yanagimoto micro-melting point apparatus and are uncorrected. Optical rotations were measured using a JASCO DIP-1000 digital polarimeter. IR spectra were recorded using a Perkin-Elmer 1720X FTIR spectrophotometer. 1H and 13C N M R spect ra  were obt a ined on a Varian INOVA 500 spectrometer with standard pulse sequences, operating at 500 and 125 MHz, respectively.  CDCl3 was used as the solvent and TMS, as the internal standard. EIMS was recorded on a Hitachi 4000H double-focusing mass spectrometer (70 eV).  Column chromatography was carried out over silica gel (70-230 mesh, Merck) and medium-pressure liquid chromatography (MPLC) was carried out with silica gel (230-400 mesh, Merck). HPLC was run on a JASCO PU-1586 instrument equipped with a differential refractometer (RI 1531).  Fractions obtained from column chromatography were monitored by TLC (silica gel 60 F254, Merck).  Preparative TLC was carried out on Merck silica gel F254 plates (20 x 20 cm, 0.5 mm thick).MaterialInonotus obliquus is succeeded in culture in Salada Melon Co. Ltd., Nayoro City, Hokkaido, Japan. Sclerotium (4 kg) of I. obliquus was obtained from the above company in April 2005.  A voucher specimen (CG-03) was deposited at the Herbarium of the Laboratory of Medicinal Chemistry, Osaka University of Pharmaceutical Sciences.Assay for cytotoxicity using P388 cell lineCytotoxicity of inotodiol (3), t rametenolic acid (4),  3β-hydroxylanos-8,24 -dien-21-al (5 ),  and inonotsuoxide A (6 )  was examined using the 3- (4,5-dimethyl-2-th iazolyl) -2 ,5-diphenyl-2H-tetrazolium bromide (MTT) method. P388 and HL-60 cells were cultured in Eagle’s Minimum Essential Medium (10% fetal calf serum) suspension at 37 ºC in 5% CO2. The test material was dissolved in dimethyl sulfoxide (DMSO) to give a concentration of 10 mM and the solution was diluted with the Essential Medium to concentrations of 200, 20, and 2 μmol. Each solution was combined with the cell suspension (1 × 105 cells/ml) in the medium. After incubation at 37 ºC for 72 h in 5% CO2, the grown cells were labeled Table 3  Cytotoxity of the metabolites from the scelerotia of Inonotus obliquus against P388 cells62with 5 mg/ml MTT in phosphate buffered saline (PBS) and the absorbance of formazan dissolved in 20% sodium dodecyl sulfate (SDS) in 0.1 N HCl was measured at 540 nm using a microplate reader (Model 450, BIO-RAD). Each absorbance value was expressed as percentage relative to the control cell suspension that was prepared without the test substance using the same procedure as that described above. All assays were performed three times. Semilogarithmic plots were constructed from the averaged data and the dose required to inhibit cell growth by 50% (IC50) was determined.Extraction and isolationThe sclerotia of white-rot fungus I. obliquus (Pers.: Fr.) Pil. (4 kg) were extracted with chloroform (10 L) in 2005. Preliminary silica gel column chromatography (3 kg) of the chloroform extract (153.9 g) of I. obliquus sclerotia was reported to yield f ive fractions (A – E28). Residue C (30.2 g) was recrystallized from MeOH to give inotodiol, and the filtrate (17.1 g) was rechromatographed on MPLC (230-400 mesh silica gel, 500 g) using n-hexane:EtOAc (5:1). This was followed by HPLC [ODS, MeOH:H2O (85:15)], affording inonotsuoxides A (6) and B28. Subsequent elution on the same column with chloroform:EtOAc (5:1) gave a crystalline mass (272.8 mg) (Fr. Nos. 54-58), which was subjected MPLC (230-400 mesh silica gel, 30 g) using n-hexane:EtOAc (4:1) to afford a mixture of compounds 1 and 2 (52.6 mg) (Fr. Nos. 29-34).  This mixture was separated by HPLC [ODS, MeOH:H2O (90:10)] to give compounds 1 (19.1 mg) and 2 (10.1 mg).Inonotsutriol D (1).   Colorless prisms; mp 292-294 ºC (from MeOH-CHCl3); HREIMS m/z: 458.3766 [M]+ (C30H50O3, calcd for 458.3760); IR (KBr) νmax cm-1: 3399 (OH), 2943, 2876, 1457, 1373, 1072, 1030; 1H and 13C NMR, see Table 1. EIMS m/z (rel. int.): 458 (9) [M]+, 425 (3), 407 (3), 357 (75), 339 (18), 311 (13), 299 (8), 281 (7), 215 (6), 187 (8). Inonotsutr iol D tr iacetate (1a).    A mixtu re of compound 1 (8.6 mg) and Ac2O (2.2 mL) in pyr idine (2 mL) was kept at room temperature overnight.  Usual work-up gave a residue (10.8 mg) that was recrystallized from MeOH-CHCl3 to yield corresponding inonotsutriol D triacetate (1a) (7.3 mg). Colorless prisms; HREIMS m/z: 584.4049 [M]+ (C36H56O6, calcd for 584.4077); 1H NMR δ: 0.68 (3H, s, Me-18), 0.86 (3H, s, Me-30), 0.88 (6H, s, Me-28 and Me-29), 0.90 (3H, d, J = 6.7 Hz, Me-21), 1.00 (3H, s, Me-19), 1.73 (3H, s, Me-27), 2.03 (3H, s, C-22 OCOCH3), 2.06 (6H, s, C-3 and 22 OCOCH3), 4.49 (1H, dd, J = 11.7, 4.5 Hz, H-3α), 4.88 (1H, dt, J = 9.2, 3.0 Hz, H-22), 4.95 (2H, m), 5.22 (1H, dd, J = 9.2, 3.5 Hz, H-24). 13C NMR δ: 12.9 (C-21), 15.7 (C-18), 16.5 (C-29), 17.5 (C-27), 18.1 (C-6), 19.2 (C-19), 21.0 (C-11), 21.2 (C-22 OCOCH3), 21.3 (C-3 and C-24 OCOCH3), 24.2 (C-2), 24.3 (C-30), 26.4 (C-7), 26.8 (C-16), 27.9 (C-28), 30.1 (C-23), 30.8 (C-15), 30.9 (C-12), 35.3 (C-1), 37.8 (C-4), 39.6 (C-20), 44.8 (C-13), 47.2 (C-17), 49.3 (C-14), 49.5 (C-14), 50.5 (C-5), 73.2 (C-22), 75.6 (C-27), 80.9 (C-3), 114.4 (C-26), 134.2 (C-8), 134.4 (C-9), 169.9 (C-24 OCOCH3), 170.4 (C-22 OCOCH3), 171.0 (C-3 OCOCH3).Inonotsutriol E (2).   Colorless prisms; mp 292-294 ºC (from MeOH-CHCl3); HREIMS m/z: 458.3762 [M]+ (C30H50O3, calcd for 458.3760); IR (KBr) νmax cm-1: 3421 (OH), 2965, 2877, 1457, 1375, 1051, 1031; 1H and 13C NMR, see Table 2.  EIMS m/z (rel. int.): 458 (9) [M]+, 407 (3), 357 (75), 339 (18), 311 (13), 299 (8), 281 (7), 215 (6), 187 (8).63Vol.3 (2009)Acknowledgment  The authors are indebted to Mr. Kazuo Sakuma (Salad Melon Co. Ltd., Nayoro, Hokkaido) for supplying the sclerotia of Inonotus obliquus (kabanoanatake).REFERENCES1) D-L. Hawksworth, P-M. Kirk, B-C. Sutton, D-N. Pegler, ‘Ainsworth and Bisbi’s dictionary of the fungi, 8th ed. CAB International, University Press, Cambridge, 1995, p. 616. 2)  M-B. Ellis, P-J. Ellis, An identification handbook, London, Chapman and Hall, 1990, p. 329.3)  T. Yamaguchi, Ringakkai Hokkaido Sibu Ronbunshu 40, 30 (1992).4)  Y. Shin, Y. Tamai, M. Terazawa, J. Med. Mushr., 4, 77-84 (2002).5)  R-S. Ludwiczak, U. Wrecino, Poczniki Chem., 36, 497-502 (1962). 6)  K. Kahlos, R. 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New lanostane triterpenoids, inonotsutriols D, and E from Inonotus Obliquus

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New lanostane triterpenoids, inonotsutriols D, and E from Inonotus Obliquus

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