Digoniodiol, Deoxygoniopypyrone A, and Goniofupyrone A: Three New Styryllactones from Goniothalamus amuyon

• Abstract
• Introduction
• Materials and Methods
• Apparatus
• Plant material
• Extraction and isolation
• Isolates
• Bioassays
• Results and Discussion
• Acknowledgements
• References

Abstract

Three new styrylpyrone analogues, digoniodiol (2), deoxygoniopypyrone A (3), and goniofupyrone A (4), along with ten known styryllactones, were isolated from the aerial parts of Goniothalamus amuyon. Among these compounds, 2 is the first example of a bis-styrylpyrone. Compound 4 represents a new skeleton for styryllactones. All structures were established on the basis of spectroscopic data. The stereochemistry of 2 and 4 was determined by X-ray crystallographic analysis. The absolute configuration of 3 and 4 was further confirmed by Mosher ester derivatives. All styryllactones were subjected to cytotoxicity assays. Among them, goniothalamin, goniothalamin epoxide, and 8-chlorogoniodiol showed significant cytotoxicity against the HepG2 cancer cell line with IC₅₀ in the range of 0.19 - 0.64 μg/mL, and moderate activity toward Hep3B, MDA-MB-231, and MCF-7 cancer cell lines.

Introduction

The genus Goniothalamus (Annonaceae) is distributed throughout the tropics and subtropics, some of which are used widely as a folk medicine to treat edema and rheumatism or as an abortifacient in Southeast Asia [1], [2], [3]. The only species in Taiwan, Goniothalamus amuyon (Blanco) Merr., is distributed over the coastal region in the southern area. Literature surveys indicated that six basic styryllactone skeletons, including styrylpyrone, furanopyrone, furanofurone, pyranopyrone, butenolide, and heptolide types, were isolated from the genus, Goniothalamus [4]. Styryllactones were reported to possess cytotoxic and anti-tumor activities [4]. The previous investigation on the Formosan G. amuyon led to the isolation of several cytotoxic styryllactones [5], [6], [7]. Among them, goniodiol 7-monoacetate exhibited potent (ED₅₀ values < 0.1 μg/mL) cytotoxicity against KB, P-388, RPMI, and TE671 tumor cell lines [5]. Goniodiol 8-monoacetate demonstrated cytotoxicity against KB, P-388, A-549, HT-29 and HL-60 with ED₅₀ values of 4.85, 1.68, 4.79, 3.99 and 1.85 μg/mL, respectively [6]. In our continuing research on bioactive compounds of this species, three new compounds, digoniodiol (2), deoxygoniopypyrone A (3), and goniofupyrone A (4), as well as ten known compounds, including (6R,7R,8R)-gonodiol (1) [8], goniothalamin (5) [9], goniothalamin epoxide (6) [10], goniodiol 7-monoacetate (7) [5], goniodiol 8-monoacetate (8) [6], 8-chlorogoniodiol (9) [7], 8-methoxygoniodiol (10) [7], 9-deoxygoniopypyrone (11) [11], goniobutenolide A (12) [12], and goniobutenolide B (13) [12], were isolated (Fig. [1]). Besides spectral data, for compounds 3 and 4 the Mosher ester derivatives were prepared to determine their absolute configurations. The relative configurations of the structures of 2 and 4 were further confirmed by X-ray crystallography. Furthermore, all compounds were evaluated for their cytotoxicity against several human cancer cell lines (HepG2, Hep3B, MDA-MB-231, and MCF-7). Three known compounds, goniothalamin (5), goniothalamin epoxide (6), and 8-chlorogoniodiol (9), exhibited significant cytotoxicity against these cancer cell lines. Compound 2 showed mild cytotoxicity towards two cancer cell lines (HepG2 and MDA-MB-231) with the HIC₅₀ values at 6.83 and 6.80 μg/mL, respectively. Compounds 7 and 8, which had been reported to be active in cytoxicity assays, showed low activity.

Materials and Methods

Apparatus

Melting points were determined using a Yanagimoto micro-melting point apparatus and were uncorrected. CD spectra were recorded on a JASCO J-810 spectrometer. IR spectra were measured on a Mattson Genesis II spectrophotometer. ¹H-NMR (400 MHz) and ¹³C-NMR (100 MHz) spectra (all in CDCl₃) were recorded with Varian NMR spectrometers. LR-EI-MS were collected on a JEOL JMS-SX/SX 102A mass spectrometer. HR-FAB-MS were collected on a JEOL JMS-HX 110 mass spectrometer. Silica gel 60 (Merck, 230 - 400 mesh) was used for column chromatography. TLC analysis was carried out on silica gel GF₂₅₄ pre-coated plates with detection using 50 % H₂SO₄ followed by heating on a hot plate. HPLC was performed on a JASCO PU-980 apparatus equipped with a JASCO UV-970 detector. Hypersil ODS 5 μm (250 × 4.6 mm i. d.) and preparative ODS 5 μm (250 × 21.2 mm i. d.) columns were used for analytical and preparative purposes.

Plant material

Fresh leaves and stems of G. amuyon (Blanco) Merr. were collected in Hengchun, Pingtung Hsien, Taiwan in September, 1999, and September, 2001, and were identified by Dr. Hsin-Fu Yen (National Museum of Natural Sciences, Taichung, Taiwan). The voucher specimens (Goniothalamus 1) are deposited in the Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.

Extraction and isolation

Fresh stems (7.4 kg) of G. amuyon were extracted repeatedly with MeOH (10 L × 5) at room temperature. The combined MeOH extracts were evaporated under reduced pressure to give a syrup, which was partitioned between CHCl₃ and H₂O. The CHCl₃ layer was concentrated to give a residue (180 g), which was extracted with 5 % H₂SO₄ to give a CHCl₃ layer (Fr. C-1) and an acidic aqueous solution. The latter was basified with NH₄OH and extracted with CHCl₃ to afford a CHCl₃ layer (25 g) (Fr. C-2). The CHCl₃ (Fr. C-1) solution was dried and evaporated to leave a brownish viscous residue (125 g). The CHCl₃ (Fr. C-1) residue was subjected to silica gel (2.5 kg, 11 × 53 cm) column chromatography, gradient eluting with n-hexane (3L), n-hexane-CHCl₃ (2 : 1, 1 : 1, each 2 L), and CHCl₃-MeOH 1 : 0 (4 L), 50 : 1 (2 L), 25 : 1 (2 L), 15 : 1 (2 L), 12.5 : 1 (2 L), 10 : 1 (2 L), 8 : 1 (2 L), 6 : 1 (2 L), 4 : 1 (2 L). 2 : 1 (2 L), 1 : 1 (2 L), 1 : 2 (2 L), 1 : 4 (2 L), and 0 : 1 (4 L). The collected fractions were combined on the basis of their TLC characteristics to give 15 fractions after removal of solvents. Fraction 5 (ca. 3 g), eluted with pure CHCl₃ (4 L), was further separated by CC over silica gel (230 - 400 mesh, 2 × 16 cm, 15 g) with CHCl₃ (1 L) to give goniothalamin (5) (300 mL, 710 mg). Fraction 6, eluted with CHCl₃/MeOH 50/1 - 25/1 (3 L), was crystallized from CHCl₃ to give goniothalamin epoxide (6) (35 mg). Fraction 7, eluted with CHCl₃/MeOH 25/1 - 15/1 (2 L), was separated by CC over silica gel (230 - 400 mesh, 2.5 × 30 cm, 60 g) with CHCl₃ (0.5 L) and further purified by recrystallization from CHCl₃ to afford 8-chlorogoniodiol (10) (50 mg). Fraction 8, eluted with CHCl₃/MeOH 15/1 - 12.5/1 (2 L), was eluted with n-hexane-EtOAc (5 : 1, 0.6 L) and further purified by recrystallization from CHCl₃ to give 8-methoxygoniodiol (9) (30 mg). Fraction 11, eluted with CHCl₃/MeOH 6/1 (2 L), was purified by RP-HPLC (Hypersil ODS column, i. d. 21.2 × 250 mm, MeCN-water, 30 : 70, flow rate 2.5 mL/min; UV detector set at 254 nm) to give goniobutenolide A (12) (5 mg, t _R = 31.93 min) and goniobutenolide B (13) (4.2 mg, t _R = 41.14 min). Fraction 14, eluted with CHCl₃/MeOH 1/1 (2 L), was purified by RP-HPLC (Hypersil ODS column, i. d. 21.2 × 250 mm, MeCN-water, 30 : 70, flow rate 2.5 mL/min; UV detector set at 254 nm) to give (6R,7R,8R)-goniodiol (1) (25 mg, t _R = 31.61 min) and digoniodiol (2) (30 mg, t _R 64.55 min).

The CHCl₃ layer (25 g) (Fr. C-2) was subjected to silica gel column chromatography (630 g, 27 × 7 cm) and eluted with gradient mixtures of CHCl₃-MeOH 1 : 0 (2 L), 50 : 1 (1 L), 25 : 1 (2 L), 10 : 1 (3 L), 8 : 1 (2 L), 4 : 1 (1 L). 2 : 1 (1 L), 1 : 1 (1 L), 1 : 2 (1 L), 1 : 4 (1 L), and 0 : 1 (3 L). The eluates were combined into 10 fractions on the basis of TLC monitoring. Fraction 6, eluted with pure CHCl₃ (750 mL), was further purified by recrystallization (CHCl₃) to give 9-deoxygoniopypyrone (11) (50 mg). Fraction 9, eluted with CHCl₃/MeOH (25/1, 500 mL), was purified by RP-HPLC (Hypersil ODS column, i. d. 21.2 × 250 mm, MeCN-water, 20 : 80, flow rate 2.5 mL/min; UV detector set at 210 nm) to give deoxygoniopypyrone A (3) (24 mg, t _R = 86.08 min) and goniofupyrone A (4) (20 mg, t _R = 65.14 min).

Goniodiol 7-monoacetate (7) and goniodiol 8-monoacetate (8) were isolated from the leaves of G. amuyon traced by TLC of authentic samples [10].

Isolates

Digoniodiol (2): Colorless prisms; m. p. 166 - 168 °C; [α]_D ²³: -35.5° (c 0.11, MeOH); IR (KBr): ν_max = 3411, 2909, 1716, 1385, 1109, 1061, 757 cm^-1; CD (MeOH): [Θ] = + 1.86 (257 nm), + 2.24 (262.7 nm), + 1.92 (272.4 nm); ¹H-NMR (400 MHz, CDCl₃): see Table [1]; ¹³C-NMR data (100 MHz, CDCl₃): see Table [1]; EI-MS (70 eV): m/z = 325 (10), 217 (100), 120 (20), 97 (92); HR-FAB-MS: m/z = 451.1757 [M + H]⁺ (calcd. for C₂₆H₂₆O₇ : 451.1762).

Crystal data for 2: A colorless prism crystal of C₂₆H₂₆O₇ having approximate dimensions of 0.60 × 0.70 × 0.80 mm was mounted on a glass fiber. All measurements were made on a Rigaku AFC7S diffractometer with graphite monochromated Mo-Kα radiation. Cell constants and an orientation matrix for data collection, obtained from a least-squares refinement using the setting angles of 17 carefully centered reflections in the range 8.98 < 2Θ < 11.18° corresponded to a primitive orthorhombic cell with dimensions: a = 12.071(2) Å, b = 16.225(2) Å, c = 11.597(3) Å, V = 2271.4(7) ų. For Z = 4 and F. W. = 450.49, the calculated density is 1.317 g/cm³, F(000) = 952.00, μ (MoKα) = 0.95 cm^-1.

Deoxygoniofupyrone A (3): colorless needles; m. p. 170 - 172 °C; [α]_D ²³: -150.3° (c 0.07, MeOH); IR (KBr): ν_{max =} 3405, 2913, 1730, 1449, 1373, 1216, 1080, 1064, 1040, 978, 940, 754 cm^-1; ¹H-NMR (400 MHz, CDCl₃): see Table [2]; ¹³C-NMR (100 MHz, CDCl₃): δ = 23.8 (C-9), 40.8 (C-4), 65.2 (C-5), 75.8 (C-8), 76.0 (C-7), 79.1 (C-1), 126.9 (C-11, 15), 128.4 (C-12, 14), 128.6 (C-13), 139.3 (C-10), 168.9 (C-3); EI-MS (70 eV): m/z = 234 [M]⁺ (3), 216 [M - H₂O] ⁺ (8), 188 (10), 177 (4), 144 (35), 128 (36), 107 (100), 91 (44), 77 (26); HR-FAB-MS: m/z = 235.0963 [M + H]⁺ (calcd. for C₁₃H₁₅O₄ : 235.0970).

Goniofupyrone A (4): colorless plates; m. p. 154 - 156 °C; [α]_D ²³: -25.6° (c 0.08, CHCl₃); IR (KBr): ν_max = 3420, 1738, 1455, 1373, 1203, 1177, 1083, 1034, 763, 701 cm^-1; ¹H-NMR (400 MHz, CDCl₃): see Table [1]; ¹³C-NMR (100 MHz, CDCl₃): see Table [1]; EI-MS (70 eV) : m/z = 217 [M - OH]⁺ (1), 128 (100), 107 (41), 105 (41), 91 (41), 77 (41); HR-FAB-MS: m/z = 235.0974 [M + H]⁺ (calcd. for C₁₃H₁₅O₄ : 235.0970).

Crystal data for 4: A colorless plate crystal of C₁₃H₁₄O₄ having approximate dimensions of 0.70 × 0.80 × 0.20 mm was mounted on a glass fiber. All measurements were made on a Rigaku AFC7S diffractometer with graphite monochromated Mo-Kα radiation. Cell constants and an orientation matrix for data collection, obtained from a least-squares refinement using the setting angles of 20 carefully centered reflections in the range 8.63 < 2Θ < 14.26° corresponded to aorthorhombic cell with dimensions: a = 9.581(3) Å, b = 10.706(2) Å, c = 10.866(3) Å, V = 1114.6(4) ų. For Z = 4 and F. W. = 234.25, the calculated density is 1.40 g/cm³, F(000) = 496.00, μ(MoKα) = 1.03 cm^-1.

The structures of the ten known compounds (Fig. [1]), (6R,7R,8R)-goniodiol (1) [14], goniothalamin (5) [9], goniothalamin epoxide (6) [10], goniodiol 7-monoacetate (7) [5], goniodiol 8-monoacetate (8) [6], 8-chlorogoniodiol (9) [7], 8-methoxygoniodiol (10) [7], 9-deoxygoniopypyrone (11) [11], goniobutenolide A (12) [12], and goniobutenolide B (13) [12], were determined by comparison with the physical and spectroscopic data reported in the literature.

Bioassays

The 3-days bioassays against HepG2, Hep3B, MDA-MB-231, and MCF-7 cell lines were carried out according to procedures described in the literature [13].

Results and Discussion

The spectral data of compounds 1 and 2 are similar. Compound 1 was obtained as colorless crystals, [α]_D ²²: + 60.9°. The molecular formula of 1 was suggested as C₁₃H₁₄O₄ by EI-MS peaks at m/z = 234 [M]⁺ and 216 [M - H₂O]⁺. The IR absorption bands at 3366 and 1710 cm^-1 indicated the presence of a hydroxy group and a carbonyl group, respectively. The ¹H- and ¹³C-NMR spectra indicated the presence of a mono-substituted phenyl moiety and an α,β-unsaturated-δ-lactone ring moiety (Table [1]) [7]. The key ¹H-¹H COSY correlations among three carbinol protons between δ = 3.70 - 4.93, as well as the corresponding three oxygen-bearing carbon resonances at δ = 73.6, 75.0, and 76.7 in the HETCOR spectrum, were suggestive of a two-carbon bridge between a mono-substituted phenyl moiety and an α,β-unsaturated-δ-lactone ring moiety. Therefore, compound 1 was identified as a goniodiol-type compound [14]. The J _7,8 coupling constant, 7.6 Hz, indicated an erythro form between H-7 and H-8 [14]. The positive Cotton effect in the CD spectrum at 250 - 272 nm (n-π*) indicated the R form at C-6 [8]. On the basis of these spectral data, compound 1 was identified as (6R,7R,8R)-goniodiol [14]. The fully elucidated structure of 1 was applied to the solution of compound 2.

Compound 2 was obtained as colorless crystals. The IR absorption bands presented the presence of a hydroxy and a carbonyl group, as well as those of 1, at 3411 cm^-1 and 1716 cm^-1. The molecular formula of 2 was established as C₂₆H₂₆O₇ by HR-FAB-MS ([M + H]⁺ at m/z = 451.1757, calcd. 451.1762). The signals in the ¹H- and ¹³C-NMR spectra (Table [1]) of compound 2 are similar to those of compound 1. Combining with the observed molecular weight, mass and NMR data of compound 2 suggested the presence of two mono-substituted phenyl moieties and two α,β-unsaturated-δ-lactone moieties. It indicated that 2 is composed of two symmetric goniodiol monomers (Fig. [2]). Three oxygen-bearing carbon pairs at δ = 77.6 (C-8/C-8′), 75.7 (C-6/C-6′), and 74.7 (C-7/C-7′) and six corresponding carbinol protons between δ = 3.37 - 4.86 were also observed. The ³ J HMBC correlations between the proton signals at δ = 4.38 (H-8/H-8′) and the ¹³C signals at δ = 77.6 (C-8′/C-8) suggested that two goniodiol monomers were dehydrated and ether-bridged between C-8 and C-8′ (Fig. [3]). Interestingly, a significant shift from δ = 73.6 (C-8 in 1) to δ = 77.6 (C-8/C-8′ in 2) coincided with the phenomena observed by Wang et al. [15].

The relative configurations at H-7/H-8 and H-7′/H-8′ were determined to be erythro by the J _7,8 (J _{7 ′,8 ′}) coupling constant (8.2 Hz) like those of 1 [7]. The configuration was derived from its positive Cotton effect in the CD spectrum at 250 - 272 nm (n-π*), which revealed that the configuration at C-6 (C-6′) should be R [8]. In addition, the X-ray crystal data provided the relative configuration of 2 (Fig. [4]). Therefore, the absolute configuration of 2 was assigned as 6R,7R,8R and 6′R,7′R,8′R. Thus, the structure of 2 was concluded as 6-{1-hydroxy-2-[2-hydroxy-2-(6-oxo(3-hydro-2H-pyran-2-yl))-1-phenylethoxy]-2-phenylethyl}-5,6-dihydro-2H-pyran-2-one, which was named as digoniodiol. Compound 2 is the first example of a symmetrical styrylpyrone dimer.

Compound 3 was isolated as colorless needles, [α]_D ²³: -150.3°. In the EI-MS, the molecular weight was indicated by a peak at m/z = 234 [M]⁺, and the presence of one hydroxy by a peak at m/z = 216 [M - H₂O]⁺. The molecular formula of 3 was established as C₁₃H₁₅O₄ by HR-FAB-MS ([M + H]⁺ at m/z = 235.0963, calcd. 235.0970). The IR absorption bands at 3405 and 1730 cm^-1 suggested the presence of a hydroxy group and δ-lactone ring, respectively. The structure was similar to 9-deoxygoniopypyrone (11), leiocarpin A, and (-)-iso-5-deoxygoniopypyrone, and proposed as 8-hydroxy-7-phenyl-2, 6-dioxabicyclo[3.3.1]nonan-3-one by comparison of their ¹H- and ¹³C-NMR spectral data (Table [2]). However, the proposed structure possesses four chiral centers, which leaves interesting problems in stereochemistry still to be solved.

The relative stereochemistry of 3 (Fig. [5]) was determined by coupling constants and the NOESY spectrum. The J _7,8 value (8.8 Hz) indicates that H-7 and H-8 were in a trans form [12], and the coupling constant J _8,1 value (1.0 Hz) indicates that the dihedral angle of H-1 and H-8 is close to 90°. The aforementioned data and the NOESY cross-peak of the H-7 proton and H-9b proton indicated that the configuration of 3 was 1R*,5R*,7R*,8R*, which was different from those of compounds 11 (1R,5R,7S,8R), leiocarpin A (1S*,5S*,7R*,8R*), and (-)-iso-5-deoxygoniopypyrone (1R*,5R*,7S*,8S*). The obvious difference was also observed in the [α]_D values {-150° for 3, + 11° for 11, -98° for leiocarpin A, and -90° for (-)-iso-5-deoxygoniopypyrone}. In order to determine the absolute configuration of 3, (R)- and (S)-methoxyfluoromethylphenylacetic acid (MTPA) esters of 3 (3r and 3s) were prepared. The NMR data of 3r and 3 s indicated the absolute configuration of C-8 to be R, Therefore, the absolute configuration of the chirality of C-1, C-5, C-7, and C-8 were assigned to be R. Thus, compound 3 is a new compound and named as deoxygoniopypyrone A.

Compound 4 was obtained as colorless crystals. The IR spectrum of 4 contained absorption bands at 3419 and 1738 cm^-1 for the hydroxy group and the δ-lactone ring moiety, respectively. The molecular weight suggested by a prominent FAB-MS peak at m/z = 235 [M + H]⁺ and the HR-FAB-MS peak at m/z = 235.0974 for the [M + H]⁺ ion (calcd. 235.0970), corresponds to the molecular formula C₁₃H₁₄O₄. The ¹H-NMR and ¹³C-NMR spectra of 4 suggested the presence of a mono-substituted phenyl group (Table [1]). In comparison with the NMR spectral data of 9-deoxygoniopypyrone (11) and those of compound 4, the ¹³C signal at δ = 169.2 suggested the presence of a saturated δ-lactone moiety, which also corresponded to a slight hyperchromic shift of the IR carbonyl absorption from 1710 (in compound 1) to 1738 cm^-1 (in compound 4).

The degree of unsaturation, the mass fragments profile and the NMR spectral analysis of compound 4 suggested that there should be a five-membered ring by an ether linkage between C-5 and C-7, different from a six-membered ring in compounds 3 and 11. The EI-MS peaks at m/z = 128 [M - PhCH₂O+H]⁺ and 107 [PhCH₂O]⁺ suggested a cleavage between C-7 and C-9. Moreover, the EI-MS peak at m/z = 217 [M - H₂O]⁺ suggested that the hydroxy group should be located at C-9 (Fig. [2]). This prediction was confirmed by the single-crystal X-ray diffraction analysis (Fig. [4]). 2D NMR techniques were useful in structural determination of 4 (Table [1]).

The relative stereochemistry of 4 was determined by coupling constants and the NOESY spectrum (Fig. [5]). The coupling constant J _7,9 value (8.8 Hz) indicates that H-7 and H-9 were in the trans orientation. Besides, due to the NOE correlation between H-7 and H-8, the β-orientation bridge of C-8 between C-1 and C-5 was determined.

The structure of compound 4 was confirmed by the single-crystal X-ray diffraction analysis, and the absolute configuration of 4 was determined by the preparation of (S)- and (R)-methoxyfluoromethylphenylacetic acid (MTPA) esters of 4 (4r and 4s). However, the ¹H NMR data (Table [3]) of 4r and 4 s are not sufficiently significant to determine the absolute configuration of C-9. Since styryllactones that were isolated from this plant possess the R configuration at C-8, compound 4 is possibly derived from styrylpyrone as a precursor [4], which suggests C-9 of 4 to have the R configuration. The absolute configuration of 4 was determined as 1R,5R,7R,9R. Thus, the tentative structure of 4 is 7-(hydroxyphenylmethyl)-2,6-dioxabicyclo[3.2.1]-octan-3-one, which was named as goniofupyrone A. Compound 4 represents a new styryllactone skeleton.

The cytotoxicity of new compounds 2 - 4 and the other known compounds 1, 5 - 13 were evaluated against a series of human cancer cell lines (Table [4]). Among them, compounds 5, 6, and 9 showed significantly cytotoxicity. Compound 2 showed more cytotoxic activity than (6R,7R,8R)-goniodiol (1) toward Hep G2 (human hepatocellular carcinoma) and MDA-MB-231 (human breast cancer) cell lines. The chlorine-substituted derivative 9 showed a fifteen-fold higher cytotoxicity than goniodiol (1) toward Hep G2 and MDA-MB-231 cell lines. It is very interesting to note that goniodiol 7-monoacetate (7) and goniodiol 8-monoacetate (8) showed cytotoxicity against several cancer cell lines [5], [6], however, they did not display the significant activity to targeted cancer cell lines shown in the present work.

Acknowledgements

This investigation was supported by a grant from the National Science Council of the Republic of China. We thank Miss Shu-Li Chen for the cytotoxic assays.

References

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Prof. Dr. Yang-Chang Wu

Graduate Institute of Natural Products

Kaohsiung Medical University

Kaohsiung 807

Taiwan

Republic of China

Fax: +886-7-311-4773

Email: yachwu@kmu.edu.tw

References

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Prof. Dr. Yang-Chang Wu

Graduate Institute of Natural Products

Kaohsiung Medical University

Kaohsiung 807

Taiwan

Republic of China

Fax: +886-7-311-4773

Email: yachwu@kmu.edu.tw