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Structure-antiemetic-activity of some diarylheptanoids and their analogues.

Summary

The structure-activity relationship of diarylheptanoids and their analogues inhibitory of emesis induced by copper sulfate in young chicks was investigated by testing 19 compounds. The compounds are 5 diarylheptanoids isolated from Alpinia katsumadai (Zingiberacea), 5 chemical derivatives of them, 6 analogues isolated from Zingiber officinale rhizome (Zingiberaceae), and 3 analogues available on the market. Among them, two types of essential functional structure of diaryiheptanoids and their analogues showed the inhibitory effects against emesis.

Key words: diarylheptanoid, anti-emetic, structure-activity relationship.

Introduction

Anti-cancer agents frequently cause nausea and vomiting as the side effects. Some traditional Chinese herbal drugs possessing anti-emetic effect seem to be potent against them. We performed systematic survey of anti-emetic compounds from Chinese medicines and other natural materials, finding many active compounds inhibitory of emesis induced by copper sulfate in young chicks. Alpinia species (Zingiberaceae) have been used as an anti-emetic agent and for the treatment of the stomach disease. Among them, A. katsumadai was investigated in detail. We reported its 8 anti-emetic principles, 6 of which are diarylheptanoids (Yang et al., 1999a, b), and concluded that diarylheptanoids are the major anti-emetic principles of A. katsumadai. However, some structurally different diaryl-heptanoids from the same plants showed no anti-emetic activity. In order to find the basic structure of diarylheptanoids effective in inhibiting emesis, we investigated the structure-activity relationship of diarylheptanoids inhibitory of e mesis induced by copper sulfate in young chicks by testing 19 compounds. The compounds are 5 diarylheptanoids isolated from A. katsumadai, 5 chemical derivatives of them, 6 analogues isolated from Zingiber officinale (Zingiberaceae), and 3 analogues available on the market.

Materials and Methods

Materials

The anti-emetic activity of 19 diarylheptanoids and their analogues (Fig. 1, 2 and 3) was examined in young chicks against copper sulfate-induced emesis. 6-, 8-, 10-Shogaol (1-3) and 6-, 8-, 10-gingerol (4-6) were isolated from Zingiber officinale in our laboratory (Akita et al., 1998). trans, trans-1,7-Diphenyl-4,6-heptadien-3-one (7), trans, trans-1,7-diphenyl-5-hydroxy-4,6-heptadien-3-one (8), (5R)-trans-1,7-diphenyl-5-hydroxy-6-hepten-3-one (9), (3S, 5S)-trans-3,5-dihydroxy- 1,7-diphenyl-1-heptene (10), and (3R,5S)-trans3,5-dihydroxy-1,7-diphenyl-1-heptene (11) were isolated from Alpinia katsumadai (Yang et al., 1999a). 1,7-Diphenyl-heptane-3-one (12), dihydroyashabushiketol (14), (3S,5R)-3,5-dihydroxy-1,7-diphenyl-heptane (15), and (3S,5S)-3,5-dihydroxy-1,7-diphenylheptane (16) were prepared from compound 7, 9, 10 and 11 by hydrogenation over palladium carbon, respectively. trans, trans-1,7-Diphenyl-1,3-heptadien-5-ol (13) was prepared from compound 7 by reducing with [NaBH.sub.4]. trans-4-Phenyl-3-buten -2-one (17) was purchased from Wako Pure Chemicals Industries Ltd. (Japan). 4-Phenylbutan-2-one (18) and trans-4-phenyl-3-buten-2ol (19) were prepared from compound 17.

1,7-Diphenyl-heptane-3-one (12)

A mixture of 7 (100.8 mg) was hydrogenated at room temperature by using 5% Pd/C catalyst (30 mg) in MeOH (50 ml). The reaction mixture was filtered, and the filtrate was evaporated under the reduced pressure to give compound 12 (52.7 mg). [H.sup.1]-NMR (CD[Cl.sub.3]) [delta]: 1.58-1.61 (4H, m), 2.40 (2H, t, J = 7 Hz), 2.59 (2H, t, J = 7 Hz), 2.70 (2H, m), 2.88 (2H, t, J = 8 Hz), 7.14-7.28 (10H, m); [C.sup.13]-NMR (CD[Cl.sub.3]) [delta]: 23.4 ([CH.sub.2]), 29.8 ([CH.sub.2]), 30.9 ([CH.sub.2]), 35.7 ([CH.sub.2]), 42.8 ([CH.sub.2]), 44.2 ([CH.sub.2]), 125.6 (CH), 125.9 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 141.0 (C), 142.0 (C), 209.7 (C).

trans, trans-1,7-Diphenyl-1,3-heptadien-5-ol (13)

A solution of 7 (300 mg) in MeOH (10 ml) was added with [NaBH.sub.4] (80 mg) and stirred for 1 hour at room temperature. The reaction mixture was neutralized with 1N HCl and extracted with CH[Cl.sub.3]. After drying with anhydrous [Na.sub.2][SO.sub.4], the organic extract was evaporated under the reduced pressure to give a residue, which was chromatographed on HPLC [silica-4251-N 10[PHI] x 250 mm, n-hexane-acetone (8:2)] to afford compound 13 (42.4 mg). [H.sup.1]-NMR (CD[Cl.sub.3]) [delta]: 1.92 (2H, m), 2.73 (2H, m), 4.23 (1H, q, J = 7 Hz), 5.85 (1H, dd, J = 15, 7 Hz), 6.39 (1H, dd, J = 15, 10 Hz), 6.55 (1H, d, J = 15 Hz), 6.77 (1H, dd, J = 15, 10Hz), 7.19-7.45 (10H, m); [C.sup.13]-NMR (CD[Cl.sub.3]) [delta]: 31.7 ([CH.sub.2]), 38.7 ([CH.sub.2]), 71.9 (CH), 125.7 (CH), 126.2 (CH), 127.5 (CH), 128.0 (CH), 128.3 (CH), 128.5 (CH), 129.0 (CH), 130.8 (CH), 132.7 (CH), 136.1 (CH), 136.9 (C), 141.6 (C). Those NMR spectral data agreed with published data (Claeson et al., 1993).

Dihydroyashabushiketol (14)

A mixture of 9 (188.0 mg) was hydrogenated at room temperature by using 5% Pd/C catalyst (50 mg) in MeOH (100 ml). The reaction mixture was filtered, and the filtrate was evaporated under the reduced pressure to give compound 14 (119.1 mg). [H.sub.1]-NMR (CD[Cl.sub.3]) [delta]: 1.62-1.84 (1H, m), 2.48-2.91 (8H, m), 3.04 (1H, br), 4.04 (1H, q, J = 3 Hz), 7.15-7.29 (10H, m). Those NMR spectral data agreed with published data (Kuroyanagi et al., 1983).

(3S,5R)-3,5-Dihydroxy-1,7-diphenylheptane (15)

A mixture of 10 (51.5 mg) was hydrogenated at room temperature by using 5% Pd/C catalyst (15 mg) in MeOH (25 ml). The reaction mixture was filtered, and the filtrate was evaporated under the reduced pressure to give compound 15 (32.8 mg). [[[alpha]].sub.D] [+ or -] 0[degrees] (c = 0.38, EtOH). HREIMS m/z: 284.1775, calcd for [C.sub.19][H.sub.24][O.sub.2], 284.1776. [H.sub.1]-NMR (CD[Cl.sub.3]) [delta]: 1.55-1.83 (6H, m), 2.64-2.91 (4H, m), 3.48 (2H, br), 3.87 (2H, m), 7.17-7.30 (10H, m). Those spectral data agreed with published data (Kuroyanagi et al., 1983).

(3S,5S)-3,5-Dihydroxy-1,7-diphenylheptane (16)

A mixture of 11 (39.4 mg) was hydrogenated at room temperature by using 5% Pd/C catalyst (15 mg) in MeOH (25 ml). The reaction mixture was filtered, and the filtrate was evaporated under the reduced pressure to give compound 16 (38.6 mg). [[[alpha]].sub.D] -5.3[degrees] (c = 0.46, EtOH). HREIMS m/z: 284.1772, calcd for [C.sub.19][H.sub.24][O.sub.2], 284.1776. [H.sup.1]-NMR (CD[Cl.sub.3]) [delta]: 1.74-1.88 (6H, m), 2.60-2.79 (4H, m), 3.48 (2H, br), 3.99 (2H, m), 7.15-7.31 (10H, m).

4-Phenyl butan-2-one (18)

A mixture of 17 (1080 mg) was hydrogenated at room temperature by using 5% Pd/C catalyst (300 mg) in MeOH (30 ml). The reaction mixture was filtered, and the filtrate was evaporated under the reduced pressure to give compound 18 (1001 mg). [H.sup.1]-NMR ([CDCl.sub.3]) [delta]: 2.13 (3H, s), 2.75 (2H, t, J = 8 Hz), 2.89 (2H, t, J = 8 Hz), 7.16--7.30 (5H, m); [C.sup.13]-NMR ([CDCl.sub.3]) [delta]: 29.8 ([CH.sub.3]), 30.1 ([CH,sub.2]), 45.2 ([CH.sub.2]), 126.0 (CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 140.8 (C), 207.7 (C).

trans-4-Phenyl-3-buten-2-ol (19)

A solution of 17 (1032.0 mg) in MeOH (30 ml) was added with NaBH4 (250 mg) and stirred for 1 hour at room temperature. The reaction mixture was neutralized with 1N HCI, and then was extracted with [CHCl.sub.3]. After drying with anhydrous [Na.sub.2][SO.sub.4], the organic extract was evaporated under the reduced pressure to afford compound 19 (980 mg). [H.sup.1]-NMR ([CDCl.sub.3]) [delta]: 1.35 (3H, d, J = 8 Hz), 4.78 (1H, ddd, J = 8, 8, 2 Hz), 6.25 (1H, dd, J = 20, 8 Hz), 6.55 (1H, d, J = 20 Hz), 7.22--7.39 (5H, in); [C.sup.13]-NMR ([CDCl.sub.3]) [delta]: 23.3 ([CH.sub.3]), 68.9 (CH), 126.4 (CH), 127.6 (CH), 128.2 (CH), 128.5 (CH), 128.9 (CH), 129.3 (CH), 133.5 (CH), 136.6 (C).

Spectrometry and chromatography

The [[alpha].sub.D] values were determined with a JASCO DIP-140 digital polalimeter. The [H.sup.1] and [C.sup.13]-NMR spectra were recorded by using a JEOL GSX-400 spectrometer in [CDCl.sub.3] with tetramethylsilane as the internal standard. Kieselgel-60[F.sub.254] (MERCK)-precoated plates were employed for thin-layer chromatography (TLC). Column chromatography was carried out on 70--230 mesh silica gel (MERCK). HPLC was performed by using an SSC-3100-J pump with an Oyo-Bunko Uvilog 7 UV detector. HREIMS were obtained by using a JEOL JMX-DX 302.

Bioassay of anti-emetic activity

The young male chicks weighing 25-35 g (Goto Furanjo Co., Inc. Saitama, Japan) were divided into 1-3 groups consisting of six each. The young chicks were set aside for 10 mm and stabilized in large beakers at 25 [degrees]C. The sample solution was administered intraperitoneally in a dose of 10 ml/kg. After 10 mm, copper sulfate anhydride was administered orally in a dose of 50 mg/kg, then the number of retching (an emetic action without vomiting gastric materials) was recorded during the next to mm. The results were judged by the decrease in numbers of retching compared with those of control. The inhibition (%) was calculated as follows:

Inhibition (%) = [(A-B)/A]x100

A: control frequency of retching

B: frequency of retching after sample treatment

Statistical analysis: all numerical data were expressed as the mean [+ or -] S. E. M. The statistical significance of the difference was determined by an unpaired Student's t-test.

Results and Discussion

We have been already reported (Akita et al., 1998) that the known anti-emetics, chloropromazine, metoclopramide and ethyl p-aminobenzoate, showed antiemetic activities at the dose of 50 mg/kg in this assay method. On the basis of the results, all compounds were tested at the dose.

We are searching for anti-emetic principles from natural sources. Some diarylheptanoids showed antiemetic acitivity, but not all, depending on their partial structures. Following our previous findings that shogaol and gingerols showed the anti-emetic activity (Akita et al., 1998), we found that anti-emetic active diarylheptanoids posess the similar functional groups in their structure. As shown in Table 1 (Akita et al., 1998) and 2, compounds 1-6, 7, 9-11, 13-16 showed the anti-emetic activity in a dose of 50 mg/kg, and compounds 8, 12, 17-19 showed no effects. After analyzing the structure of these diarylheptanoids and related compounds, the anti-emetic compounds were classified into two groups. As shown in Fig. 1, compounds 1-3, 7, 13, which contain A type functional structure, were classified into A group. Compounds 4-6, 9-11, 14-16, which contain B type functional structure (Fig. 2) and showed the anti-emetic activity, were classified into B group. Compounds 8, 12, 17-19, which showed no anti-emetic effec ts, contain neither A nor B type functional structure (Fig. 3). These results revealed that A and B type functional structures are the essential structural parts of the compounds to show the anti-emetic activity. This finding would be important for the anti-emetic drug design and synthesis in the future.

Diarylheptanoids are very common in the Zingiberaceae, and are isolated from A. officinarum (Itokawa et al., 1981, 1985; Uehara et al., 1987), A. oxyphylla (Itokawa et al., 1982; Shoji et at., 1984), A. conchigera (Athamprasangsa et al., 1994), A. bleparocalyx (Kadota et al., 1994), and Curcuma comosa and C. xanthorrhiza (Uehara et al., 1987). These have been used as the anti-emetics in Chinese traditional medicine. As shown in Fig. 4, these diarylheptanoids also contain A or B type partial structure. Therefore, we concluded that diarylheptanoids of types A and B might be the main and common anti-emetic principles of Zingiberaceae.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]
Table 1

Anti-emetic effects of 6-, 8-, 10-shogaol (1-3) and 6-, 8-, 10-
gingerol (4-6) on copper sulfate induced-emesis in young chicks (Akita
et al., 1998).

Drugs Dose (mg/kg) No. of young chicks


control 5
6-shogaol (1) 50 6
control 6
8-shogaol(2) 50 6
control 6
10-shogaol (3) 50 6
control 6
6-gingerol (4) 50 6
control 6
8-gingerol (5) 50 6
control 6
10-gingerol (6) 50 5

Drugs No. of retching Inhibition (%)
 (mean [+ or -] S. E. M.)

control 39.6 [+ or -] 1.52
6-shogaol (1) 19.8 [+ or -] 2.34 *** 49.2
control 41.0 [+ or -] 1.67
8-shogaol(2) 19.0 [+ or -] 2.13 *** 53.7
control 50.3 [+ or -] 2.20
10-shogaol (3) 15.6 [+ or -] 3.17 *** 69.0
control 45.7 [+ or -] 2.79
6-gingerol (4) 19.2 [+ or -] l.74 *** 58.0
control 45.5 [+ or -] 2.28
8-gingerol (5) 21.5 [+ or -] 2.25 *** 52.7
control 40.2 [+ or -] 1.30
10-gingerol (6) 21.6 [+ or -] 3.61 *** 46.3

Significantly different from the control value

*** p < 0.001.
Table 2

Anti-emetic effects of diarylheptanoids and related compounds on copper
sulfate induced-emesis in young chicks.

Drugs Dose (mg/kg) No. of young chicks No. of retching
 (mean [+ or -] S.E.M.)

control 6 84.4 [+ or -] 1.31
7 50 6 53.8 [+ or -] 4.01 **
control 6 82.2 [+ or -] 2.27
8 50 6 64.7 [+ or -] 5.22
control 6 75.8 [+ or -] 2.33
9 50 6 33.5 [+ or -] 3.71 **
control 6 82.2 [+ or -] 2.27
10 50 6 36.5 [+ or -] 2.20 **
control 6 74.2 [+ or -] 4.76
11 50 6 21.7 [+ or -] 1.19 ***
control 6 75.8 [+ or -] 3.67
12 50 6 70.0 [+ or -] 2.65
control 6 75.8 [+ or -] 3.67
13 50 6 38.4 [+ or -] 4.62 **
control 6 78.7 [+ or -] 3.19
14 50 6 41.7 [+ or -] 1.47
control 6 73.7 [+ or -] 3.11
15 50 6 38.5 [+ or -] 4.53 ***
control 6 77.5 [+ or -] 2.77
16 50 6 41.0 [+ or -] 3.94 ***
control 6 78.7 [+ or -] 3.19
17 50 6 63.2 [+ or -] 4.36
control 6 77.5 [+ or -] 2.77
18 50 6 61.0 [+ or -] 4.26
control 6 78.7 [+ or -] 3.19
19 50 6 67.8 [+ or -] 4.44

Drugs Inhibition (%)


control
7 36.6
control
8 17.3
control
9 55.6
control
10 55.6
control
11 70.8
control
12 7.5
control
13 47.4
control
14 46.9
control
15 47.8
control
16 47.1
control
17 19.7
control
18 21.3
control
19 13.8

Significantly different from the control value

** p < 0.01

*** p < 0.001.


Acknowledgements

The authors would like to thank Professor emeritus Shoji Shibata, University of Tokyo, for his encouragement. This study was partly supported by Sasakawa Scientific Research Grant from Japan Science Society (1996-7).

References

Akita, Y, Yang, Y, Kawai, T., Kinoshita, K., Koyama, K., Takahashi, K., Watanabe, K.: New assay method for surveying anti-emetic compounds from natural sources. Nat. Prod. Sci. 4 (2): 72-77, 1998.

Athamprasangsa, S., Buntrarongroj, U., Dampawan, P., Ongkavoranan, N., Rukachaisirikul, V., Sethijinda, S., Sornnarintra, M., Sriwub, P., Taylor, W.C.: A 1,7- diarylheptanoid from Alpinia conchigera. Phytochemistry 37: 871-873, 1994.

Claeson, P., Panthong, A., Tuchinda, P., Reutrakul, V., Kanjinapoyhi, D., Taylor, W., Santisuk, T.: Three non-phenolic diarylheptanoids with anti-inflammatory activity from Curuma xanthorrhiza. Planta Med. 59: 451-454, 1993.

Itokawa, H., Morita, M., Mihashi, S.: Two new diarylheptanoids from Alpinia officinarum HANCE. Chem. Pharm. Bull. 29: 2383- 2385, 1981.

Itokawa, H., Aiyama, R., Ikuta, A.: A pungent principle from Alpinia oxyphylla. Phytochemistry 21: 241-243, 1982.

Itokawa, H., Morita, H., Midorikawa, L., Aiyama, R., Morita, M.: Diarylheptanoids from the rhizome of Alpinia officinarum HANCE. Chem. Pharm. Bull. 33: 4889-4893, 1985.

Kadota, S., Hui, D., Basnet, P., Prasain, J., Xu, G.-X., Namba, T.: Three novel diarylheptanoids, calyxin A, calyxin B, and 3-epi-calyxin B from a Chinese crude drug "Yunnan Cao Kou" (Alpinia blepharocalyx K. SCHVM). Chem. Pharm. Bull. 42: 2647-2649, 1994.

Kuroyanagi, M., Noro, T., Fukushima, S., Aiyama, R., Ikuta, A., Itokawa, H., Morita, M.: Studies on the constituents of the seeds of Alpinia katsumadai Hayata. Chem. Pharm. Bull. 31: 1544-1550, 1983.

Shoji, N., Umeyama, A., Takemoto, T., Ohizhumi, Y: Isolation of a cardiotonic principle from Alpinia oxyphylla. Planta Med. 50: 186-187, 1984.

Uehara, S. I., Yasuda, I., Akiyama, K., Morita, H., Takeya, K., Itokawa, H.: Dirarylheptanoids from the rhizome of Curcuma xanthorrhiza and Alpinia officinarum. Chem. Parm. Bull. 35: 3298-3304, 1987.

Yang, Y., Kinoshita, K., Koyama, K., Takahashi, K., Tai, T., Nunoura, Y, Watanabe, K.: Anti-emetic principles of Alpinia katsumadai Hayata. Nat. Prod. Sci. 5 (1): 20-24, 1999a.

Yang, Y, Kinoshita, K., Koyama, K., Takahashi, K., Tai, T., Nunoura, Y, Watanabe, K.: Two novel anti-emetic principles of Alpinia katsumadai. J. Nat. Prod. 62: 1672-1674, 1999b.

Y. Yang (1), K. Kinoshita (1), K. Koyama (1), K. Takahashi (1), S. Kondo (2) and K. Watanabe (3)

(1) Department of Pharmacognosy and Phytochemistry, Meiji Pharmaceutical (1University, Tokyo, Japan

(2) Kotaro Pharmaceutical Co. Ltd., Osaka, Japan

(3) Faculty of Pharmaceutical Sciences, Chiba University, Chiba, Japan

Address

K. Takahashi, Department of Pharmacognosy and Phytochemistry, Meiji Pharmaceutical University, Noshio 2-522-1, Kiyose-shi, Tokyo 204-8588, Japan.

Tel. and Fax: (424) 95-8912; e-mail: diamonds@my-pharm.ac.jp
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Author:Yang, Y.; Kinoshita, K.; Koyama, K.; Takahashi, K.; Kondo, S.; Watanabe, K.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Date:Mar 1, 2002
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