Zerumbone衍生物之製備與生物活性研究

薑科薑屬植物─薑花(Zingiber zerumbet Smith)是一種廣泛為熱帶國家所用之香料食材與藥材。近年研究發現其根莖成份具抗腫瘤、抗白血病、抗發炎、抗菌、治療失智症、鎮痛等活性。其主成分球薑酮(zerumbone)具有多種抗癌活性，且其結構具高度化學、位置與立體選擇性(chemo-, regio-, and stereoselectivity)，為一個有潛力的天然物，值得進行其衍生物之活性研究。因此本研究擬大量分離球薑酮，以之為起始物製備一系列含氮衍生物，以探討其抗癌活性。　　本研究將薑花乾燥根莖以加熱乙醇萃取，進行極性分割得二氯甲烷、正丁醇和水可溶部分，其中二氯甲烷可溶部分經初步分離，除得到大量球薑酮(2)外，另得到兩個倍半萜類(1, 3)與兩個黃酮類(4, 5)化合物。以2為起始物，經：(1) Michael addition選擇性在C-3接上不同之烷化胺基得到化合物Ia－g;(2)位置選擇之C-10雙鍵氫化反應得到化合物IIa－d；(3) C-1羰基還原反應得到化合物IIIa－d；(4) C-6、C-10雙鍵之完全氫化反應得到化合物IVa－d。另外，利用具光學活性之羧酸進行消旋產物Id之光學分割，其光學純度以核磁共振氫譜分析監測，最後以X-ray單晶繞射確定(+)-Id之絕對立體結構為2S, 3S-。　　將化合物進行荷爾蒙非依賴型之前列腺癌細胞(PC-3)之抑制活性測試，結果顯示球薑酮之活性最佳(IC50 14.0 μM)，而衍生物之活性皆較低。其中側鏈為丙烷胺基之化合物Id、IIc、IVc與同系列之產物相較下，有較高的抑制活性。而C-1羰基還原產物之細胞毒性則普遍較差，指出C-3烷化胺基之碳鏈長度與C-1羰基會影響抗前列腺癌活性。此外，球薑酮骨架化合物對甲型葡萄糖水解酶幾乎無抑制活性，顯示此類化合物具有標的選擇性。

關鍵字

球薑酮；含胺球薑酮衍生物；前列腺癌；細胞毒殺性；甲型葡萄糖水解酶

並列摘要

Zingiber zerumbet Smith is widely used as a spice and ethnomedicine in tropic areas. Recent studies have revealed the constituents of its rhizome to possess various bioactivities, including antitumor, antileukemia, antiinflammatory, antibacteria, antinociceptive, and antidementia. The major component zerumbone (2) being responsible for cytotoxicity against several cancer cell lines is a potential natural product with structural chemo-, regio-, and stereoselectivity and its derivatives are worth undertaking bioactivity study. Thus, the aim of this study was to isolate large amount of 2 for preparing a series of amino-zerumbone derivatives and to investigate their anticancer activity. 　　　The EtOH extract of the dried rhizome was further divided into fractions soluble in CH2Cl2, n-BuOH and H2O. From the CH2Cl2 layer, two sesquiterpenes (1, 3) and two flavonoids (4, 5) in addition to the major 2 were isolated. Starting from 2, 3-alkylamino derivatives (Ia－g) were prepared via Michael addition, followed by selective hydrogenation to give IIa－d, NaBH4 reduction to give IIIa－d, and exhaustive hydrogenation to yield IVa－d. The racemic Id was further resolved optically with the aid of (+)-di-O-4-toluoyl-D-tartaric acid. The optical purity was examined by 1H NMR analysis. The 2S, 3S- absolute configuration of (+)-Id was determined by single crystal X-ray diffraction on its tartaric acid salt. 　　The cytotoxicity of these derivatives against human hormone refractory prostate cancer cell line (PC-3) through SRB assay was evaluated. Of these, 2 is the most active one (IC50 14.0 μM). In addition, compounds Id, IIc and IVc with a 3-propylamino group revealed higher cytotoxicity than other 3-alkylamino derivatives. In general, the products void of C-1 carbonyl group exhibit poorest activity. These results indicated that the length of C-3 aminoalkyl side chain and C-1 carbonyl function will affect the cytotoxicity against prostate cancer. Compounds with zerumbone scaffold are almost inactive against α-glucosidase, indicating that such compounds possess target selectivity.

並列關鍵字

Zerumbone ； amino-zerumbone derivatives ； prostate cancer ； cytotoxicity ； α-glucosidase

參考文獻

1. Dev, S., Zerumbone, a monocyclic sesquiterpene ketone. Tetrahedron 1960, 8 (3-4), 171-180.

2. Hall, S. R.; Nimgirawath, S.; Raston, C. L.; Sittatrakul, A.; Thadaniti, S.; Thirasasana, N.; White, A. H., Crystal-structure of zerumbone [(2E,6E,10E)- 2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one]. Australian Journal of Chemistry 1981, 34 (10), 2243-2247.

3. Dai, J. R.; Cardellina, J. H.; McMahon, J. B.; Boyd, M. R., Zerumbone, an HIV-inhibitory and cytotoxic sesquiterpene of Zingiber aromaticum and Z.zerumbet. Natural Product Letters 1997, 10 (2), 115-118.

4. Murakami, A.; Takahashi, M.; Jiwajinda, S.; Koshimizu, K.; Ohigashi, H., Identification of zerumbone in Zingiber zerumbet Smith as a potent inhibitor of 12-O-tetradecanoylphorbol-13-acetate-induced Epstein-Barr virus activation. Bioscience, Biotechnology, and Biochemistry 1999, 63 (10), 1811-1812.

5. Murakami, A.; Tanaka, T.; Lee, J. Y.; Surh, Y. J.; Kim, H. W.; Kawabata, K.; Nakamura, Y.; Jiwajinda, S.; Ohigashi, H., Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice. International Journal of Cancer 2004, 110 (4), 481-90.

國際替代計量

Zerumbone衍生物之製備與生物活性研究

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