沉香及港柯發炎調節植物化學成分之研究

Phytochemical investigation on inflammatory-modulating agents of Aquilaria malaccensis and Lithocarpus harlandii

王維多(Vitthal D. Wagh)

指導教授 ： 張芳榮

高雄醫學大學/藥學院/天然藥物研究所博士班/博士(2018年)

摘要

沉香是一種珍貴的芳香樹酯。在東亞，傳統上被廣泛地應用於對抗多種發炎相關的疾病上。沉香樹（瑞香科）則沉香的來源物料。利用活性導引分離法，分離出新化合物：12-O-(2′Z,4′E,6′E)-tetradeca-2,4,6-trienoylphorbol-13-acetate (aquimavitalin) (1)。在進一步的植物化學研究中，發現了另外四個新佛波酯化合物，如：12-O-(2′E,4′E)-6-oxohexa-2′,4′-dienoylphorbol-13-acetate (2), 12-deoxy-13-O-acetylphorbol-20-(9′Z)-octadecenoate (3), 12-O-(2′E,4′E)-6′,7′-(erythro)-dihydroxytetradeca-2′,4′-dienoylphorbol-13-acetate (4) and 12-O-(2′E,4′E)-6′,7′-(threo)-dihydroxytetradeca-2′,4′-dienoylphorbol-13-acetate (5)；兩個已知的佛波酯化合物6（首次自天然界中被分得）及7；兩個二酸甘油脂8及9；單酸甘油脂10及其與甘油酯的混合物10及11。所有分離得到的佛波酯都增加了超氧陰離子的釋放。有趣的是，分得的其中一些佛波酯（1, 2, 6及7）則會抑制人類嗜中性白血球釋放彈性蛋白酶。結果顯示，佛波酯可能在發炎的過程中扮演了雙向調節的角色。另外，這些化合物經評估則對HepG2（肝癌）, MDA-MB231（乳癌）及A549（肺癌）等細胞株沒有細胞毒殺活性(IC50 >10 μM)。上述這些結果顯示，沉香種子的萃取物或純化合物具有治療發炎相關疾病的潛力。
研究港柯枝葉甲醇萃取物的過程中則發現，其對於人類嗜中性白血球釋放彈性蛋白酶（10μg/ mL的劑量下抑制率為83.8%）及超氧陰離子的產生（10μg/ mL的劑量下抑制率為76.8%）具有良好的抑制效果。該萃取物對HepG2，MDA-MB-231和A549等細胞株皆無細胞毒殺作用。我們從甲醇層純化出有活性的化合物，並評估其抗發炎活性。目前為止， 兩個已知化合物，如 lupeol and 3-epi-glutinol已經從港柯枝葉甲醇萃取物分離出來。其他的分離產物之結構測定和發炎調節活性評估則尚在進行中。

關鍵字

沉香種子 ； 佛波酯 ； 港柯

並列摘要

Aquilaria malaccensis (Thymelaeaceae) tree is a source of agarwood, a precious fragrant resin, widely used in traditional medicines in East Asia against various inflammatory diseases. Utilizing a bioactivity-guided fractionation approach, phorbol ester 12-O-(2′Z,4′E,6′E)-tetradeca-2,4,6-trienoylphorbol-13-acetate (aquimavitalin) (1) was isolated. Further phytochemical investigation afforded four new phorbol esters, 12-O-(2′E,4′E)-6-oxohexa-2′,4′-dienoylphorbol-13-acetate (2), 12-deoxy-13-O-acetylphorbol-20-(9′Z)-octadecenoate (3), 12-O-(2′E,4′E)-6′,7′-(erythro)-dihydroxytetradeca-2′,4′-dienoylphorbol-13-acetate (4) and 12-O-(2′E,4′E)-6′,7′-(threo)-dihydroxytetradeca-2′,4′-dienoylphorbol-13-acetate (5), two known phorbol esters 6 (isolated from nature for the first time) and 7, two diglycerides 8 and 9, monoglyceride 10, and a mixture of glycerides 10 and 11. All isolated phorbol esters exerted enhancing activity on superoxide anion generation. Interestingly, some of the isolated phorbol esters (1, 2, 6, and 7) inhibited elastase release in human neutrophils. The results indicated that phorbol esters may play bilateral modulating role in the processes of inflammation. In addition, the compounds were evaluated for their cytotoxic properties against HepG2 (hepatoma), MDA-MB231 (breast) and A549 (lung) cancer cells, but all compounds were inactive (IC50 >10 μM). The results demonstrated that extracts and pure compounds of A. malaccensis seeds have the potential for use in the treatment of diseases related to inflammation.
In study of Lithocarpus harlandii, the MeOH layer of leaves and twigs exhibited good inhibitory activity on both elastase release (83.8% inhibition at 10 μg/mL) and superoxide anion generation (76.8% inhibition at 10 μg/mL) in human neutrophils. The extract showed no cytotoxic effect against HepG2, MDA‑MB‑231, and A549 cell lines. We purify the active compounds from the MeOH layer, and evaluate their anti-
inflammatory activity. So far, two known compounds, lupeol and 3-epi-glutinol were isolated from the leaves and twigs of L. harlandii. Structure determination of some additional isolates and evaluation of the inflammation modulatory activities are in progress.

並列關鍵字

Aquilaria malaccensis seeds ； phorbol ester ； Lithocarpus harlandii

參考文獻

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