摘要
姜黄为姜科姜黄属(Curcuma)多年生草本植物姜黄Curcuma longa L．的干燥根茎，在亚洲的热带地区广为栽培。姜黄作为传统中药具有多种功效，同时作为食品添加剂，不仅具有着色的作用，而且兼顾医疗及保健的功能，因此在国际市场上享有很高声誉，是联合国粮食与农业组织(FAO)和世界卫生组织(WHO)所规定的使用安全性很高的天然色素之一。姜黄味苦、辛、性温，归脾、肝经，具有破血行气、通经止痛之功效。印度传统医学认为其可以治疗胆病、厌食、鼻炎、咳嗽、糖尿病、肝病、风湿病和窦炎等。现代药理研究表明姜黄具有抗炎、抗氧化、抗癌、抗HIV等多方面作用。姜黄的化学研究表明挥发油及姜黄素为其主要活性成分。但迄今为止，对姜黄的研究多集中于药理、姜黄素的提取分离工艺等方面，姜黄的化学成分研究除姜黄素外报道较少。本论文对姜黄进行了较系统的化学研究，利用现代色谱分离手段，从姜黄的80％乙醇提取物中分离得到37个化合物，通过各种谱学数据(UV、NMR、MS)分析鉴定了36个化合物，包括一个没药烷类衍生物：(bisabola 4′-methyl-4′,10′-diene-9′-one-3′-yl)-(bisabola 4″-methyl-1″,4″-dihydroxy-5″,10″-diene-9″-one-3″-yl)-methane(1)；四个异没药烷类化合物：isobisabolone A(2)、isobisabolone B(3)、isobisabolone C(4)、isobisabolone D(5)；九个没药烷类化合物：turmerone A(6)、turmerone B(7)、turmerone C(8)、turmerone D(9)、turmerone E(10)、turmeronol B(11)、bisabolone(12)、bisabolone-9-one(13)、turmeronol A(14)；九个二苯庚烷类化合物：(E)-1-(1,2-dihydro-6-hydroxyinden-3-ylidene)-4-(4-hydroxyphenyl)butan-2-one (15)，(4E,6E)-2,5-epoxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-1,4,6-heptatrien-3-one(16)、(1S)-1,5-epoxy-1-(3-methoxy-4-hydroxyphenyl)-7-(4-hydroxyphenyl)-4,6-heptadien-3-one(17)、(1S)-1,5-epoxy-1-(4-hydroxyphenyl)-7-(3-methoxy-4-hydroxyphenyl)-4,6-heptadien-3-one(18)、(1E,4E,6E)-1-(3-methoxy-4-hydroxyphenyl)-7-(4-hydroxyphenyl)-1,4,6-heptatrien-3-one(19)、1,7-bis(4-hydroxyl-phenyl)-3-hydroxy-1,3-heptadien-5-one(20)、姜黄素(21)、去甲氧基姜黄素(22)、双去甲氧基姜黄素(23)；二个Calebin类衍生物：4″-(3″′-methoxy-4″′-hydroxyphenyl)-2″-oxo-3″-butenyl-3-(4′-hydroxylphenyl)-propenoate(24)、4″-(4″′-hydroxyphenyl)-2″-oxo-3″-butenyl-3-(3′-methoxy-4′-hydroxyphenyl)-propenoate(25)；一个二苯戊烷类化合物：1-(4-羟基-3-甲氧基苯基)-5-(4-羟基苯基)-(1E，4E)-戊二烯-3-酮(26)；九个酚酸类衍生物：4-羟基-3-甲氧基苯丙烯醛(27)、阿魏酸甲酯(28)、4-羟基苯丙烯酸甲酯(29)、4-羟基苯甲醛(30)、4-羟基苯丙烯酸(31)、甲酰阿魏酸(32)、4-羟基苯丙烯醛(33)、香兰素(34)、反式阿魏酸(35)及一个甾醇类化合物：谷甾醇(36)。其中，1为具有新骨架的化合物；2-4为首次发现的异没药烷型倍半萜类化合物，15为首次发现的具有苯并戊烷结构的二苯庚烷类化合物，16为首次发现的具有五元呋喃环结构的二苯庚烷类化合物结构，6-8，17-19和24为新化合物；5为新的人工产物；9和25为新的天然产物；13和27-31为首次从该属植物中分离得到的化合物。上述研究结果丰富了姜黄化学成分的结构类型，同时为进一步的生物活性研究奠定了物质基础。
姜黄素类成分包括姜黄素、去甲氧基姜黄素及双去甲氧基姜黄素。近年来研究表明姜黄素类成分具有抗肿瘤、调节血脂、抗HIV和抗老年痴呆等多方面药理作用。然而，口服姜黄素类成分体内血药浓度和生物利用度较低，代谢研究亦发现其生物转化率高，因此，代谢产物研究对口服用药的姜黄素类成分显得格外重要。在姜黄素类三种主要成分中，姜黄素的代谢研究报道较多，而去甲氧基姜黄素及双去甲氧基姜黄素的代谢截止目前仅发现一篇有关体外实验研究的报道。去甲氧基姜黄素与姜黄素母核结构相同，但两端苯环的取代模式不同，其体内代谢与体外以及姜黄素的体内体外代谢是否一致尚不明确，为此，我们开展了对去甲氧基姜黄素的体内代谢研究。
利用现代色谱分离手段，从大鼠灌胃去甲氧基姜黄素的尿液及粪便中共分离得到了9个去甲氧基姜黄素的一相代谢产物，通过波谱学等手段确定它们的结构。其中7个为首次发现的代谢产物，分别为：5-去羟基-六氢去甲氧基姜黄素A(M-1)，5-去羟基-六氢去甲氧基姜黄素B(M-2)，5-去羟基-八氢去甲氧基姜黄素A(M-3)and 5-去羟基-八氢去甲氧基姜黄素B(M-4)，5-O-甲基-六氢去甲氧基姜黄素A(M-7)，5-O-甲基-六氢去甲氧基姜黄素B(M-8)，和5-去羟基-二氢去甲氧基姜黄素B(M-9)，2个已知的代谢产物为六氢去甲氧基姜黄素A(M-5)和六氢去甲氧基姜黄素B(M-6)。代谢产物1-4为从粪便中分离得到，5-9为从尿液中分离得到。
与以往姜黄素类化合物的代谢研究相比，本研究首次发现了脱羟基及O-甲基化还原代谢产物，同时还发现了多对异构体的存在，这些结果是对姜黄素类化合物代谢研究的有益补充。该部分研究不仅明确了去甲氧基姜黄素在大鼠体内的一相代谢途径，为今后其人体内代谢研究以及药代动力学研究提供参考，而且为进一步阐明其口服后体内发挥药效的作用形式奠定基础。
The rhizomes of Curcuma Longa, a tropical herb indigenous to southern Asia, has played an important role in the pharmaceutical, food and textile industries in China, Japan and southeastern Asia for thousands of years. It has been widely used as an aromatic stomachic, carminative, anthelmintic, laxative, and as condiments in foods as well as for liver ailment. With regard to the chemical constituents of this plant, essential oil and curcuminoids were shown to be the major active principles, and the content of bisabolane type sesquiterpenes in volatile oil is high. Curcuminoids, consist mainly of three diarylheptanoids: curcumin, demethoxycurcumin, and bisdemethoxycurcumin. These are recognized for their beneficial effects such as a choleretic, as anti-oxidant, anti-inflammatory agents, for treating human immunodeficiency virus infections and as anticarcinogens. In recent years, their ability to protect neuronal cells fromβA insult has also attracted great attention. Demethoxycurcumnin was found to be the more effective in protecting PC12 and HUVEC cells fromβA insult than curcumin. Bisabolane-type sesquiterpenes have been reported to show antitumor, antifungal, anti-bacteria, antioxidant and antivenom effects. Although great attentions have been paid to the chemical and pharmacological research of curcumin, demethoxycurcumin and bisdemethoxycurcumin, there was little information on the other constituents of C. longa. Therefore, a systematic chemical research on the constituents of C. longa was carried out, which resulted in the isolation of 37 compounds. The chemical structures of 36 compounds were identified by spectral methods, including one bisabolane dirivate: (bisabola 4'-methyl-4',10'-diene-9'-one-3'-yl)-(bisabola 4"-methyl-1",4"-dihydroxy-5",10"-diene-9"-one- 3"-yl)-methane (1); four isobisabolane-type compounds: isobisabolone A (2), isobisabolone B (3), isobisabolone C (4), isobisabolone D (5); nine bisabolane-type compounds: turmerone A (6), turmerone B (7), turmerone C (8), turmerone D (9), turmerune E (10), turmeronol B (11), bisabolone(12), bisabolone-9-one(13), turmeronol A(14): nine diarylheptanoids:(E)-1-(1,2-dihydro-6-hydroxyinden-3-ylidene)-4-(4-hydroxyphenyl)butan-2.one (15), (4E,6E)-2,5-epoxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (16), (1S)-1,5-epoxy-1-(3-methoxy-4-hydroxyphenyl)-7-(4-hydroxyphenyl)-4,6-heptadien-3-one (17), (1S)-1,5-epoxy-1-(4-hydroxylphenyl)-7-(3-methoxy-4-hydroxyphenyl)-4,6-heptadien-3-one (18), (1E,4E,6E)1-(3-methoxy-4-hydroxyphenyl)-7-(4-hydroxylphenyl)-1,4,6-heptatrien-3-one (19), 1,7-bis(4- hydroxyphenyl)-3-hydroxy-1,3-heptadien-5-one (20), curcumin (21), demethoxycurcumin (22),bisdemethoxycurcumin (23); two calebin derivatives: 4"-(3"'-methoxy-4"'-hydroxyphenyl)-2"-oxo-3"-butenyl-3-(4'-hydroxylphenyl)-propenoate (24)、4"-(4"-hydroxyphenyl)-2"-oxo-3"-butenyl-3-(3'-methoxy-4'-hydroxyphenyl)-propenoate (25); one diarylpentanoid constituent: 1-(4-hydroxy-3-methoxyphenyl)-5-(4-hydroxyphenyl)-(1E,4E)-pentadiene-3-one (26); nine phenolic acid derivatives: 4-hydroxy-3-methoxy cinnamaldehyde (27), ferulic acid methyl ester (28), 4-hydroxycinnamic acid methyl ester (29), 4-hydroxybenzaldehyde (30), 4-hydroxycinnamic acid (31), formylferulic acid (32), 4-hydroxy-cinnamaldehyde (33), vanillin (34), trans-ferulic acid (35) and one sterol compound: sitosterol(36). Among them 1 was novel compounds with new skeleton; 2-4 were isobisabolane-type sesquiterpenes discovered for the first time; 6-8, 15-19 and 24 were new compounds; 5 was a new artifact; 9 and 25 were new natural products; 13 and 27-31were isolated for the first time from the plants of this genus.
The investigation enriched the constituent-types of C. longa and could provide material basic for further activity screening.
Although numerous aspects of the pharmacology of curcuminoids, in particular its activity as chemopreventive agent, have been studied, the metabolism in humans and experimental animals have not been fully characterized. The metabolism of curcumin has mostly been studied in rats in vivo and in vitro. More recently, information on the metabolism of curcumin in humans has been obtained from in vitro studies with hepatic and intestinal cells and subcellular fractions, as well as from clinical studies with cancer patients. The metabolism of demethoxycurcumin, which is the major active component in curcuminoids such as curcumin, has only been studied on one report. In that investigation, in vitro studies with tissue slices and subcellular fractions from rat fiver were reported. No data have yet been published on the metabolism of demethoxycurcumin in vivo. Therefore, studies of the metabolic products of demethoxycurcumin in feces and urine after oral administration in male Wistar rats were undertaken. And nine phaseⅠreductive products were isolated. Four new metabolites: 5-dehydroxy-hexahydro-demethoxycurcumin-A (M-1), 5-dehydroxy-hexahydro-demethoxycurcumin -B (M-2), 5-dehydroxy-octahydro--demethoxycurcumin-A (M-3) and 5-dehydroxy-octahydrodemethoxycurcumin-B (M-4) were isolated from the feces, and three new metabolites: 5-O-methylhexahydro-demethoxycurcumin-A (M-7), 5-O-methyl-hexahydro-demethoxycurcumin-B (M-8), and 5-dehydroxy-dihydro-demethoxycurcumin-B(M-9) in addition to two known metabolites: hexahydro-demethoxycurcumin-A(M-5), hexahydro-demethoxycurcumin-B (M-6) from the urine of male Wistar rats. Their structures were established by spectral methods.
Demethoxycurcumin in vivo follows almost the same pathway as curcumin and demethoxycurcumin in vitro: no oxidative metabolites were observed, and the reduction pattern of hydrogenation was about the same. However, there were two new discoveries in the present study: first the existence of the dehydroxy or methylated metabolites was demonstrated and secondly the existence of the isomers with a methoxy group substituted on a different benzene ring. These results are important for the understanding of demethoxycurcumin metabolism in rats and should provide information and reference for the further metabolic investigation of demethoxycurcumin in humans.
引文
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