Research on chemical components and biological activities of the iridoids in <i>Morinda</i> genus

SHEN Yi; ZHANG Qi; LIU Mengqin; HE Yuqiong; XIN Hailiang; QIN Luping; ZHANG Qiaoyan

doi:10.3969/j.issn.1006-0111.201907143

Volume 38 Issue 2

Apr. 2020

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Article Navigation > Journal of Pharmaceutical Practice and Service > 2020 > 38(2): 110-114, 119

SHEN Yi, ZHANG Qi, LIU Mengqin, HE Yuqiong, XIN Hailiang, QIN Luping, ZHANG Qiaoyan. Research on chemical components and biological activities of the iridoids in Morinda genus[J]. Journal of Pharmaceutical Practice and Service, 2020, 38(2): 110-114, 119. doi: 10.3969/j.issn.1006-0111.201907143

Citation:

SHEN Yi, ZHANG Qi, LIU Mengqin, HE Yuqiong, XIN Hailiang, QIN Luping, ZHANG Qiaoyan. Research on chemical components and biological activities of the iridoids in Morinda genus[J]. Journal of Pharmaceutical Practice and Service, 2020, 38(2): 110-114, 119. doi: 10.3969/j.issn.1006-0111.201907143

Research on chemical components and biological activities of the iridoids in Morinda genus

doi: 10.3969/j.issn.1006-0111.201907143

SHEN Yi^{1, 2, 3
,},
ZHANG Qi²,
LIU Mengqin²,
HE Yuqiong¹,
XIN Hailiang¹,
QIN Luping^3
,,
ZHANG Qiaoyan^{1, 2, 3
,
,}

1.
Department of Pharmacognosy, School of Pharmacy, Naval Medical University, Shanghai 200433, China
2.
School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
3.
School of Pharmacy, Zhejiang University of Traditional Chinese Medicine, Hangzhou 310053, China

Received Date: 2019-07-30
Rev Recd Date: 2020-02-06

Available Online: 2020-04-23

Publish Date: 2020-03-01

Abstract

Morinda genus of Rubiaceae has been widely used in medicine at home and abroad. Many parts of Morinda tree are utilized in research, mainly including roots, stems, leaves, branches and seeds. Through the research of online databases, the chemical components and biological activities of the iridoids in Morinda genus were summarized in this paper. Up to now, more than 50 kinds of iridoids have been identified. In addition, more and more studies proved that Morinda iridoids might benefit human via such anti-inflammatory, antinociceptive, anti-oxidation, anti-tumor and bone protection. The theoretical basis was provided for the further development and utilization of the iridoids in Morinda genus.
- Rubiaceae,
- Morinda genus,
- iridoid,
- chemical component,
- biological activity

References

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巴戟天属（Morinda）系茜草科（Rubiaceae）植物，据中国植物志记载，在全世界约有102种，分布于热带、亚热带和温带地区，其中我国主要分布在广东、广西、福建和海南等地^[1]。该属植物中研究较多的有巴戟天M. officinalis How.、海巴戟（诺丽）M. citrifolia L.、M. lucida B.、假巴戟M. shuhuaensis C.Y.Chen et M.S.Huang、羊角藤M. umbellata L.、M. corera、M. morindoides等。而巴戟天属植物国内外品种差异较大，入药部位也有差异，如根、叶、果实等均可，多用于传统民间用药，主要具有补肝肾、强筋骨、祛风湿的作用。

巴戟天属植物中主要由多糖、蒽醌、环烯醚萜类、寡糖等成分，具有广泛的药理活性，如环烯醚萜类化合物，巴戟天中水晶兰苷具有确切的抗炎镇痛的作用，近年来对其抗骨质疏松的研究也日渐成熟，这与其祛风湿、强筋骨作用具有密切关系^[2-3]。本文总结了国内外近几十年来对巴戟天属环烯醚萜类化学成分及其生物活性方面的研究，对环烯醚萜类成分的研究概况进行综述。

1. 巴戟天属植物中的环烯醚萜类成分

环烯醚萜类化合物在巴戟天属植物中的数量较多，分布较广，是巴戟天属植物中主要活性成分之一。环烯醚萜类成分主要从巴戟天M. officinalis How.、海巴戟（诺丽）M. citrifolia L.、M. lucida B.、假巴戟M. shuhuaensis C.Y.Chen et M.S.Huang、羊角藤M. umbellata L.、M. corera、M. morindoides等植物的根、枝、叶和果实中分离得到的环烯醚萜类化合物。迄今为止，从该属植物中分离得到了50余种环烯醚萜类成分，其来源、结构见表1。

序号.	化合物名称	分子式	巴戟天属	植物部位	参考文献
1	香茅苷（citrifolinoside）	C₂₇H₃₀O₁₇	M. citrifolia	叶	[4]
2	骨化三醇A-1（citrifolinin A-1）	C₃₄H₄₂O₂₃	M. citrifolia	叶	[4]
3	oruwacin	C₂₁H₁₈O₈	M. lucida	叶	[5]
4	phumericin	C₁₅H₁₄O₆	M. lucida	叶	[5]
5	车叶草苷（asperuloside）	C₁₈H₂₂O₁₁	M. citrifolia	果实、叶和根	[6-9]
			M. officinalis	叶	[10]
			M. corera	叶	[10]
6	水晶兰苷（monotropein）	C₁₆H₂₂O₁₁	M. officinalis	根	[8]
7	车叶草苷四乙酸脂（asperuloside tetraacetate）	C₂₆H₃₀O₁₅	M. officinalis	根	[8]
8	车叶草苷酸（asperulosidic acid）	C₁₈H₂₄O₁₂	M. officinalis	根	[9]
			M. citrifolia	叶、果实	[7, 10]
			M. corera	果实	[11]
9	去乙酰基车叶草苷（deacetyl asperuloside）	C₁₆H₂₀O₁₁	M. corera	叶	[9]
10	去乙酰基车叶草苷酸（deacetyl asperulosidic acid）	C₁₆H₂₂O₁₁	M. officinalis	根	[9]
11	morofficinaloside	C₁₇H₂₆O₁₁	M. officinalis	根	[9]
12	morindolide	C₉H₁₂O₃	M. officinalis	根	[9]
13	6-O-acetylscandoside	C₁₈H₂₄O₁₂	M. corera	叶和枝	[10]
14	10-O-乙酰基水晶兰苷（10-O-acetylmonotropein）	C₁₈H₂₄O₁₂	M. corera	叶和枝	[10]
15	yopaaosides A	C₂₇H₂₈O₁₅	M. corera	叶和枝	[10]
16	yopaaosides B	C₂₆H₂₈O₁₄	M. corera	叶和枝	[10]
17	yopaaosides C	C₁₇H₂₆O₁₂	M. corera	叶和枝	[10]
18	香茅苷A（citrifolinoside A）	C₂₆H₂₈O₁₄	M. citrifolia	叶	[11]
19	6α-hydroxyadoxoside	C₁₇H₂₆O₁₁	M. citrifolia	果实	[12]
20	6β,7β-epoxy-8-epi-splendoside	C₁₇H₂₄O₁₂	M. citrifolia	果实	[12]
21	morindacin	C₁₀H₁₄O₅	M. citrifolia	果实	[13]
22	epoxygaertneroside	C₂₆H₂₈O₁₄	M. morindoides	叶	[14]
23	epoxymethoxygaertneroside	C₂₇H₃₀O₁₅	M. morindoides	叶	[14]
24	gaertneroside	C₂₆H₂₈O₁₃	M. morindoides	叶	[14]
25	dehydrogaertneroside	C₂₆H₂₆O₁₃	M. morindoides	叶	[14]
26	6-acetylgaertneroside	C₂₈H₃₀O₁₄	M. morindoides	叶	[14]
27	dehydromethoxygaertneroside	C₂₇H₂₈O₁₄	M. morindoides	叶	[14]
28	gaertneric acid	C₂₅H₂₆O₁₃	M. morindoides	叶	[14]
29	dehydroepoxymethoxy-gaertneroside	C₂₇H₂₈O₁₅	M. citrifolia	-	[15]
30	citrifoside	C₁₆H₂₂O₁₀	M. citrifolia	叶	[16]
31	鸡矢藤苷甲酯（scandoside methyl ester）	C₁₇H₂₄O₁₁	M. citrifolia	果实	[17]
32	9-epi-6α-methoxy geniposidic acid	C₁₇H₂₄O₁₁	M. citrifolia	果实	[17]
33	tinctoroid	C₁₉H₂₆O₁₀	M. tinctoria	根	[18]
34	morintoside A	C₂₀H₂₆O₁₃	M. tomentosa	叶	[19]
35	morintoside B	C₂₆H₂₆O₁₄	M. tomentosa	叶	[19]
36	umbellatolides A	C₉H₁₂O₄	M. umbellata	地上部分	[20]
37	umbellatolides B	C₉H₁₂O₄	M. umbellata	地上部分	[20]
38	longifolides A	C₉H₁₂O₄	M. longifolia	叶和枝	[21]
39	longifolides B	C₉H₁₂O₄	M. longifolia	叶和枝	[21]
40	molucidin	C₂₁H₁₈O₈	M. lucida.	叶	[22]
41	ML-2-3	C₂₀H₁₆O₈	M. lucida.	叶	[23]
42	ML-F52	C₂₂H₂₀O₈	M. lucida.	叶	[23]
43	morinlongoside C	C₂₁H₃₀O₁₅	M. longissima	根	[24]
44	10-dimethoxyfermiloside	C₁₉H₂₈O₁₂	M. citrifolia	果实	[25]
45	4-epi-dunnisinin	C₁₁H₁₄O₅	M. citrifolia	果实	[26]
46	骨化三醇Ba（citrifolinin Ba）	C₁₇H₂₂O₁₂	M. citrifolia	叶	[27]
47	骨化三醇Bb（citrifolinin Bb）	C₁₇H₂₂O₁₂	M. citrifolia	叶	[27]
48	morinipticoside	C₂₆H₂₆O₁₄	M. elliptica	叶和枝	[28]
49	车叶草苷酸甲酯（asperulosidic acid methyl ester）	C₁₇H₂₄O₁₁	M. citrifolia	果实和叶	[29]
50	马钱苷酸（loganic acid）	C₁₆H₂₄O₁₀	M. citrifolia	籽	[30]
51	rhodolatouside	C₂₀H₃₀O₁₁	M. citrifolia	籽	[30]
52	6-acetylmethoxygaertneroside	C₂₉H₃₂O₁₅	M. morindoides	叶	[31]
53	骨化三醇A（citrifolinin A）	C₂₇H₂₈O₁₄	M. citrifolia	叶	[32]
54	borreriagenin	C₁₀H₁₄O₅	M. citrifolia	果实	[15]
55	4-epi-borreriagenin	C₁₀H₁₄O₅	M. citrifolia	果实	[33]

2. 巴戟天属植物中环烯醚萜类成分的生物活性研究

2.1. 抗炎镇痛

研究表明，小鼠醋酸扭体模型和二甲苯耳肿胀模型证明水晶兰苷具有确切的镇痛和抗炎作用^[2]；水晶兰苷能够抑制脂多糖（LPS）诱导的RAW264.7巨噬细胞肿瘤坏死因子（TNF-α）、白细胞介素-1β（IL-1β）的mRNA表达，降低核因子NF-κB的活性^[34]。以上结果表明水晶兰苷具有确切的抗炎镇痛的作用。

2.2. 骨保护作用

巴戟天中分离得到的水晶兰苷首先通过下调体内膝关节滑液中的促炎性细胞因子表现出软骨保护活性，并对体外培养的大鼠骨关节炎软骨细胞具有抗凋亡和抗分解代谢作用，有效的抑制IL-1β诱导的骨关节炎软骨细胞的凋亡和分解代谢^[35]；而水晶兰苷作用于卵巢切除术诱导的小鼠骨质疏松症后，小鼠的骨矿物质含量、骨矿物质密度、骨体积分数均明显增加，骨微结构明显改善；且作用于成骨MC3T3-E1细胞后，细胞的矿化和碱性磷酸酶（ALP）活性显著增加^[3]。综合以上结果，表明水晶兰苷具有抗骨质疏松的作用。

2.3. 抗肿瘤

研究表明，巴戟天属植物环烯醚萜类成分具有一定的抗肿瘤活性，对肿瘤细胞具有一定的抑制作用。如Sang等^{[11, 36]}从海巴戟的叶子分离出香茅苷和骨化三醇A，能显著抑制紫外线诱导的、在肿瘤诱发和生长中起重要作用的蛋白活化剂AP-1的活性。同时Frew等^[37]研究发现，半抑制浓度IC₅₀为2.0 mmol的车叶草苷对磷脂酰肌醇-3-活化醇素（PtdIns-3-K，肿瘤形成过程中的一种重要的蛋白酶）活性也有抑制作用。Akihisa等^[17]又通过实验发现，9-epi-6α-methoxy geniposidic acid、车叶草苷酸、鸡矢藤苷甲酯在100 μmol下黑色素含量降低34%～49%，对黑色素瘤细胞展现了较强的抑制作用。

2.4. 抗氧化

骨化三醇Ba和骨化三醇Bb首次从海巴戟叶中分离，并通过实验发现30 μmol的浓度即能清除1,1-二苯基-2-三硝基苯肼（DPPH）自由基^[27]。而6β-7β-epoxy-8-epi-splendoside和6α-hydroxyadoxo- side则无清除DPPH自由基和过氧化亚硝酸离子（ONOO.）的作用^[12]。

2.5. 泄下作用

小鼠服用水晶兰苷后，其半数有效量ED₅₀大于0.5 g/kg时，出现缓泻作用^[38]。而Shen等^[39]在巴戟天环烯醚萜苷的组织分布实验中发现，水晶兰苷和去乙酰基车叶草苷酸给药后主要分布在大鼠的肠道中。以上结果表明，水晶兰苷可能通过影响肠道中的菌群，从而使小鼠出现缓泻的作用。

2.6. 改善血液流动性

探究海巴戟天果实提取物（MCF-ext，其中的一种活性化合物是环烯醚萜苷，即车叶草苷酸）对血液聚集和纤维蛋白溶解的影响，结果显示MCF-ext能够抑制聚凝胺诱导的红细胞聚集和凝血酶活性^[40]。这一发现表明了MCF-ext可作为一种潜在有用的健康食品，同时可对车叶草苷酸进行深入的研究，发掘其改善血液流动性等相关疾病的作用机制，为血液疾病的防治提供新的治疗策略。

2.7. 抗疟疾

Tamura等^[31]在M. morindoides的甲醇提取物中分离得到的新型的苯丙素结合环烯醚萜类化合物6-Acetylmethoxygaertneroside，已知化合物6-Acetylgaertneroside、Dehydromethoxygaertneroside 和Methoxygaertneroside均具有抗疟疾的作用（IC₅₀分别为0.1、4.1、21.9、0.04 μmol）。以上结果表明环烯醚萜类成分抗疟疾的作用，可能与结构中苯丙素的结合存在一定的关系。

2.8. 补体抑制作用

Cimanga等^[14]研究发现，Gaertneroside、6-acetylgaertneroside和gaertneric acid具有抑制补体系统经典途径激活的作用，且其IC₅₀值为58～69 mmol，效果显著。

2.9. 抗锥虫病

Suzuki等^[22]从M. lucida叶的三氯甲烷部分分离纯化得到molucidin，通过实验进一步证明molucidin具有很强的抗锥虫活性，其IC₅₀值为1.27 μmol。同时对正常细胞系和癌细胞系的细胞毒性进行研究，结果表明molucidin对两种正常成纤维细胞的选择性指数（SI）大于4.73；又采用molucidin和oregonin进行结构-活性关系研究，结果表明其与日本桤木的抗锥虫活性成分相同。

2.10. 免疫激活

Murata等^[41]发现M. citrifolia果实提取物（Noni-ext）能抑制细胞介导的免疫抑制；并能促进艾氏癌荷瘤小鼠中IL-2的产生，激活正常小鼠中的自然杀伤细胞。结果表明，Noni-ext对细胞介导免疫的恢复具有多重作用。此外，从Noni-ext活性成分中分离得到去乙酰车叶草苷酸，发现其能减轻耳肿胀度，并消除IL-2产生的抑制，且与Noni-ext相同的方式激活自然杀伤细胞。以上结果表明，去乙酰车叶草苷酸具有免疫调节的作用，同时还具有一定的抗炎作用。

2.11. 抗阿米巴活性

刚果民主共和国使用M. morindoides叶子，传统用来治疗阿米巴病，Cimanga等^[42]从M. morindoides叶中获得的80%甲醇提取物，从中分离得到的5种环烯醚萜类化合物，淫羊藿苷、methoxygaertneroside、葛根素、乙酰胆碱和高芥酸，结果显示具有抗阿米巴药理活性，且在250 μg/ml的最高测试浓度下，所有化合物均对MT-4细胞没有任何毒性作用。

3. 小结

巴戟天属植物虽为传统的药物，但由于环烯醚萜是一类生物活性较强、药效较为特殊的化合物，因而在国内外的应用十分广泛，其化学成分和药理活性的研究也是备受关注。Shen等^[39]研究发现，环烯醚萜苷给药后主要分布在胃肠道、性腺、下丘脑等组织器官，至于其是否能在上述部位发挥药理作用，都有待进一步考察。譬如主要分布在胃肠道中，它是否跟近年来研究火热的肠道菌群有联系，因此，对巴戟天属的环烯醚萜化合物进行更加深入的研究，尤其是近年对海巴戟和巴戟天的研究越来越多，继续探究其药理活性及深入的机制研究，为将其开发成新药提供理论基础。

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