药学学报

No.	Name	Structure	R1	R2	R3	R4	Source	Ref.
1	Dammar-24-en-3β, 20(S), 26-triol 3-O-caffeate	A	β-O-Caffeoyl	H	H	/	B. maximowicziana	^[4]
2	Dammar-24-en-3β, 20(S), 26-triol 3-O-p-coumarate	A	β-O-p-Coumaroyl	H	H	/	B. maximowicziana	^[4]
3	Dammar-24-en-3β, 11α, 20(S)-triol	B	β-OH	α-OH	H	H	B. ermanii	^[5]
4	3-O-β-D-2-O-Acetylglucopyranoside of 3	B	β-O-2-Acetyl-β- D-Glc	α-OH	H	H	B. ermanii	^[5]
5	Dammarendiol Ⅱ 3-caffeate	B	β-O-Caffeoyl	H	H	H	B. maximowicziana	^[4-6]
							B. ermanii
							B. platyphylla
6	12-O-Acetylbetulafolienetetraol	B	α-OH	H	β-OAc	α-OH	B. maximowicziana	^[4]
7	Betulafolienetetraol	B	α-OH	H	β-OH	α-OH	B. maximowicziana	^[4]
8	Betulafolienetriol	B	α-OH	H	β-OH	H	B. platyphylla	^[6]
9	12-O-Acetyl-3-O-malonylbetulafolienetriol	B	α-O-Malonyl	H	β-OAc	H	B. platyphylla	^[6]
10	12-O-Acetylbetulafolienediolone	B	O	H	β-OAc	H	B. platyphylla	^[6]
11	Dammarenediol Ⅱ 3-O-p-coumarate	B	β-O-p-Coumaroyl	H	H	H	B. platyphylla	^[6]
12	12-O-Acetyl-3α, 12β, 17α, 20(S)-tetrahydroxydammar-24-en-3-yl hydrogen propanedioate	B	α-O-Malonyl	H	β-OAc	α-OH	B. pendula	^[7]
13	12-O-Acetyl-3α, 12β, 20(S), 25-tetrahydroxydammar-23(E)-en-3-yl hydrogen propanedioate	C	α-O-Malonyl	β-OAc	H	H	B. pendula	^[7]
14	12-O-Acetyl-3α, 12β, 17α, 20(S), 25-pentahydroxydammar-23(E)-en-3-yl hydrogen propanedioate	C	α-O-Malonyl	β-OAc	α-OH	H	B. pendula	^[7]
15	20(S)-Hydroxy-25-methoxy-dammar-23-en-3-one	C	O	H	H	Me	B. platyphylla	^[8]
16	3α, 20(S)-Dihydroxy-25-methoxy-dammar-23-ene	C	α-OH	H	H	Me	B. platyphylla	^[8]
17	12-O-Acetyl-3α, 12β, 20(S), 24(R)-tetrahydroxydammar-25-en-3-yl hydrogen propanedioate	D	α-O-Malonyl	β-OAc	β-OH	H	B. pendula	^[7]
18	12-O-Acetyl-3α, 12β, 20(S), 24(S)-tetrahydroxydammar-25-en-3-yl hydrogen propanedionate	D	α-O-Malonyl	β-OAc	α-OH	H	B. pendula	^[7]
19	12-O-Acetyl-3α, 12β, 17α, 20(S), 24(R)-pentahydroxydammar-25-en-3-yl hydrogen propanedioate	D	α-O-Malonyl	β-OAc	β-OH	α-OH	B. pendula	^[7]

No.	Name	Structure	R1	R2	R3	R4	Source	Ref.
1	Dammar-24-en-3β, 20(S), 26-triol 3-O-caffeate	A	β-O-Caffeoyl	H	H	/	B. maximowicziana	^[4]
2	Dammar-24-en-3β, 20(S), 26-triol 3-O-p-coumarate	A	β-O-p-Coumaroyl	H	H	/	B. maximowicziana	^[4]
3	Dammar-24-en-3β, 11α, 20(S)-triol	B	β-OH	α-OH	H	H	B. ermanii	^[5]
4	3-O-β-D-2-O-Acetylglucopyranoside of 3	B	β-O-2-Acetyl-β- D-Glc	α-OH	H	H	B. ermanii	^[5]
5	Dammarendiol Ⅱ 3-caffeate	B	β-O-Caffeoyl	H	H	H	B. maximowicziana	^[4-6]
							B. ermanii
							B. platyphylla
6	12-O-Acetylbetulafolienetetraol	B	α-OH	H	β-OAc	α-OH	B. maximowicziana	^[4]
7	Betulafolienetetraol	B	α-OH	H	β-OH	α-OH	B. maximowicziana	^[4]
8	Betulafolienetriol	B	α-OH	H	β-OH	H	B. platyphylla	^[6]
9	12-O-Acetyl-3-O-malonylbetulafolienetriol	B	α-O-Malonyl	H	β-OAc	H	B. platyphylla	^[6]
10	12-O-Acetylbetulafolienediolone	B	O	H	β-OAc	H	B. platyphylla	^[6]
11	Dammarenediol Ⅱ 3-O-p-coumarate	B	β-O-p-Coumaroyl	H	H	H	B. platyphylla	^[6]
12	12-O-Acetyl-3α, 12β, 17α, 20(S)-tetrahydroxydammar-24-en-3-yl hydrogen propanedioate	B	α-O-Malonyl	H	β-OAc	α-OH	B. pendula	^[7]
13	12-O-Acetyl-3α, 12β, 20(S), 25-tetrahydroxydammar-23(E)-en-3-yl hydrogen propanedioate	C	α-O-Malonyl	β-OAc	H	H	B. pendula	^[7]
14	12-O-Acetyl-3α, 12β, 17α, 20(S), 25-pentahydroxydammar-23(E)-en-3-yl hydrogen propanedioate	C	α-O-Malonyl	β-OAc	α-OH	H	B. pendula	^[7]
15	20(S)-Hydroxy-25-methoxy-dammar-23-en-3-one	C	O	H	H	Me	B. platyphylla	^[8]
16	3α, 20(S)-Dihydroxy-25-methoxy-dammar-23-ene	C	α-OH	H	H	Me	B. platyphylla	^[8]
17	12-O-Acetyl-3α, 12β, 20(S), 24(R)-tetrahydroxydammar-25-en-3-yl hydrogen propanedioate	D	α-O-Malonyl	β-OAc	β-OH	H	B. pendula	^[7]
18	12-O-Acetyl-3α, 12β, 20(S), 24(S)-tetrahydroxydammar-25-en-3-yl hydrogen propanedionate	D	α-O-Malonyl	β-OAc	α-OH	H	B. pendula	^[7]
19	12-O-Acetyl-3α, 12β, 17α, 20(S), 24(R)-pentahydroxydammar-25-en-3-yl hydrogen propanedioate	D	α-O-Malonyl	β-OAc	β-OH	α-OH	B. pendula	^[7]

No.	Name	Structure	R1	R2	R3	R4	Source	Ref.
20	20(S), 24(R)-Epoxydammaran-3β	E	β-OH	α-OH	H	H	B. ermanii	^[5]
21	11α, 25-Triol, 3-O-β-D-glucopyranoside of 20	E	β-O-β-D-Glc	α-OH	H	H	B. ermanii	^[5]
22	2′-Acetate of 21	E	β-O-2-Acetyl-β-D-Glc	α-OH	H	H	B. ermanii	^[5]
23	11, 2′-Diacetate of 21	E	β-O-2-Acetyl-β-D-Glc	α-OAc	H	H	B. ermanii	^[5]
24	12-O-Acetylbetulafolienetetraol oxide	E	β-OH	H	β-OAc	α-OH	B. dahurica	^[9]
25	12β-Acetoxy-20(S), 24(R)-epoxy-3α, 17α, 25-trihydroxydammarane	E	α-OH	H	β-OAc	α-OH	B.maximowicziana	^[4]
26	20(S), 24(R)-Epoxy-3α, 17α, 25-trihydroxydammarane	E	α-OH	H	H	α-OH	B. maximowicziana	^{[4, 8]}
27	3-Epi-ocotillol Ⅱ	E	α-OH	H	H	H	B. maximowicziana	^[4]
28	12β-Acetoxy-20(S), 24(R)-epoxy-3α, 25-dihydroxydammarane	E	α-OH	H	β-OAc	H	B. maximowicziana	^[4]
29	12β-Acetoxy-20(S), 24(R)-epoxy-3α, 17α, 25-trihydroxydammarane 3-O-β-D-glucopyranoside/Betulamaximoside A	E	α-O-β-D-Glc	H	β-OAc	α-OH	B. maximowicziana	^[4]
30	12β-Acetoxy-20(S), 24(R)-epoxy-3α, 17α, 25-trihydroxydammarane 3-O-β-D-(6-O-acetyl)-glucopyranoside/Betulamaximoside B	E	α-O-6-Acetyl-β-D-Glc	H	β-OAc	α-OH	B. maximowicziana	^[4]
31	12-O-Acetyl-20, 24-epoxy-3α, 12β, 20(S), 24(R), 25-pentahydroxydammar-3-yl hydrogen propanedioate/Papyriferic acid	E	α-O-Malonyl	H	β-OAc	H	B. neoalaskana	^{[6, 7, 9-11]}
						/B. pendula
						/B. platyphylla
32	Deacetylpapyriferic acid	E	α-O-Malonyl	H	β-OH	H	B. pendula	^[11]
33	Ocotillol Ⅱ 3-O-caffeate	E	β-O-Caffeoyl	H	H	H	B. platyphylla	^[6]
34	3-O-Methylmalonyl-3α, 17α, 25-trihydroxy-20(S), 24(R)-epoxydammarane	E	α-O-Methymalonyl	H	H	α-OH	B. platyphylla	^[8]
35	12β-Acetoxyl-ocotillone	E	O	H	β-OH	H	B. platyphylla	^[8]
36	Ocotillol	E	β-OH	H	H	H	B. platyphylla	^[8]
37	3-O-EthylmalonylepiocotillolII	E	α-O-Ethylmalonyl	H	H	H	B. platyphylla	^[8]
38	3-O-Butylmalonylepiocotillol Ⅱ	E	α-O-Ethylmalonyl	H	β-OAc	H	B. platyphylla	^[8]
39	Ethyl papyriferate	E	α-O-Butylmalonyl	H	H	H	B. platyphylla	^[8]
40	Butyl papyriferate	E	α-O-Butylmalonyl	H	β-OAc	H	B. platyphylla	^[8]

No.	Name	Structure	R1	R2	R3	R4	Source	Ref.
20	20(S), 24(R)-Epoxydammaran-3β	E	β-OH	α-OH	H	H	B. ermanii	^[5]
21	11α, 25-Triol, 3-O-β-D-glucopyranoside of 20	E	β-O-β-D-Glc	α-OH	H	H	B. ermanii	^[5]
22	2′-Acetate of 21	E	β-O-2-Acetyl-β-D-Glc	α-OH	H	H	B. ermanii	^[5]
23	11, 2′-Diacetate of 21	E	β-O-2-Acetyl-β-D-Glc	α-OAc	H	H	B. ermanii	^[5]
24	12-O-Acetylbetulafolienetetraol oxide	E	β-OH	H	β-OAc	α-OH	B. dahurica	^[9]
25	12β-Acetoxy-20(S), 24(R)-epoxy-3α, 17α, 25-trihydroxydammarane	E	α-OH	H	β-OAc	α-OH	B.maximowicziana	^[4]
26	20(S), 24(R)-Epoxy-3α, 17α, 25-trihydroxydammarane	E	α-OH	H	H	α-OH	B. maximowicziana	^{[4, 8]}
27	3-Epi-ocotillol Ⅱ	E	α-OH	H	H	H	B. maximowicziana	^[4]
28	12β-Acetoxy-20(S), 24(R)-epoxy-3α, 25-dihydroxydammarane	E	α-OH	H	β-OAc	H	B. maximowicziana	^[4]
29	12β-Acetoxy-20(S), 24(R)-epoxy-3α, 17α, 25-trihydroxydammarane 3-O-β-D-glucopyranoside/Betulamaximoside A	E	α-O-β-D-Glc	H	β-OAc	α-OH	B. maximowicziana	^[4]
30	12β-Acetoxy-20(S), 24(R)-epoxy-3α, 17α, 25-trihydroxydammarane 3-O-β-D-(6-O-acetyl)-glucopyranoside/Betulamaximoside B	E	α-O-6-Acetyl-β-D-Glc	H	β-OAc	α-OH	B. maximowicziana	^[4]
31	12-O-Acetyl-20, 24-epoxy-3α, 12β, 20(S), 24(R), 25-pentahydroxydammar-3-yl hydrogen propanedioate/Papyriferic acid	E	α-O-Malonyl	H	β-OAc	H	B. neoalaskana	^{[6, 7, 9-11]}
						/B. pendula
						/B. platyphylla
32	Deacetylpapyriferic acid	E	α-O-Malonyl	H	β-OH	H	B. pendula	^[11]
33	Ocotillol Ⅱ 3-O-caffeate	E	β-O-Caffeoyl	H	H	H	B. platyphylla	^[6]
34	3-O-Methylmalonyl-3α, 17α, 25-trihydroxy-20(S), 24(R)-epoxydammarane	E	α-O-Methymalonyl	H	H	α-OH	B. platyphylla	^[8]
35	12β-Acetoxyl-ocotillone	E	O	H	β-OH	H	B. platyphylla	^[8]
36	Ocotillol	E	β-OH	H	H	H	B. platyphylla	^[8]
37	3-O-EthylmalonylepiocotillolII	E	α-O-Ethylmalonyl	H	H	H	B. platyphylla	^[8]
38	3-O-Butylmalonylepiocotillol Ⅱ	E	α-O-Ethylmalonyl	H	β-OAc	H	B. platyphylla	^[8]
39	Ethyl papyriferate	E	α-O-Butylmalonyl	H	H	H	B. platyphylla	^[8]
40	Butyl papyriferate	E	α-O-Butylmalonyl	H	β-OAc	H	B. platyphylla	^[8]

桦木属植物三萜类化合物研究进展

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李焱鑫 , 巩婷 , 陈晶晶 , 陈天娇 , 杨金玲 ^* , 朱平 ^*

药学学报 | 综述 2023,58(5): 1211-1220

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药学学报 | 综述 2023, 58(5): 1211-1220

桦木属植物三萜类化合物研究进展

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李焱鑫, 巩婷, 陈晶晶, 陈天娇, 杨金玲^*, 朱平^*

作者信息

中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 国家卫生健康委员会天然药物生物合成重点实验室 & 中国医学科学院酶与天然药物生物催化重点实验室, 北京 100050

通讯作者:

*杨金玲, Tel: 86-10-63165199, E-mail: yangjl@imm.ac.cn;

朱平, Tel: 86-10-63165199, E-mail: zhuping@imm.ac.cn

Research progress on triterpenoids of Betula plants

Yan-xin LI, Ting GONG, Jing-jing CHEN, Tian-jiao CHEN, Jin-ling YANG^*, Ping ZHU^*

Affiliations

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biosynthesis of Natural Products, CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

出版时间: 2023-05-12 doi: 10.16438/j.0513-4870.2022-1232

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摘要

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植物次生代谢产物是天然药物的重要来源。桦木属植物具有丰富的药用价值, 药理作用机制复杂, 这与其中的三萜类化合物具有密不可分的关系。桦木属植物三萜类化合物主要分为达玛烷型、奥克梯隆型、齐墩果烷型、羽扇豆烷型和环阿屯烷型; 桦木属植物提取物具有抗肿瘤、抗炎、抗氧化、抗菌等多种活性; 桦木属植物三萜类化合物的生物合成途径自2, 3-氧化鲨烯之后根据环氧角鲨烯环化酶的不同分为达玛烯二醇Ⅱ、羽扇豆醇、环阿屯醇和香树酯四个分支。本文对桦木属植物三萜类化学成分、药理活性和生物合成途径解析三个方面进行了综述, 以期为利用桦木属植物三萜类化合物进行新药研发及利用合成生物学方法在微生物细胞工厂中生产这类化合物提供参考。

关键词

桦木属 / 三萜 / 化学成分 / 药理活性 / 生物合成

Abstract

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The secondary metabolites of plants are important sources of natural drugs. Betula plants have abundant pharmacological value, complex mechanism and wide applications, which are closely related to the triterpenoids of theirs. Triterpenoids in Betula species are mainly divided into dammarane-type, ocotillol-type, oleanane-type, lupane-type and cycloaltunane-type. The extracts of Betula species have varieties of activities such as anti-tumor, anti-inflammatory, anti-oxidant, anti-bacterial, etc. And the biosynthetic pathways of triterpenoids after 2, 3-oxidosqualene are split into four branches of dammarenediol-Ⅱ, lupeol, cycloartenol and amyrin according to the different oxidosqualene cyclases. This review summarizes the chemical constituents, pharmacological activities and biosynthetic pathways of triterpenoids in Betula plants. It provides a reference for the research and development of new drugs and the production of these triterpenoids in microbial cell factories by synthetic biology methods.

Key words

Betula / triterpenoids / chemical constituent / pharmacological activity / biosynthesis

引用本文

李焱鑫, 巩婷, 陈晶晶, 陈天娇, 杨金玲, 朱平. 桦木属植物三萜类化合物研究进展. 药学学报, 2023 , 58 (5) : 1211 -1220 . DOI: 10.16438/j.0513-4870.2022-1232

Yan-xin LI, Ting GONG, Jing-jing CHEN, Tian-jiao CHEN, Jin-ling YANG, Ping ZHU. Research progress on triterpenoids of Betula plants[J]. Acta Pharmaceutica Sinica, 2023 , 58 (5) : 1211 -1220 . DOI: 10.16438/j.0513-4870.2022-1232

正文

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桦木科植物(Betulaceae Gray) 由6个属组成, 分别为桤木属(Alnus Mill.)、桦木属(Betula Linn.)、鹅耳枥属(Carpinus Linn.)、榛属(Corylus Linn.)、铁木属(Ostrya Scop.) 和虎榛子属(Ostryopsis Decne.), 主要分布在北温带和北极地区, 中美洲和南美洲也有分布^[1]。桦木科的6个属在中国均有分布, 共有70余种。桦木属为桦木科植物的模式属, 也是这个家族中最大的属, 我国自然分布着31个种和6个变种^[2]。

桦木属植物的许多部位都具有药用价值, 在我国传统医学中应用已久。桦树皮具有清热利湿、祛痰止咳、消肿解毒的功效, 常用于治疗肺炎、痢疾、尿路感染、慢性气管炎等疾病, 也可外用治疗烧烫伤和痈疖肿毒; 桦树液祛痰止咳的功效突出, 且营养成分丰富, 常用来配制药剂, 治疗肺结核等呼吸系统疾病, 也可酿酒、配制成清凉口感的饮料, 或制成糖浆和糖精等食物添加剂^[2]。

三萜类化合物是桦木属植物主要的次生代谢产物, 在每年的7~9月生长季达到积累高峰, 树皮中的总三萜含量最高可达干重的16.8%, 叶片中含量可达干重的12.6%^[3]。本文总结了近年来关于桦木属植物三萜类化合物的研究成果, 在对其化学成分和药理活性进行综述的基础上, 首次对其生物合成途径的解析及其关键酶的功能表征进行了总结, 以期为桦木属植物三萜类化合物生物合成途径的深入解析以及通过合成生物学途径获得三萜类活性化合物提供有价值的参考。

1 三萜类化学成分

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桦木属植物中三萜类化合物的构型主要包括达玛烷型(dammarane-type, 图 1结构式A~D, 化合物1~19见表 1^[4-8])、奥克梯隆型(ocotillol-type, 图 1结构式E, 化合物20~40见表 2^[4-11])、齐墩果烷型(oleanane-type, 图 1结构式F, 化合物41~45见表 3^{[4-6, 9, 12-17]})、羽扇豆烷型(lupane-type, 图 1结构式G, 化合物46~53见表 4^{[4-6, 9, 12-15, 18, 19]})和环阿屯烷型(cycloartane-type)。这些三萜类化合物的C-3、C-11、C-12、C-17和C-25位常被羟基化, C-3位常与丙二酸、咖啡酸或对香豆酸发生酯化, C-3、C-11和C-12位常被乙酰化, 相对而言, 其糖基化产生的糖苷种类较少, 目前仅有少量葡萄糖苷和乙酰葡萄糖苷被报道^[20]。

白桦脂醇(化合物47, 表 4) 和白桦脂酸(化合物50, 表 4) 是桦木属植物中研究最多的三萜类成分, 主要存在于树干外皮, 属于羽扇豆烷型五环三萜类化合物。羽扇豆醇是白桦脂醇和白桦脂酸的关键前体, 白桦脂酸由白桦脂醇经两步氧化反应而得, 白桦脂醇约占白桦树外皮干重的3.6%, 白桦脂酸约占0.83%^[21]。

桦叶烯三醇(化合物8, 表 1) 和桦叶烯四醇(化合物7, 表 1) 也是桦木属植物中重要的三萜类成分, 主要存在于树叶中, 共约占叶片干重的0.25%, 在根皮中也有分布, 属于达玛烷型四环三萜类化合物, 不同种植物叶片中的达玛烷型三萜结构存在差异。

2 药理活性

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桦木属植物的提取物在亚洲许多国家被用于治疗多种疾病, 如癌症、各种炎症、糖尿病、结核病和胃肠道疾病等^[22]。现代药理学研究表明, 桦木属植物提取物表现出抗肿瘤、抗炎、抗氧化、抗菌、抗真菌、抗病毒、抗HIV、抗糖尿病、抗过敏、利尿和美白等多种活性。目前, 仅有一款来源于桦木属植物提取物的新药oleogel-S10于2016年获欧盟批准上市。该药为含有10%桦树皮提取物和90%葵花籽油的凝胶, 主要活性成分为白桦脂醇, 其他活性标志物也包括白桦脂酸、羽扇豆醇、齐墩果酸等三萜类化合物, 通过调控炎症因子和促进上皮细胞再生加速伤口愈合, 用于治疗成人局部深度创伤。目前该药正在全球多国开展一项针对大疱性表皮松解症(EB) 的Ⅲ期临床试验, 如果获批, oleogel-S10将成为欧洲首个用于EB患者的治疗方法^{[23, 24]}。

2.1 抗肿瘤

白桦脂酸被证明具有丰富的药理活性, 主要包括抗肿瘤、抗HIV和抗炎等, 其中对于其抗肿瘤作用的研究最为深入。白桦脂酸早期被确定为一种新的抗黑色素瘤药物, 最近的研究发现其对其他癌也较为敏感, 如头颈部鳞状细胞癌、胆囊癌、卵巢癌、乳腺癌和子宫颈腺癌等。

Thurnher等^[25]首次报道了白桦脂酸抗头颈部鳞状细胞癌的活性, 与其抗恶性黑色素瘤的有效浓度相当, 对头颈部鳞状细胞癌SCC25和SCC9细胞的抑制活性优于顺铂。Wang等^[26]发现白桦脂酸能通过RNA干扰下调硬脂酰辅酶A去饱和酶1 (SCD1) 的表达水平, 在体外抑制人胆囊癌NOZ细胞的增殖并诱导细胞凋亡, 在裸鼠体内抑制肿瘤的生长, 表明其可能是治疗高表达SCD1胆囊癌患者的有效药物。Liao等^[27]在体外实验中发现, 白桦脂酸对卵巢癌细胞系SKOV3的增殖有时间和剂量依赖性抑制作用; 体内实验证明, 白桦脂酸对卵巢癌SKOV3细胞带瘤小鼠皮下肿瘤的重量和体积的增长也有明显抑制作用。此外, 白桦脂酸也可以通过抑制上皮-间质的转化过程从而抑制癌细胞的转移。Damle等^[28]发现白桦脂酸对乳腺癌MCF-7细胞有体外细胞毒活性, 在小鼠体内给药也可以减小肿瘤体积。Dehelean等^[29]发现白桦脂醇和白桦脂酸对A431皮肤表皮癌、A2780卵巢癌和HeLa子宫颈腺癌细胞系的生长也有显著的抑制作用。

人们最初认为, 桦树皮的细胞毒性是由于白桦脂酸的存在所致, 然而研究者在对糙皮桦树皮的乙醇提取物进行分馏时, 发现存在于乙酸乙酯馏分中的熊果酸比白桦脂酸活性更强^[30]。实验证明, 熊果酸可以激活MCF-7细胞外源性凋亡途径, 同时抑制乳腺肿瘤的迁移, 且其对正常乳腺上皮细胞的细胞毒性相对较小。此外, 熊果酸介导的细胞内ROS生成和线粒体膜电位破坏也对其抗癌活性起到了关键作用。

2.2 抗炎

桦木属植物如西桦、垂枝桦、糙皮桦、白桦等的不同溶剂提取物均有抗炎活性的报道, 主要是由于三萜类化合物白桦脂醇的存在所致, 白桦脂酸的抗肿瘤和抗HIV活性较强, 但抗炎活性不如白桦脂醇。

从西桦茎的乙醇提取物中可以分离得到5个五环三萜类化合物: 白桦脂醇、白桦脂酸、羽扇豆醇、齐墩果酸和熊果酸, 均对脂多糖(LPS) 诱导的NO的产生有明显的抑制作用^[31]。其中白桦脂醇可以通过降低NO的水平显示出抗炎作用; 白桦脂酸抑制细胞中COX-2的表达和前列腺素E2的产生, 并通过调节肿瘤坏死因子α (TNF-α) 的产生来保护小鼠免受LPS的影响^[32]; 羽扇豆醇可以降低LPS诱导的巨噬细胞中TNF-α和白细胞介素1β (IL-1β) 的水平, 并能降低哮喘小鼠模型中细胞因子IL-4、IL-5和IL-13的水平^[33]; 齐墩果酸可以通过下调NF-κB的表达和TNF-α的产生, 显著抑制醋酸诱导的高渗透性和羧甲基纤维素诱导的白细胞体内迁移的活性^[34]; 而熊果酸则能降低LPS刺激的巨噬细胞产生IL-1β、IL-6和TNF-α的水平, 同时增加IL-10的产生。Oliveira等^[35]单独评估了白桦脂酸在内毒素休克小鼠模型中同样具有上述作用, 可以将致死剂量LPS刺激下的细胞和动物存活率提高到100%。证明白桦脂酸在体内、外均具有强大的抗炎活性, 通过依赖IL-10的机制调节体内巨噬细胞产生TNF-α, 从而保护小鼠免受内毒素攻击。

对于桦木属植物其他物种, Wacker等^[36]研究了垂枝桦树叶提取物对大鼠角膜移植后角膜炎症的影响, 发现其在体外可以特异性抑制T细胞增殖且不影响细胞表型; 在体内可以联合环孢素A, 显著延迟移植后受体大鼠角膜混浊的发生, 有潜力成为用于治疗角膜炎的新抗炎药; Kumar等^[37]对糙皮桦树皮中的三萜类化学成分进行分子对接, 发现各提取物对环氧合酶COX-1和COX-2均具有很强的抑制活性, 其中氯仿提取物对COX-2抑制活性甚于塞来昔布, 还有几种化合物对COX-2有较好的对接选择性, 有望成为有选择性的COX-2抑制剂, 用于开发没有任何胃肠道溃疡不良反应的新抗炎药; Dehelean等^[29]发现白桦的乙醇提取物及白桦脂醇均可以在体内减轻小鼠耳朵水肿的症状, 其中白桦脂醇的作用与吲哚美辛相当, 表现出很强的抗炎活性。

2.3 抗氧化

在对于不同种桦木属植物的研究中, Shukla等^[38]发现印度两个不同地区来源的糙皮桦树叶的甲醇、乙醇和水3种溶剂提取物均对DPPH自由基有很高的清除活性; Vamanu^[39]发现疣皮桦树叶的乙醇和甲醇提取物有保护人类红细胞膜免受AAPH氧化的作用, 其中乙醇提取物在清除DPPH和ABTS自由基方面, 以及还原力、螯合作用和红细胞溶血抑制方面的活性均高于甲醇提取物, 可以用作防止氧化应激的辅助剂; Penkov等^[40]研究了不同浓度的垂枝桦树叶提取物对ABTS自由基的清除作用, 结果表明其抗氧化活性具有浓度和时间依赖性, 提取物浓度越高, 抗氧化活性越强; Germano等^[41]发现垂枝桦树叶的乙醇提取物对酪氨酸酶催化的左旋多巴的氧化有非竞争性抑制作用, 能够在其活性部位螯合铜离子, 并表现出Fe²⁺螯合能力、还原能力和自由基清除活性。

对于白桦脂酸也有抗氧化活性的报道。Wu等^[42]探究了白桦脂酸对T-2毒素诱导的小鼠睾丸损伤的保护作用, 发现在小鼠暴露于T-2毒素之前给予白桦脂酸灌胃可以显著提高小鼠的精子活性和睾酮分泌水平, 显著提高总抗氧化的能力、超氧化物歧化酶和过氧化氢酶的活性以及谷胱甘肽的含量, 降低丙二醛的含量。此外, 白桦脂酸还可减轻睾丸损伤, 减少凋亡细胞数, 并显著降低Janus激酶2、信号转导和转录激活因子3、Caspe-3和Bcl-2相关X蛋白的表达。

2.4 抗菌、抗真菌、抗病毒

Duric等^[43]发现从垂枝桦树皮中分离得到的三萜类化合物如白桦脂醇、白桦脂酸、齐墩果酸和羽扇豆醇, 可以选择性地对枯草芽孢杆菌、金葡菌和铜绿假单胞菌显示抗菌活性, 其中齐墩果酸对枯草芽孢杆菌和金葡菌的活性最突出。Jones等^[44]发现白桦的乙醇提取物显示出对酿酒酵母生长的抑制作用。Webster等^[45]检测了多种桦木属植物的提取物对酿酒酵母单菌落生长的抑制程度, 其中黄桦提取物对酿酒酵母的抑制作用最强, 毛桦提取物对金葡菌有较好的抑菌活性^[46], 西桦的80%甲醇和乙酸乙酯提取物也被报道均具有很高的抗微生物活性^[47]。

2.5 其他活性

桦木属植物提取物还有抗HIV、降血糖、抗过敏和保护肾脏的作用^[48], 还可以作为美白保湿的成分添加在化妆品和护肤品中, 因此, 除了在药学领域的应用, 其在化妆品行业也有较大的开发价值。

Chaniad等^[31]发现从西桦茎的乙醇提取物中分离得到的五环三萜类化合物都对HIV-1整合酶有抑制作用, 其中白桦脂醇的作用最强。通过分子对接发现了活性化合物与酶活性中心的作用关系, 即这些五环三萜类化合物在C-17处的微小结构修饰导致了其对HIV-1整合酶抑制作用的显著差异, 羟基是与该酶活性位点结合的潜在官能团。该研究为西桦在传统医学中用于治疗艾滋病提供了进一步的科学依据。

Pongpiriyadacha等^[49]发现西桦的甲醇提取物对α-葡萄糖苷酶、蔗糖酶和麦芽糖酶的活性均有抑制作用, 可以有效抑制大鼠口服20%蔗糖后30和60 min内血清葡萄糖水平的上升, 从而控制血糖水平, 在治疗Ⅱ型糖尿病方面有很大的潜力。

Oh等^[50]发现白桦的乙醇提取物可以减少组胺诱导的小鼠搔痒行为和二硝基氯苯诱导的小鼠特异性皮炎, 还可以抑制大鼠腹膜间皮细胞中组胺的释放和炎症细胞因子的产生, 激活NF-κB和caspase-1。这项研究的发现为白桦治疗过敏性炎症疾病的药理机制提供了证据。

Shah等^[51]发现糙皮桦提取物可明显降低对乙二醇诱导的肾结石大鼠升高的所有生化指标, 包括钙、磷酸盐、草酸盐、肌酐、血尿素氮和尿酸等, 使尿液pH值恢复正常, 并明显增加尿量。俄罗斯目前市面上售有桦树叶提取物制成的固体泡腾片, 研究者发现, 1%角叉菜胶诱导的足肿胀大鼠模型在接受桦树叶提取物泡腾片给药后, 足体积显著减小, 尿量显著增加, 证明该泡腾片具有抗炎和利尿的作用, 并可以对大鼠的肾脏功能产生积极影响^[52]。

3 生物合成途径解析

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天然产物是药物发现的重要来源, 目前, 有60%以上的抗癌药物和75%以上的传染病治疗药物来源于天然产物及其衍生物。但由于天然产物在原植物中含量甚微、提取分离效率低, 而大量种植又面临培育周期长和连作障碍等问题; 且由于三萜类化合物结构复杂, 化学合成步骤繁琐、成本较高、难以准确得到目标立体构型, 还会带来环境污染。因此, 通过生物合成的方法获得三萜类化合物日渐成为众多研究者关注的热点。

三萜类化合物的上游生物合成途径为: 以糖酵解产物乙酰辅酶A (acetyl-CoA) 为初始供体, 经甲羟戊酸途径, 在细胞质中形成由5个碳原子组成的异戊二烯单元——异戊烯基焦磷酸(IPP), 经异戊烯基焦磷酸异构酶(IDI) 催化生成其异构体二甲基烯丙基焦磷酸(DMAPP), 在烯丙基转移酶的催化下, DMAPP与IPP经两次头尾缩合, 依次生成具有C₁₀骨架的牻牛儿基焦磷酸(GPP) 和具有C₁₅骨架的法呢基焦磷酸(FPP), 后由两分子的FPP头-头还原偶联生成具有C₃₀骨架的角鲨烯(squalene), 然后被鲨烯环氧酶(ERG1) 催化生成三萜类化合物的共同前体2, 3-氧化鲨烯(2, 3-oxidosqualene)^[53]。

在桦木属植物中, 2, 3-氧化鲨烯之后的代谢途径根据环氧角鲨烯环化酶(OSCs) 的不同分为4个分支: ①由达玛烯二醇合酶(DS) 催化生成达玛烯二醇Ⅱ (dammarenediol-Ⅱ), 再进一步生成桦叶烯三醇(betulafolienetriol)和桦叶烯四醇(betulafolienentetraol); ②由羽扇豆醇合酶(LUS) 催化生成羽扇豆醇(lupeol), 再进一步生成白桦脂醇(betulin), 再经过C28位的-CH₂OH氧化生成白桦脂酸(betulinic acid); ③在环阿屯醇合酶(CAS) 的作用下生成环阿屯醇和甾酮类三萜; ④在香树酯合酶(AS) 的作用下生成香树酯(amyrin) 或齐墩果酸(oleanolic) 类化合物^[54] (图 2)。

Zhang等^[55]从白桦树中克隆了4个OSCs基因, 并在酵母中验证了其功能, 即BPW (羽扇豆醇合酶基因)、BPY (β-香树脂合酶基因)、BPX (环阿屯醇合酶基因) 和BPX2。Yin等^[56]从东北白桦中克隆了两个OSCs基因, 分别命名为BpCAS和Bpβ-AS, 通过茉莉酸甲酯、赤霉素、脱落酸、乙烯和机械损伤诱导其表达, 利用反向遗传学方法确定了这两个基因在桦木三萜类化合物合成中的功能: 抑制Bpβ-AS基因对白桦脂酸的合成有正向调节作用, 干扰BpCAS能显著促进BPW和BPY基因的上调, 并促进2, 3-氧化鲨烯向下游产物白桦脂酸和齐墩果酸的转化。该课题组研究者从相同来源的东北白桦中首次克隆了法尼基焦磷酸合成酶基因BpFPS, 并发现在酿酒酵母中过表达该基因可以促进三萜前体角鲨烯含量的增加, 而在白桦植物中过表达该基因也可以促进白桦脂酸、齐墩果酸和白桦脂醇含量分别增加1.081、4.064和2.191倍^[56], 表明BpFPS在三萜类化合物的合成中起着重要作用。上述基因的获得及其功能的鉴定为今后利用基因工程和合成生物学在桦木属植物或酵母中高效合成三萜类化合物奠定了基础。

一种植物中可能存在多个OSCs基因, 具有多种不同的催化功能, 一种植物中也存在多个LUSs基因, 例如, Khakimov等^[57]在欧洲山芥(Barbarea vulgaris)中发现了BvLUP2和BvLUP5酶, Jennifer等^[58]在拟南芥(Arabidopsis thaliana)中发现了AtLUP1、AtLUP2和AtPEN6酶, 但催化产物都不单一。例如, 除了以羽扇豆醇为主要产物外, AtLUP1还会催化生产β-香树酯和3β, 20-二羟基羽扇豆醇。在桦木属植物也是如此。近年来, 在桦木属植物中除了一些OSCs基因已被解析以外, 仅有部分鉴定催化羽扇豆醇支路的细胞色素P450酶(CYPs) 的报道。目前所有被表征为能够催化白桦脂酸的C-28氧化的CYPs都属于CYP716亚家族。Khakimov等^[57]在欧洲山芥中发现了两个CYPs, 其中CYP716A80能高效地氧化羽扇豆醇和β-香树酯, 分别产生白桦脂酸和齐墩果酸, 而CYP716A81则能催化生成更多的产物。之前虽然已经证明了一些CYP716A亚家族成员可以将羽扇豆醇氧化成微量的白桦脂酸, 但在植物体中的主要功能还是将α-香树酯和β-香树酯分别转化为熊果酸和齐墩果酸^[59]。

白桦脂酸不仅分布在桦木属植物中, 其他植物中也有存在, 如迷迭香和夏枯草等。Huang等^[60]在迷迭香中鉴定了一种对羽扇豆醇具有非常高的底物选择性的酶CYP716A155, 可以高效地将羽扇豆醇氧化成白桦脂醇, 再氧化成白桦脂酸。尽管其也可以将α-香树酯和β-香树酯分别氧化为熊果酸和齐墩果酸, 但在将羽扇豆醇氧化为白桦脂酸方面显示出更高的效率。该课题组使用迷迭香来源的RoCYP/RoCPR组合, 最终构建了一株能够生产1.5 g·L^-1白桦脂酸和1.0 g·L^-1白桦脂醇的酿酒酵母工程菌, 此研究为桦木属植物中三萜或其他类活性成分的生物合成途径解析提供了新的思路和借鉴。

4 小结与展望

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桦木属植物具有丰富的药用价值, 药理作用机制复杂, 应用广泛, 这与其中的三萜类化合物具有密不可分的关系。本文对桦木属植物的三萜类化学成分、药理活性和生物合成途径解析三方面进行了综述。桦木属植物中三萜类化合物的构型主要包括达玛烷型、奥克梯隆型、齐墩果烷型、羽扇豆烷型和环阿屯烷型。其中, 树干外皮的主要活性成分是羽扇豆烷型的白桦脂醇和白桦脂酸, 树叶中的主要活性成分是达玛烷型的桦叶烯三醇和桦叶烯四醇。桦木属植物提取物药理作用广泛, 具有抗肿瘤、抗炎、抗氧化、抗菌、抗真菌、抗病毒、抗HIV、抗糖尿病、抗过敏、利尿和美白等多种活性。桦木属植物三萜类化合物的生物合成途径自2, 3-氧化鲨烯之后根据环氧角鲨烯环化酶的不同分为四个分支, 分别为达玛烯二醇Ⅱ、羽扇豆醇、环阿屯醇和香树酯分支。

关于桦木属植物三萜类化合物的提取、分离与鉴定研究较多, 但目前对桦木属植物药理活性的研究工作大多针对不同溶剂的提取物, 对于单体化合物的活性研究仅集中在羽扇豆烷类的白桦脂醇和白桦脂酸, 而对于其他化合物则鲜有报道。分离单体化合物有助于构效关系的研究, 明确的构效关系可以进一步推动桦木属植物天然代谢产物的结构修饰, 从而探索活性更高、性质更稳定的化合物。目前对于桦木属植物三萜类化合物的生物合成途径, 仅建立了大体框架, 下游途径中关键酶的鉴定与途径解析还有待进一步完善, 例如OSCs下游各分支的CYPs还需继续挖掘。相关酶的鉴定与途径解析将为最终利用合成生物学方法在微生物细胞工厂中高效、绿色地生产该类化合物创造条件。

作者贡献: 李焱鑫负责调研文献、整理资料、执笔、作图; 杨金玲和朱平负责指导和修改; 巩婷、陈晶晶和陈天娇负责修改和审校。

利益冲突: 所有作者均不存在利益冲突。

基金

收起

“十四五”国家重点研发计划(2022YFF1100300)
北京市自然科学基金面上项目(7212158)
国家自然科学基金项目(81673341)

参考文献

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文献

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2023年第58卷第5期

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doi: 10.16438/j.0513-4870.2022-1232

接收时间：2022-11-16
首发时间：2025-11-21
出版时间：2023-05-12

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收稿日期：2022-11-16
修回日期：2023-02-13

基金

“十四五”国家重点研发计划(2022YFF1100300)

北京市自然科学基金面上项目(7212158)

国家自然科学基金项目(81673341)

作者信息

通讯作者:

*杨金玲, Tel: 86-10-63165199, E-mail: yangjl@imm.ac.cn;

朱平, Tel: 86-10-63165199, E-mail: zhuping@imm.ac.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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No.	Name	Structure	R1	R2	R3	R4	Source	Ref.
1	Dammar-24-en-3β, 20(S), 26-triol 3-O-caffeate	A	β-O-Caffeoyl	H	H	/	B. maximowicziana	^[4]
2	Dammar-24-en-3β, 20(S), 26-triol 3-O-p-coumarate	A	β-O-p-Coumaroyl	H	H	/	B. maximowicziana	^[4]
3	Dammar-24-en-3β, 11α, 20(S)-triol	B	β-OH	α-OH	H	H	B. ermanii	^[5]
4	3-O-β-D-2-O-Acetylglucopyranoside of 3	B	β-O-2-Acetyl-β- D-Glc	α-OH	H	H	B. ermanii	^[5]
5	Dammarendiol Ⅱ 3-caffeate	B	β-O-Caffeoyl	H	H	H	B. maximowicziana	^[4-6]
							B. ermanii
							B. platyphylla
6	12-O-Acetylbetulafolienetetraol	B	α-OH	H	β-OAc	α-OH	B. maximowicziana	^[4]
7	Betulafolienetetraol	B	α-OH	H	β-OH	α-OH	B. maximowicziana	^[4]
8	Betulafolienetriol	B	α-OH	H	β-OH	H	B. platyphylla	^[6]
9	12-O-Acetyl-3-O-malonylbetulafolienetriol	B	α-O-Malonyl	H	β-OAc	H	B. platyphylla	^[6]
10	12-O-Acetylbetulafolienediolone	B	O	H	β-OAc	H	B. platyphylla	^[6]
11	Dammarenediol Ⅱ 3-O-p-coumarate	B	β-O-p-Coumaroyl	H	H	H	B. platyphylla	^[6]
12	12-O-Acetyl-3α, 12β, 17α, 20(S)-tetrahydroxydammar-24-en-3-yl hydrogen propanedioate	B	α-O-Malonyl	H	β-OAc	α-OH	B. pendula	^[7]
13	12-O-Acetyl-3α, 12β, 20(S), 25-tetrahydroxydammar-23(E)-en-3-yl hydrogen propanedioate	C	α-O-Malonyl	β-OAc	H	H	B. pendula	^[7]
14	12-O-Acetyl-3α, 12β, 17α, 20(S), 25-pentahydroxydammar-23(E)-en-3-yl hydrogen propanedioate	C	α-O-Malonyl	β-OAc	α-OH	H	B. pendula	^[7]
15	20(S)-Hydroxy-25-methoxy-dammar-23-en-3-one	C	O	H	H	Me	B. platyphylla	^[8]
16	3α, 20(S)-Dihydroxy-25-methoxy-dammar-23-ene	C	α-OH	H	H	Me	B. platyphylla	^[8]
17	12-O-Acetyl-3α, 12β, 20(S), 24(R)-tetrahydroxydammar-25-en-3-yl hydrogen propanedioate	D	α-O-Malonyl	β-OAc	β-OH	H	B. pendula	^[7]
18	12-O-Acetyl-3α, 12β, 20(S), 24(S)-tetrahydroxydammar-25-en-3-yl hydrogen propanedionate	D	α-O-Malonyl	β-OAc	α-OH	H	B. pendula	^[7]
19	12-O-Acetyl-3α, 12β, 17α, 20(S), 24(R)-pentahydroxydammar-25-en-3-yl hydrogen propanedioate	D	α-O-Malonyl	β-OAc	β-OH	α-OH	B. pendula	^[7]

No.

Name

Structure

Source

Ref.

Dammar-24-en-3β, 20(S), 26-triol 3-O-caffeate

β-O-Caffeoyl

B. maximowicziana

^[4]

Dammar-24-en-3β, 20(S), 26-triol 3-O-p-coumarate

β-O-p-Coumaroyl

B. maximowicziana

^[4]

Dammar-24-en-3β, 11α, 20(S)-triol

β-OH

α-OH

B. ermanii

^[5]

3-O-β-D-2-O-Acetylglucopyranoside of 3

β-O-2-Acetyl-β- D-Glc

α-OH

B. ermanii

^[5]

Dammarendiol Ⅱ 3-caffeate

β-O-Caffeoyl

B. maximowicziana

^[4-6]

B. ermanii

B. platyphylla

12-O-Acetylbetulafolienetetraol

α-OH

β-OAc

α-OH

B. maximowicziana

^[4]

Betulafolienetetraol

α-OH

β-OH

α-OH

B. maximowicziana

^[4]

Betulafolienetriol

α-OH

β-OH

B. platyphylla

^[6]

12-O-Acetyl-3-O-malonylbetulafolienetriol

α-O-Malonyl

β-OAc

B. platyphylla

^[6]

12-O-Acetylbetulafolienediolone

β-OAc

B. platyphylla

^[6]

Dammarenediol Ⅱ 3-O-p-coumarate

β-O-p-Coumaroyl

B. platyphylla

^[6]

12-O-Acetyl-3α, 12β, 17α, 20(S)-tetrahydroxydammar-24-en-3-yl hydrogen propanedioate

α-O-Malonyl

β-OAc

α-OH

B. pendula

^[7]

12-O-Acetyl-3α, 12β, 20(S), 25-tetrahydroxydammar-23(E)-en-3-yl hydrogen propanedioate

α-O-Malonyl

β-OAc

B. pendula

^[7]

12-O-Acetyl-3α, 12β, 17α, 20(S), 25-pentahydroxydammar-23(E)-en-3-yl hydrogen propanedioate

α-O-Malonyl

β-OAc

α-OH

B. pendula

^[7]

20(S)-Hydroxy-25-methoxy-dammar-23-en-3-one

B. platyphylla

^[8]

3α, 20(S)-Dihydroxy-25-methoxy-dammar-23-ene

α-OH

B. platyphylla

^[8]

12-O-Acetyl-3α, 12β, 20(S), 24(R)-tetrahydroxydammar-25-en-3-yl hydrogen propanedioate

α-O-Malonyl

β-OAc

β-OH

B. pendula

^[7]

12-O-Acetyl-3α, 12β, 20(S), 24(S)-tetrahydroxydammar-25-en-3-yl hydrogen propanedionate

α-O-Malonyl

β-OAc

α-OH

B. pendula

^[7]

12-O-Acetyl-3α, 12β, 17α, 20(S), 24(R)-pentahydroxydammar-25-en-3-yl hydrogen propanedioate

α-O-Malonyl

β-OAc

β-OH

α-OH

B. pendula

^[7]

No.	Name	Structure	R1	R2	R3	R4	Source	Ref.
20	20(S), 24(R)-Epoxydammaran-3β	E	β-OH	α-OH	H	H	B. ermanii	^[5]
21	11α, 25-Triol, 3-O-β-D-glucopyranoside of 20	E	β-O-β-D-Glc	α-OH	H	H	B. ermanii	^[5]
22	2′-Acetate of 21	E	β-O-2-Acetyl-β-D-Glc	α-OH	H	H	B. ermanii	^[5]
23	11, 2′-Diacetate of 21	E	β-O-2-Acetyl-β-D-Glc	α-OAc	H	H	B. ermanii	^[5]
24	12-O-Acetylbetulafolienetetraol oxide	E	β-OH	H	β-OAc	α-OH	B. dahurica	^[9]
25	12β-Acetoxy-20(S), 24(R)-epoxy-3α, 17α, 25-trihydroxydammarane	E	α-OH	H	β-OAc	α-OH	B.maximowicziana	^[4]
26	20(S), 24(R)-Epoxy-3α, 17α, 25-trihydroxydammarane	E	α-OH	H	H	α-OH	B. maximowicziana	^{[4, 8]}
27	3-Epi-ocotillol Ⅱ	E	α-OH	H	H	H	B. maximowicziana	^[4]
28	12β-Acetoxy-20(S), 24(R)-epoxy-3α, 25-dihydroxydammarane	E	α-OH	H	β-OAc	H	B. maximowicziana	^[4]
29	12β-Acetoxy-20(S), 24(R)-epoxy-3α, 17α, 25-trihydroxydammarane 3-O-β-D-glucopyranoside/Betulamaximoside A	E	α-O-β-D-Glc	H	β-OAc	α-OH	B. maximowicziana	^[4]
30	12β-Acetoxy-20(S), 24(R)-epoxy-3α, 17α, 25-trihydroxydammarane 3-O-β-D-(6-O-acetyl)-glucopyranoside/Betulamaximoside B	E	α-O-6-Acetyl-β-D-Glc	H	β-OAc	α-OH	B. maximowicziana	^[4]
31	12-O-Acetyl-20, 24-epoxy-3α, 12β, 20(S), 24(R), 25-pentahydroxydammar-3-yl hydrogen propanedioate/Papyriferic acid	E	α-O-Malonyl	H	β-OAc	H	B. neoalaskana	^{[6, 7, 9-11]}
						/B. pendula
						/B. platyphylla
32	Deacetylpapyriferic acid	E	α-O-Malonyl	H	β-OH	H	B. pendula	^[11]
33	Ocotillol Ⅱ 3-O-caffeate	E	β-O-Caffeoyl	H	H	H	B. platyphylla	^[6]
34	3-O-Methylmalonyl-3α, 17α, 25-trihydroxy-20(S), 24(R)-epoxydammarane	E	α-O-Methymalonyl	H	H	α-OH	B. platyphylla	^[8]
35	12β-Acetoxyl-ocotillone	E	O	H	β-OH	H	B. platyphylla	^[8]
36	Ocotillol	E	β-OH	H	H	H	B. platyphylla	^[8]
37	3-O-EthylmalonylepiocotillolII	E	α-O-Ethylmalonyl	H	H	H	B. platyphylla	^[8]
38	3-O-Butylmalonylepiocotillol Ⅱ	E	α-O-Ethylmalonyl	H	β-OAc	H	B. platyphylla	^[8]
39	Ethyl papyriferate	E	α-O-Butylmalonyl	H	H	H	B. platyphylla	^[8]
40	Butyl papyriferate	E	α-O-Butylmalonyl	H	β-OAc	H	B. platyphylla	^[8]

No.

Name

Structure

Source

Ref.

20(S), 24(R)-Epoxydammaran-3β

β-OH

α-OH

B. ermanii

^[5]

11α, 25-Triol, 3-O-β-D-glucopyranoside of 20

β-O-β-D-Glc

α-OH

B. ermanii

^[5]

2′-Acetate of 21

β-O-2-Acetyl-β-D-Glc

α-OH

B. ermanii

^[5]

11, 2′-Diacetate of 21

β-O-2-Acetyl-β-D-Glc

α-OAc

B. ermanii

^[5]

12-O-Acetylbetulafolienetetraol oxide

β-OH

β-OAc

α-OH

B. dahurica

^[9]

12β-Acetoxy-20(S), 24(R)-epoxy-3α, 17α, 25-trihydroxydammarane

α-OH

β-OAc

α-OH

B.maximowicziana

^[4]

20(S), 24(R)-Epoxy-3α, 17α, 25-trihydroxydammarane

α-OH

B. maximowicziana

^{[4, 8]}

3-Epi-ocotillol Ⅱ

α-OH

B. maximowicziana

^[4]

12β-Acetoxy-20(S), 24(R)-epoxy-3α, 25-dihydroxydammarane

α-OH

β-OAc

B. maximowicziana

^[4]

12β-Acetoxy-20(S), 24(R)-epoxy-3α, 17α, 25-trihydroxydammarane 3-O-β-D-glucopyranoside/Betulamaximoside A

α-O-β-D-Glc

β-OAc

α-OH

B. maximowicziana

^[4]

12β-Acetoxy-20(S), 24(R)-epoxy-3α, 17α, 25-trihydroxydammarane 3-O-β-D-(6-O-acetyl)-glucopyranoside/Betulamaximoside B

α-O-6-Acetyl-β-D-Glc

β-OAc

α-OH

B. maximowicziana

^[4]

12-O-Acetyl-20, 24-epoxy-3α, 12β, 20(S), 24(R), 25-pentahydroxydammar-3-yl hydrogen propanedioate/Papyriferic acid

α-O-Malonyl

β-OAc

B. neoalaskana

^{[6, 7, 9-11]}

/B. pendula

/B. platyphylla

Deacetylpapyriferic acid

α-O-Malonyl

β-OH

B. pendula

^[11]

Ocotillol Ⅱ 3-O-caffeate

β-O-Caffeoyl

B. platyphylla

^[6]

3-O-Methylmalonyl-3α, 17α, 25-trihydroxy-20(S), 24(R)-epoxydammarane

α-O-Methymalonyl

α-OH

B. platyphylla

^[8]

12β-Acetoxyl-ocotillone

β-OH

B. platyphylla

^[8]

Ocotillol

β-OH

B. platyphylla

^[8]

3-O-EthylmalonylepiocotillolII

α-O-Ethylmalonyl

B. platyphylla

^[8]

3-O-Butylmalonylepiocotillol Ⅱ

α-O-Ethylmalonyl

β-OAc

B. platyphylla

^[8]

Ethyl papyriferate

α-O-Butylmalonyl

B. platyphylla

^[8]

Butyl papyriferate

α-O-Butylmalonyl

β-OAc

B. platyphylla

^[8]

No.

Name

Structure

Source

Ref.

Oleanolic acid

β-OH

β-COOH

B. dahurica

^{[5, 6, 9, 12-14]}

/B. ermanii

/B. pendula

/B. platyphylla

/B. schmidtii

/B. utilis

Oleanolic acid 3-O-caffeate

β-O-Caffeoyl

β-COOH

B. dahurica

^{[4, 5, 9, 14]}

/B. ermanii

/B. maximowicziana

Acetyl-oleanolic acid

β-OAc

β-COOH

B. maximowicziana

^{[4, 6, 15]}

/B. platyphylla

/B. utilis

Karachic acid

β-OH

α-OAc

β-COOH

B. utilis

^[16]

Betuloleanolic acid acetate

β-OAc

CH₃

β-COOH

B. pendula

^[17]

No.

Name

Structure

Source

Ref.

Lupeol

β-OH

β-CH₂OH

CH₂

B. ermanii

^{[4-6, 12, 14, 15]}

/B. maximowicziana

/B. pendula

/B. platyphylla

/B. schmidtii

/B. utilis

Betulin

β-OH

β-CH₂OH

CH₂

B. dahurica

^{[4-6, 9, 12-15, 18, 19]}

/B. ermanii

/B. maximowicziana

/B. ovalifolia

/B. pendula

/B. platyphylla

/B. schmidtii

/B. utilis

Betulone

β-CH₂OH

CH₂

B. schmidtii

^[14]

Betulonic acid

β-COOH

CH₂

B. pendula

^[14]

/B. platyphylla

/B. utilis

Betulinic acid

β-OH

β-COOH

CH₂

B. pendula

^{[6, 12, 19]}

/B. platyphylla

/B. utilis

Betulin 3-caffeate /Lupeol caffeate

β-O-Caffeoyl

β-CH₂OH

CH₂

/B. ermanii

^{[4-6, 9, 18]}

/B. maximowicziana

/B. ovalifolia

/Betul

/B. platyphylla

Monogynol A

β-OH

β-CH₃

CH₃, OH

B. dahurica

^{[4, 5, 9]}

/B. ermanii

/B. maximowicziana

Lupane-3β, 20, 28-triol 3-O-caffeate

β-O-Caffeoyl

β-CH₂OH

CH₃, OH

B. maximowicziana

^[4]