Dihydrophenanthrenes from medicinal plants of Orchidaceae: A review.

The plants of Orchidaceae are widely distributed in the world, 47 species of which have been used as folk medicines with a long history. The tubers and stems of them exhibit diverse efficacy, including clearing heat and resolving toxin, moistening lung and relieving cough and promoting blood circulation. Since dihydrophenanthrenes were responsible for the medical purposes, the characteristic skeletons, pharmacological effects and clinical applications of dihydrophenanthrenes were summarized in this review, so as to provide a theoretical basis for the comprehensive study, development and application of DPs from medicinal plants of Orchidaceae.

Introduction

Orchidaceae family is the largest group of flowering plants including 24 500 species in 775 genera. Forty-seven species in Orchidaceae family have been used as folk medicines with a long history. For example, the tubers of Bletilla striata (Thunb.) Rchb. f. (Baiji) is recorded in the Chinese Pharmacopoeia (2020) to relieve swelling and traumatic bleeding. In Compendium of Materia Medica (Ben Cao Gang Mu), the tubers of B. striata was reported to be used to stop bleeding by grinding the tubers to powder. Some classical folk prescriptions containing B. striata are used for epistaxis, lung atrophy, furuncle, coughing and low-grade fever, such as “Baiji San”, “Baiji Pipa Wan”, “Bai Zi Gao” and “Jin Xian San”. At present, the tubers of B. striata has been served as the main ingredients of some Chinese patent medicines, and these medicines are recorded in the Chinese Pharmacopoeia (2020) and used to treat peptic ulcer, antral gastritis and digestive tracts, such as “Kuai Wei Tablets”, “Weikangling Capsules” and “Jianwei Yuyang Granules” (Jiang and Ye, 2013, Pei, 1979). As a traditional Chinese medicine and a Mongolian medicine, pseudobulbs of Cremastra appendiculata (D. Don) Makino, one of the botanical origins of Shancigu exhibit the efficacy of clearing heat and resolving toxin, moistening lung and relieving cough. Since the Qing Dynasty, pseudobulbs of C. appendiculata have been used to treat breast cancer and gastric cancer. The New Compendium of Materia Medica records that pseudobulbs of C. appendiculata belongs to “dispelling poison” and can eliminate malignant tumors in human body (Chen, 1996). The pseudobulbs of C. appendiculata can not only inhibit the growth and proliferation of cancer cells, induce apoptosis but also interfere with invasion and migration, which has been widely used in clinical practice. Currently, five Chinese patent medicines containing the pseudobulbs of C. appendiculata have been developed and marked in China, which are used for the treatment of liver cancer and gastric cancer, such as “Ci Dan Capsules”, “Ruanjian Oral Liguid”, “Ai Yu Capsules”, “Jin Pu Capsules” and “Ru Pi Qing Pills” (Dong, 2014, Yang, 2016). Therefore, their bioactive ingredients and pharmacological effects have attracted much attention of the medicinal chemists.

Phytochemical research showed that medicinal plants of Orchidaceae are rich of dihydrophenanthrenes (DPs), flavonoids, triterpenoids, alkaloids and bibenzyls, in which DPs are the major bioactive ingredients. Modern pharmacological studies showed that DPs in medicinal plants of Orchidaceae possess anti-inflammatory, anti-tumor, anti-oxidation and anti-bacterial activities (Ishiuchi et al., 2015, Ma et al., 2016). DPs might be used in the quality control of TCMs from Orchidaceae plants, mainly spread in Pholidota, Bletilla, Dendrobium and Pleione genus (Fig. 1).

Fig. 1

Distribution of DPs in medicinal plants of Orchidaceae (Sp. = Species).

DPs isolated from Orchidaceae plants

Up to now, 217 DPs have been isolated from medicinal plants of Orchidaceae. According to the number of DP units, they are usually divided into two major groups: DP monomers and DP polymers (Fig. 2). In addition, the numbers and origins of DPs from medicinal plants of Orchidaceae in each subtype are summarized in Fig. 3.

Fig. 2

Chemical structural types of DPs from medicinal plants of Orchidaceae.

Fig. 3

Numbers of DPs from medicinal plants of Orchidaceae in each subtype.

DP monomers

Seventy-one percent of the natural DPs from medicinal plants of Orchidaceae are DP monomers (1–155). According to the feature of substituents in the chemical structures, DP monomers are divided into simple DP monomers, dihydrophenanthrenequinones, dihydrophenanthrofurans and dihydrophenanthropyrans.

Simple DP monomers

More than 80% of simple DP monomers are from Pholidota, Bletilla, Dendrobium and Spiranthes. The substituents including hydroxy, methoxy and isoprene groups usually link at C-2, C-6 and C-7. The special type, with a five- or six- membered ring formed at C-4 and C-5, has only been isolated from Pholidota genus. The representative structures are afforded in Fig. 4 and the chemical structures, names and origins displayed in Fig. S1 and Table 1.

Fig. 4

Representative chemical structures of simple DP monomers.

Table 1

Names, origins of DPs isolated from medicinal plants of Orchidaceae.

No.	Names	Origins	References
1	Lusianthridin	Pholidota chinensis	Wang, Wang, & Kitanaka. (2007)
2	Cannabidihydrophenanthrene	Pholidota chinensis	Wang, Wang, & Kitanaka. (2007)
3	4,5-Dihydroxy-2-methoxy-9,10-dihydrophenanthrene	Pholidota chinensis	Wang, Wang, & Kitanaka. (2007)
4	Eulophiol	Pholidota chinensis	Wang, Wang, & Kitanaka. (2007)
5	Orchinol	Pholidota chinensis	Hu et al. (2018)
6	Coelonin	Pholidota chinensis	Rueda, et al. (2014)
7	Hircinol	Pholidota chinensis	Wang, Wang, & Kitanaka. (2007)
8	2,4,7-Trihydroxy-9,10-dihydrophenanthrene	Pholidota chinensis	Wang, Wang, & Kitanaka. (2007)
9	7-Methoxy-9,10-dihydrophenanthrene-2,4-diol	Pholidota chinensis	Wu, Qu, & Cheng. (2008)
10	Erianthridin	Pholidota chinensis	Wang, Wang, & Kitanaka. (2007)
11	7-Hydroxy-2,3,4-trimethoxy-9,10-dihydrophenanthrene	Pholidota chinensis	Hu et al. (2018)
12	2,5-Dihydroxy-3,4-dimethoxy-9,10-dihydrophenanthrene	Pholidota chinensis	Hu et al. (2018)
13	2,5-Dihydroxyl-3,4,6-trimethoxy-9,10-dihydrophenanthrene	Pholidota chinensis	Hu et al. (2018)
14	2,7-Dihydroxy-3,4,6-trimethoxy-9,10-dihydrophenanthrene	Pholidota chinensis	Hu et al. (2018)
15	Pholidotol	Pholidota chinensis	Hu et al. (2018)
16	Phocantol	Pholidota chinensis	Hu et al. (2018)
17	Flavidin	Pholidota chinensis	Hu et al. (2018)
18	Flaccidin	Pholidota chinensis	Hu et al. (2018)
19	Coelogin	Pholidota chinensis	Hu et al. (2018)
20	Imbricatin	Pholidota chinensis	Hu et al. (2018)
21	Isoflavidinin	Pholidota chinensis	Hu et al. (2018)
22	1-(4′-Hydroxybenzyl)-imbricatin	Pholidota yunnanensis	Dong, et al. (2013)
23	iso-Oxoflavidinin	Pholidota chinensis	Hu et al. (2018)
24	Oxoflavidin	Pholidota chinensis	Hu et al. (2018)
25	O-methylorchinol	Bletilla striata	Bai, Yamaki, Inoue, & Takagi. (1990)
26	2,5,8-Trihydroxy-7-methoxy-9,10-dihydrophenanthrene	Bletilla striata	Zhou, et al. (2019)
27	2,7-Dihydroxy-l-(4′-hydroxybenzyl)-9,10-dihydrophenanthrene-4′-O-β-D-glucoside	Bletilla striata	Zhou, et al. (2019)
28	Bletillatin C	Bletilla striata	Zhou, et al. (2019)
29	2,7-Dihydroxy-1-(p-hydroxybenzyl)-4-methoxyphenanthrene-9,10-dihydrophenanthrene-4′-O-β-D-diglucoside	Bletilla striata	Zhou, et al. (2019)
30	1-(p-Hydroxybenzyl)-4-methoxy-9,10-dihydrophenanthrene	Bletilla striata	Yamaki, Bai, Inoue, & Takagi. (1990)
31	1-(4-Hydroxybenzyl)-4,7-dimethoxy-9,10-dihydrophenanthrene-2,8-diol	Bletilla striata	Zhou, et al. (2019)
32	2,7-Dihydroxy-3-(p-hydroxybenzyl)-9,10-dihydrophenanthrene-4-O-β-D-glucoside	Bletilla striata	Zhou, et al. (2019)
33	2,7-Dihydroxy-3-(p-hydroxybenzyl)-4-methoxy-9,10-dihydrophenanthrene	Bletilla striata	Yamaki, Bai, Inoue, & Takagi. (1990)
34	2,7-Dihydroxy-1,6-bis(4-hydroxybenzyl)-4-methoxy-9,10-dihydrophenanthrene	Bletilla striata	Yamaki, Bai, Inoue, & Takagi. (1990)
35	2,7-Dihydroxy-1,3-bis(p-hydroxybenzyl)-4-methoxy-9,10-dihydrophenanthrene	Bletilla striata	Bai, Kato, Inoue, Yamaki, & Takagi. (1991)
36	Bletillatin B	Bletilla striata	Zhou, et al. (2019)
37	2,7-bis(Allyloxy)-5-methoxy-3-methyl-9,10-dihydrophenanthrene	Bletilla ochracea	Cai, Zhao, & Zhang. (2007)
38	4,7-Dihydroxy-2,3,6-trimethoxy-9,10-dihydrophenanthrene	Dendrobium sinense	Tan, et al. (2017)
39	4,5-Dihydroxy-2,3-dimethoxy-9,10-dihydrophenanthrene	Dendrobium sinense	Cai, et al. (2020)
40	2,5,7-Trihydroxy-4-methoxy-9,10-dihydrophenanthrene	Dendrobium sinense	Tan, et al. (2017)
41	Ephemeranthol B	Dendrobium officinale	Wang, Ma, Yang, & Pan. (1997)
42	Ephemeranthol A	Dendrobium officinale	Cui, Lu, Zhao, Liu, & Zhang. (2019)
43	Cannithrene 2	Dendrobium nobile	Li. (2011)
44	1,5-Dihydroxy-3,4,7-trimethoxy-9,10-dihydrophenanthrene	Dendrobium moniliforme	Zhao, Yang, Zhang, Chen, & Chen. (2016)
45	4,6-Dimethoxy-9,10-dihydrophenanthrene-2,3,7-triol	Dendrobium amplum	Majumder, Rahaman, Roychowdhury, & Dhara. (2008)
46	2,4,5-Trihydroxy-9,10-dihydrophenanthrene	Dendrobium fimbriatum	Xu, Xu, & Hou. (2014)
47	Emphernathol A	Dendrobium plicatile	Chen, et al. (2020)
48	2,4,7-Trimethoxy-9,10-dihydrophenanthrene-3-ol	Dendrobium hainanense	Zhang, et al. (2015)
49	3,4,7-Trimethoxy-9,10-dihydrophenanthrene-2,8-diol	Dendrobium nobile	Yang, Sung, & Kim. (2007)
50	4,7-Dimethoxy-9,10-dihydrophenanthrene-2-ol	Dendrobium nobile	Yang, Sung, & Kim. (2007)
51	3,4-Dimethoxy-1-(methoxymethyl)-9,10-dihydrophenanthrene-2,7-diol	Dendrobium hainanense	Zhang, et al. (2019)
52	Dendroinfundin A	Dendrobium infundibulum	Na Ranong, Likhitwitayawuid, Mekboonsonglarp & Sritularak. (2019)
53	Dendroinfundin B	Dendrobium infundibulum	Na Ranong, Likhitwitayawuid, Mekboonsonglarp & Sritularak. (2019)
54	Rotundatin	Dendrobium loddigesii	Majumder, Banerjee, Lahiri, Mukhoti, & Sen. (1998)
55	(9S)-9,10-dihydro-5-methoxy-4,7,9-phenanthrenetriol	Dendrobium denneanum	Lin, Wang, & Yang. (2013)
56	(9S)-9,10-dihydro-4-methoxy-2,5,7,9-phenanthrenetetrol	Dendrobium nobile	Ladan & Ali. (2017)
57	(9S)-9,10-dihydro-5-methoxy-2,4,7,9-phenanthrenetetrol	Dendrobium denneanum	Lin, Wang, & Yang. (2013)
58	(9R)-5,9-dihydroxy-4-methoxy-9,10-dihydrophenanthrene-2-yl-2-hydroxyacetate	Dendrobium nobile	Zhou, Zheng, Wu, Chen, & Zhang (2017)
59	2,5,9-Trihydroxy-9,10-dihydrophenanthrene-4-yl-2-hydroxyacetate	Dendrobium primulinum	Ye, Mei, Yang, Cheng, & Kong. (2016)
60	1,2,4,9R-tetrahydroxy-9,10-dihydrophenanthrene-5-O-β-D-glucopyranoside	Dendrobium denneanum	Lin, Wang, & Yang. (2013)
61	Spiranthesphenanthrene D	Spiranthes sinensis	Liu, et al. (2019a)
62	2,4-Dihydroxy-5-methoxy-9,10-dihydrophenanthrene	Spiranthes sinensis	Liu, et al. (2019a)
63	Sinensol A	Spiranthes sinensis	Liu, Li, Zhong, Yang, & Li, 2013
64	Sinensol H	Spiranthes sinensis	Lin, Wang, Kuo, & Liu, 2001
65	Spiranthon A	Spiranthes sinensis	Liu, Li, Zhong, Yang, & Li, 2013
66	Spiranthesol B	Spiranthes sinensis	Lin, Huang, Don, & Kuo, 2000
67	Sinensol C	Spiranthes sinensis	Liu, Li, Zhong, Yang, & Li, 2013
68	Sinensol G	Spiranthes sinensis	Lin, Wang, Kuo, & Liu, 2001
69	Spiranthol B	Spiranthes sinensis	Liu, et al. (2019a)
70	Spirasineol A	Spiranthes sinensis	Lin, Huang, Don, & Kuo, 2000
71	Sinensol B	Spiranthes sinensis	Lin, Huang, Don, & Kuo, 2000
72	Sinensol F	Spiranthes sinensis	Lin, Huang, Don, & Kuo, 2000
73	Shancidin	Pleione bulbocodioides	Zhu (2014)
74	Pleioanthrenin	Pleione formosana	Zhu (2014)
75	7-Hydroxy-4-methoxy-9,10-dihydrophenanthrene-2-O-β-D-glucopyranoside	Cremastra appendiculata	Sun et al. (2018)
76	7-Hydroxy-5-methoxy-9,10-dihydrophenanthrene-2-O-β-D-glucopyranoside	Cremastra appendiculata	Sun et al. (2018)
77	4-Methoxy-9,10-dihydrophenanthrene-2,7-diyl-O-β-D-glucopyranoside	Cremastra appendiculata	Wang, Guan, & Meng. (2013)
78	2,7-Dihydroxy-1-(4-hydroxybenzyl)-4-methoxy-9,10-dihydrophenanthrene	Cremastra appendiculata	Liu, et al. (2015)
79	1-(3′-Methoxy-4′-hydroxybenzyl)-7-methoxy-9,10-dihydrophenanthrene-2,4-diol	Cremastra appendiculata	Zhu (2014)
80	Cephathrene A	Cyrtopodium paniculatum	Auberon, et al. (2016)
81	Cephathrene B	Cyrtopodium paniculatum	Auberon, et al. (2016)
82	(9S)-3,4-dimethoxy-9,10-dihydrophenanthrene-2,7,9-triol	Cyrtopodium paniculatum	Auberon, et al. (2016)
83	1-(p-Hydroxybenzoyl)-2-methoxy-4,7-dihydroxy-9,10-dihydrophenanthrene	Monomeria barbata	Yang et al. (2010a)
84	5,7-Dimethoxy-9,10-dihydrophenanthrene-2,6-diyl diacetate	Eria flava	Majumder, Pal, & Joardar. (1990)
85	Flavanthrinin diacetate	Eria flava	Majumder, Pal, & Joardar. (1990)
86	Nudol diacetate	Eria flava	Majumder, Pal, & Joardar. (1990)
87	Lusianthrin diacetate	Eria flava	Majumder, Pal, & Joardar. (1990)
88	9,10-Dihydro-2,5-dimethoxy-4,6-phenanthrenediol	Calanthe arisanensis	Lee, et al. (2009)
89	5,7-Dimethoxy-9,10-dihydrophenanthrene-1,4,6-triol	Calanthe arisanensis	Lee, et al. (2009)
90	9,10-Dihydro-5,6-dimethoxy-1,4,7-phenanthrenetriol	Calanthe arisanensis	Lee, et al. (2009)
91	Marylaurencinol A	Marie laurencin	Yoshikawa et al. (2012)
92	Marylaurencinol B	Marie laurencin	Yoshikawa et al. (2012)
93	Marylaurencinoside A	Marie laurencin	Yoshikawa et al. (2012)
94	2,3,4,7,8-Pentamethoxy-9,10-dihydrophenanthrene	Flickingeria fimbriata	Wu et al. (2017)
95	5-Methoxy-9,10-dihydrophenanthrene-2,7,8-triol	Flickingeria fimbriata	Wu et al. (2017)
96	Septeophiol diacetate	Eulophia graminea	Bhandari & Kapadi. (1983)
97	9,10-Dihydro-2,5-dimethoxy-1,7-phenanthrenediol	Eulophia macrobulbon	Temkitthawon, Changwichit, Khorana, Viyoch, Suwanborirux, & Ingkaninan. (2017)
98	Gymconopin A	Gymnadenia conopsea	Wang, Wang, Zhai, Liao, Zhang, & Huang. (2012)
99	Gymconopin B	Gymnadenia conopsea	Matsuda, Morikawa, Xie, & Yoshikawa (2004)
100	Arundigramin	Arundina graminifolia	Auberon, et al. (2016)
101	Callosin	Agrostophyllum callosum	Majumder, Banerjee, Lahiri, Mukhoti, & Sen. (1998)
102	Aerosin	Aerides rosea	Cakova, et al. (2015)
103	Ochrone A	Pholidota chinensis	Hu et al. (2018)
104	Phocantone	Pholidota chinensis	Hu et al. (2018)
105	Denbinobin B	Dendrobium sinense	Chen, et al. (2013b)
106	Dendronone	Dendrobium cariniferum	Chen. (2013a)
107	Ephenmeranthoquinone	Dendrobium densiflorum	Chen. (2013a)
108	2-Hydroxy-4-methoxy-9,10-dihydrophenanthrene-1,4-dione	Dendrobium draconis	Sritularak, Anuwat, & Likhitwitayawuid. (2011)
109	Ephenmeranthoquinone B	Odontioda Marie Noel	Masuda, Suzuki, & Sakagami. (2012)
110	3-Hydroxy-2,4-dimethoxy-9,10-dihydrophenanthrene-1,4-dione	Calanthe arisanensis	Lee, Yen, Chang, Wud, & Wu. (2014)
111	Dendrodevonin B	Dendrobium devonianum	Wu, Lu, Ding, Zhao, Xu, & Chou. (2019)
112	Spiranthoquinone	Spiranthes sinensis	Tezuka, Ji, Hirano, Ueda, Nagashima, & Kikuchi. (2010)
113	Bleochranol C	Bletilla ochracea	Li, et al. (2018)
114	Bleochranol D	Bletilla ochracea	Li, et al. (2018)
115	{(9S,10R)-3-hydroxy-9-(4-hydroxy-3-methoxyphenyl)-1-methoxy-6,8,9,10-tetrahydro-5H-cyclopenta[b]phenanthren-10-yl}methyl acetate	Bletilla striata	Zhou, et al. (2019)
116	2-(4-Hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-7-methoxy-2,3,9,10- tetrahydrophenanthro[2,3-b]furan-5-ol	Pholidota chinensis	Hu et al. (2018)
117	2-(4-Hydroxy-3,5-dimethoxyphenyl)-3-hydroxymethyl-8-methoxy-2,3,10,11- tetrahydrophenanthro[1,2-b]furan-5,6-diol	Pholidota chinensis	Hu et al. (2018)
118	(7′S,8′R-trans)-7-hydroxy-7′-(4′-hydroxy-3′,5′-dimethoxyphenyl)-8′-hydroxymethyl-5-methoxy-9,10,7′,8′-tetrahydrophenanthro [2,3-b]furan	Pleione bulbocodioides	Li. (2016)
119	Bletillatin A	Bletilla striata	Zhou, et al. (2019)
120	Shanciol H	Pleione bulbocodioides	Liu, et al. (2019b)
121	Shanciol B	Pleione bulbocodioides	Liu, et al. (2019b)
122	{3-Hydroxy-9-(4′-hydroxy-3′-methoxyphenyl)-11-methoxy-5,6,9,10-tetrahydrophenanthro[2,3,-b]furan-10-yl}methyl acetate	Pleione bulbocodioides	Zhu (2014)
123	9-(4′-Hydroxy-3′-methoxyphenyl)-10-(hydroxymethyl)-11-methoxy-5,6,9,10- tetrahydrophenanthro[2,3,-b]furan-3-ol	Pleione bulbocodioides	Liu, et al. (2019b)
124	4,5-Epoxy-2-(4-hydroxy-3,5-dimethoxyphenyl)-3-hydroxymethyl-1-methoxy-2,3,9,10-tetrahydrophenanthro[2,3-b]furan-7-ol	Pholidota chinensis	Hu et al. (2018)
125	{(2R,3S)-7-hydroxy-2-(3-hydroxy-5-methoxyphenyl)-10-methoxy-2,3,4,5-tetrahydrophenanthro[2,1-b]furan-3-yl}methyl acetate	Bletilla striata	Zhou, et al. (2019)
126	(2,3-trans)-2-(4-Hydroxy-3-methoxyphenyl)-3-hydroxymethyl-10-methoxy-2,3,4,5- tetrahydrophenanthro[2,1-b]furan-7-ol	Cremastra appendiculata	Sun et al. (2018)
127	Cyrtonesin B	Bletilla striata	Zhou, et al. (2019)
128	Pleionesin D	Pleione bulbocodioides	Liu, et al. (2019b)
129	Pleionesin B	Pleione yunnanensis	Liu, et al. (2019b)
130	Pleionesin C	Pleione bulbocodioides	Liu, et al. (2019b)
131	Shanciol G	Pleione bulbocodioides	Liu, et al. (2019b)
132	(2R,3R)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-N-(4-hydroxyphenethyl)-10-methoxy-2,3,4,5-tetrahydrophenanthro[2,1-b]furan-3-carboxamide	Cyrtopodium paniculatum	Auberon, et al. (2016)
133	4-Hydroxy-2-methoxy-8-furano[4′,5′,7,8]-9,10-dihydrophenanthrene	Spiranthes sinensis	Liu, Su, Li, Wen, & Li. (2012)
134	Spiranthesphenanthrene C	Spiranthes sinensis	Liu, et al. (2019a)
135	Spiranthesphenanthrene F	Spiranthes sinensis	Liu, et al. (2019a)
136	Spirantol C	Spiranthes sinensis	Tezuka, Ji, Hirano, Ueda, Nagashima, & Kikuchi. (2010)
137	Sinensol E	Spiranthes sinensis	Lin, Huang, Don, & Kuo, 2000
138	Shanciol D	Pleione bulbocodioides	Liu, et al. (2019b)
139	Bletilol C	Pleione bulbocodioides	Zhu (2014)
140	Chrysotoxol A	Dendrobium chrysotoxum	Hu, Fan, Dong, Miao, & Zhou. (2012)
141	Chrysotoxol B	Dendrobium chrysotoxum	Hu, Fan, Dong, Miao, & Zhou. (2012)
142	Shanciol E	Pleione bulbocodioides	Li. (2016)
143	Shancil	Pleione bulbocodioides	Li, Chen, & Xin. (2014)
144	Shanciol F	Pleione bulbocodioides	Liu, et al. (2019b)
145	Shanciol C	Pleione bulbocodioides	Liu, et al. (2019b)
146	Bletilol A	Pleione bulbocodioides	Zhu (2014)
147	Bletilol B	Pleione bulbocodioides	Zhu (2014)
148	Dendrocandin P2	Dendrobium. officinale	Zhao, Deng, & Zhang (2018)
149	Erathrins A	Eria bambusifolia	Zhan, Wang, Yin, Liu, & Chen, 2016
150	Spiranthesphenanthrene A	Spiranthes sinensis	Liu, et al. (2019a)
151	Spirasineol B	Spiranthes sinensis	Tezuka, Ji, Hirano, Ueda, Nagashima, & Kikuchi. (2010)
152	4-Hydroxy-2-methoxy-8-{2′,2′-dimethylpyrano[5′,6′,7,8]}-9,10-dihydrophenanthrene	Spiranthes sinensis	Liu, Su, Li, Wen, & Li. (2012)
153	Spiranthesphenanthrene B	Spiranthes sinensis	Liu, et al. (2019a)
154	Spiranthesphenanthrene E	Spiranthes sinensis	Liu, et al. (2019a)
155	Sinensol D	Spiranthes sinensis	Lin, Huang, Don, & Kuo, 2000
156	Phochinenin A	Pholidota chinensis	Yao, Tang, Li, & Ye. (2009)
157	Phochinenin G	Pholidota chinensis	Hu et al. (2018)
158	Phochinenin H	Pholidota chinensis	Hu et al. (2018)
159	Gymconopin C	Pholidota chinensis	Hu et al. (2018)
160	2,2′-Dihydroxy-5,5′,7,7′-tetramethoxy-9,9′,10,10′-tetrahydro-3,3′-biphenanthrene	Spiranthes sinensis	Li et al. (2013)
161	Phoyunnanin C	Pholidota chinensis	Hu et al. (2018)
162	Blestrianol A	Bletilla striata	Bai, Kato, Inoue, Yamaki, & Takagi. (1991)
163	Blestrianol B	Bletilla striata	Bai, Kato, Inoue, Yamaki, & Takagi. (1991)
164	Bleformin D	Bletilla formosana	Lin, et al. (2016)
165	Bleformin H	Bletilla formosana	Lin, et al. (2016)
166	Amplumthrin	Dendrobium. amplum	Majumder, Rahaman, Roychowdhury, & Dhara. (2008)
167	Flavanthrin tetraacetate	Cirrhopetalum maculosum	Majumder, Pal, & Joardar (1990)
168	Flavanthrin	Pholidota chinensis	Hu et al. (2018)
169	9,9′,10,10′-Tetrahydro-2,2′-dimethoxy-(1,1′-biphenanthrene)-4,4′,7,7′-tetrol	Pholidota chinensis	Hu et al. (2018)
170	9,9′,10,10′-Tetrahydro-2,2′-dimethoxy-(1,1′-biphenanthrene)-4,4′,7-triol	Pholidota chinensis	Hu et al. (2018)
171	2,2′-Dimethoxy-4,4′,7,7′-tetrahydroxy-9,9′,10,10′-tetrahydro-1,1′-biphenanthrene	Flickingeria fimbriata	Chen (2013a)
172	4,7,4′-Trimethoxy-9′,10′-dihydro(1,1′-biphenanthrene)-2,2′,7′-triol	Bletilla striata	Lin, Huang, Don, & Kuo, 2000
173	2,2′,4,4′,7,7′-Hexamethoxy-9,9′,10,10′-tetrahydro-1,1′-biphenanthrene	Bletilla yunnanensis	Yang (2016)
174	Phochinenin C	Pholidota chinensis	Yao, Tang, Li, & Ye. (2009)
175	Phochinenin D	Pholidota chinensis	Yao, Tang, Li, & Ye. (2009)
176	Phochinenin E	Pholidota chinensis	Yao, Tang, Li, & Ye. (2009)
177	Phoyunnanin E	Pholidota chinensis	Hu et al. (2018)
178	Blestrin A	Pholidota chinensis	Hu et al. (2018)
179	Bulbophythrin B	Bulbophyllum odoratissimum	Xu, Yu, Qing, Zhang, Liu, & Chen. (2009)
180	Spiranthesol	Spiranthes sinensis	Liu, Li, Zhong, Yang, & Li, 2013
181	Bulbophythrin A	Bulbophyllum odoratissimum	Xu, Yu, Qing, Zhang, Liu, & Chen. (2009)
182	8,8′-Biflavidin	Otochilus porrectus	Shi, et al. (2010)
183	Blestrin B	Bletilla striata	Yamaki, et al. (1992)
184	Monbarbatain D	Monomeria barbata	Yang et al. (2010a)
185	4,4′-Dimethoxy-9,10-dyhydro(6,1′-biphenanthrene)-2,2′,7,7′-tetraol	Cremastra appendiculata	Sun et al. (2018)
186	4,7,7′-Trimethoxy-9′,10′-dihydro(1,3′-biphenanthrene)-2,2′,5′-triol	Bletilla striata	Lin, Huang, Don, & Kuo, 2000
187	4,4′,7-Trimethoxy-9′,10′-dihydro(1,3′-biphenanthrene)-2,2′,7′-triol	Cremastra appendiculata	Liu, Li, Zeng, Jiang, & Tu. (2016)
188	5,6,7′-Trimethoxy-9′,10′-dihydro(1,3′-biphenanthrene)-2,2′,5′,7-tetraol	Cyrtopodium paniculatum	Auberon, et al. (2016)
189	3,4,7′-Trimethoxy-9′,10′-dihydro(1,3′-biphenanthrene)-2,2′,5′,7-tetraol	Cyrtopodium paniculatum	Auberon, et al. (2016)
190	Monbarbatain B	Monomeria barbata	Yang, Cai, & Tai. (2010b)
191	Blestrianol C	Bletilla striata	Bai, Kato, Inoue, Yamaki, & Takagi. (1991)
192	Bleformin I	Bletilla formosana	Lin, et al. (2016)
193	Bulbocodioidin G	Pleione bulbocodioides	Wang, Shao, Han, & Li. (2019)
194	Phochinenin B	Pholidota chinensis	Yao, Tang, Li, & Ye. (2009)
195	Blestriarene B	Bletilla striata	Yang, Tang, Zhao, Shu, & Mei. (2012)
196	4,7,3′,5′-Tetramethoxy-9′,10′-dihydro(1,1′-biphenanthrene)-2,2′,7′-triol	Bletilla striata	Lin, Huang, Don, & Kuo, 2000
197	Monbarbatain A	Monomeria barbata	Yang, Cai, & Tai. (2010b)
198	4,7,3′,5′-Tetramethoxy-9′,10′-dihydro(1,2′-biphenanthrene)-2,7′-diol	Bletilla striata	Zhou et al. (2019)
199	Blestrin E	Appendicula reflexa	Apel, Dumontet, Lozach, Meijer, Guéritte & Litaudon. (2012)
200	Blestrin C	Bletilla striata	Yamaki, et al. (1992)
201	(2,3-trans)-3-[(2,7-Dihydroxy-4-methoxy-phenanthren-1-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-10-methoxy-2,3,4,5-tetrahydro-phenanthro[2,1-b]furan-7-ol	Dendrobium amplum	Majumder, Rahaman, Roychowdhury, & Dhara. (2008)
202	Phoyunnanin A	Pholidota yunnanensis	Hu et al. (2018)
203	Phochinenin I	Pholidota chinensis	Hu et al. (2018)
204	Phochinenin J	Pholidota chinensis	Hu et al. (2018)
205	Phoyunnanin B	Pholidota yunnanensis	Hu et al. (2018)
206	Phochinenin M	Bletilla striata	Zhou et al. (2019)
207	Phochinenin K	Bletilla striata	Zhou et al. (2019)
208	Bulbocodioidin H	Pleione bulbocodioides	Wang, Shao, Han, & Li. (2019)
209	Bleformin C	Bletilla formosana	Lin, et al. (2016)
210	Phochinenin L	Pholidota chinensis	Yao, et al. (2008)
211	Phoyunnanin D	Pholidota yunnanensis	Hu, et al. (2018)
212	Shancilin	Pleione bulbocodioides	Liu et al. (2019b)
213	Monbarbatain E	Monomeria barbata	Yang, Cai, Fang, Yang, Fang, & Ding. (2014)
214	Bleochranol A	Bletilla ochracea	Li, et al. (2018)
215	(2,3-trans)-3-[2-Dihydroxy-6-(3-hydroxyphenyl)-4-methoxyphenyl]-2-(4-hydroxy-3-methoxyphenyl)-10-methoxy-2,3,4,5-tetrahydrophenanthro[2,1-b]furan-7-ol	Cremastra appendiculata	Wang, Guan, & Meng. (2013)
216	Phochinenin F	Pholidota chinensis	Yao, Tang, Li, & Ye. (2009)
217	Dendrosignatol	Dendrobium signatum	Mittraphab, Muangnoi, Likhitwitayawuid, Rojsitthisak, & Sritularak. (2016)

Dihydrophenanthrenequinones

Several dihydrophenanthrenequinones have been identified with hydroxy, methyl, methoxy and isoprene groups. The representative structures are afforded in Fig. 5 and the chemical structures, names and origins displayed in Fig. S2 and Table 1.

Fig. 5

Representative chemical structures of dihydrophenanthrenequinones.

Dihydrophenanthrofurans and dihydrophenanthropyrans

In dihydrophenanthrofurans and dihydrophenanthropyrans, the rings are mainly attached to the DP core at C-6 and C-7, C-7 and C-8. Moreover, the absolute configuration of most compounds at C-7 was described to be (R), C-6 and C-8 were described to be (S). The representative structures are afforded in Fig. 6 and the chemical structures, names and origins displayed in Fig. S3 and Table 1.

Fig. 6

Representative chemical structures of dihydrophenanthrofurans and dihydrophenanthropyrans.

DP polymers

Until now, 61 dimers and a trimer have been reported from medicnal plants of Orchidaceae. DP monomers can connect by their substituents or a single C–C', CH2, CH2-CH2 or C-O-C' coupling. According to the different polymeric fragments, DP polymers could be classified into DPs and DPs, DPs and phenanthrenes, DPs and bibenzyls.

DPs and DPs

Twenty-nine constituents belong to this type and connect at different positions, such as C-1,3′ (156–160, 169–171, 175, 177), C-1,1′ (161–163, 172–174, 176, 181–183), C-2,2′ (179), C-3,1′ (178, 184) and C-1,2′ (164–168, 180). The representative structures are afforded in Fig. 7 and the chemical structures, names and origins displayed in Fig. S4 and Table 1.

Fig. 7

Representative chemical structures of DPs and DPs.

DPs and phenanthrenes

The second type is characterized between DPs and phenanthrenes monomers and the connection position at C-1,1′ (185, 188–190, 199–200), C-1,3′ (186–187, 194–198, C-1,2′ (191–193) and C-2,9′ (201). The representative structures are afforded in Fig. 8 and the chemical structures, names and origins displayed in Fig. S5 and Table 1.

Fig. 8

Representative chemical structures of DPs and phenanthrenes.

DPs and bibenzyls

All DPs are of bibenzyl origin, and a number of DPs and bibenzyls polymers are formed through C-3,1′ (202–204, 206), C-1,1′ (207, 209–211, 213), C-2,1′ (205, 214), C-4,1′ (215), C-11,1′ (212), C-12,1′ (217) linkages between two monomers. The representative compositions are afforded in Fig. 9 and the chemical structures, names and origins displayed in Fig. S6 and Table 1.

Fig. 9

Representative chemical structures of DPs and bibenzyls.

Pharmacology

The applications of medicinal plants of Orchidaceae have a long history. The tubers of B. striata, stems of Dendrobium nobile Lindl., whole herbs of Pholidota chinensis Lindl. and roots of Spiranthes sinensis (Pers.) Ames have been used as traditional Chinese medicines with the efficacy of clearing heat and resolving toxin, moistening lung and relieving cough, promoting blood circulation. However, very few studies have elaborated the relationship between traditional efficacy and modern pharmacology of DPs in medicinal plants of Orchidaceae. At present, some researches have demonstrated that DPs of medicinal plants of Orchidaceae have a wide range of biological activities such as cytotoxic, anti-oxidant, anti-inflammatory activities.

Cytotoxic activity

A large number of natural DPs have been proved to exhibit cytotoxic effects. Xu et al. noticed that the whole herbs of Bulbophyllum odoratissimum (Sm.) Lindl. showed strong cytotoxic activities in human leukemia cell lines K562 and HL-60, human lung adenocarcinoma A549, human hepatoma BEL-7402 and human stomach cancer SGC-7901. Bulbophythrin A (181), reported as a new dimeric DP, could inhibit the growth of HL-60, BEL-7402 and A549 with IC50 values of 1.3, 1.2 and 1.2 nmol/L (Xu, Yu, Qing, Zhang, Liu, & Chen, 2009).

Compounds 88–90, isolated from the roots of Calanthe arisanensis Hayata, exhibited strong cytotoxic activities against A549, MCF-7 and PC-3 cancer cell lines with IC50 values ranged from 2.3 to 7.7 μg/mL by sulforhodamine B assays (Lee, et al., 2009).

Using water-soluble tetrazolium-8 and lactatedehydrogenase assays, ephenmeranthoquinone B (109), being present with high concentration in the roots of Marie laurencin, could inhibit the growth of HL-60, NCI-H460 and M14 cell lines with IC50 values of 2.8, 5.0 and 1.5 μmol/L (Williams et al., 2012).

Monbarbatains B and D (190, 184) from the stems of Monomeria barbata and showed cytotoxic activities against HepG-2 (IC50: 17.1 μmol/L; IC50: 17.6 μmol/L) and HL60 (IC50: 7.3 μmol/L; IC50: 10.2 μmol/L) cell lines by MTT assays (Yang, Tang, Zhao, Shu, & Mei, 2010).

DP monomers have stronger cytotoxic activity compared to polymers. Furthermore, compared with 89 and 90, it appears that the 6-OH and 7-OCH3 groups might increase the cytotoxic activity. The structures and IC50 values of DPs from medicinal plants of Orchidaceae with significant cytotoxic activities displayed in Fig. 10.

Fig. 10

DPs from medicnal plants of Orchidaceae with significant cytotoxic activities.

Anti-inflammatory activity

Inflammation is the defense response of the living tissues to the simulations of injury factors, which plays an important role in the occurrence and development of many diseases (Hou, Sun, Gao & Xiao, 2015).

Lin et al. (2013) reported that compounds 3, 55, 58 and 60 from the ethanol extract of the stems of Dendrobium denneanum Lindl. showed inhibitory effects on NO production in lipopolysaccharide (lipopolysaccharide（LPS)-activated mouse macrophage RAW 264.7 cells) (IC50: 7.6 μmol/L; IC50: 3.1 μmol/L; IC50: 4.2 μmol/L; IC50: 0.7 μmol/L).

Lusianthridin (1) and hircinol (7) isolated from 80% ethanol extract of the stems of Dendrobium loddigesii Lindl., exerted inhibitory activities on LPS-induced NO production in a murine macrophage-like cell line RAW 264.7 with IC50 values of 4.6 and 29.2 μmol/L. Lusianthridin (1) was more active than that of the positive control aminoguanidine (IC50: 17.5 μmol/L) (Ito et al., 2010).

Phochinenin K (207) was isolated from the dried tubers of B. striata and evaluated by LPS-stimulated BV-2 cells with IC50 value of 1.9 μmol/L (Zhou, et al., 2019). Compounds 1, 8, 13, 19 and 22, isolated from Pholidota yunnanensis were evaluated for their anti-inflammatory activities on LPS-induced NO production in RAW 264.7 cells and showed growth inhibitory effects in the concentration range of 4.2–7.7 μmol/L with MG-132 used as the positive control (IC50: 17.5 μmol/L) (Dong, et al., 2013).

Coelonin (6), an active component isolated from the ethanol extract of the tubers of B. striata. It significantly inhibited LPS-induced IL-1β, IL-6 and TNF-α expression at 2.5 μg/mL by using the LPS-induced macrophage inflammation model and phosphoantibody arrays (Jiang, et al., 2019).

Based on the molecular structures and bioassay activities, we found that most active ingredients were monomers. In addition, we found that 2, 5-OGlc group might play a role in enhancing anti-inflammatory activity. The structures and IC values of DPs from medicinal plants of Orchidaceae with significant anti-inflammatory activities displayed in Fig. 11.

Fig. 11

DPs from medicinal plants of Orchidaceae with significant anti-inflammatory activities.

Anti-oxidant activity

The excessive free radicals can lead to aging, cancer and other diseases, and antioxidants can overcome the damage caused by excess free radicals (Meng et al., 2018). Compounds 1, 4, 8, 20, 171, 202 and 205 were isolated from the whole herbs of Pholidota yunnanensis, and proved to be as active (EC50: 22.3 μmol/L; EC50: 27.7 μmol/L; EC50: 10.0 μmol/L; EC50: 8.8 μmol/L; EC50: 47.3 μmol/L; EC50: 55.9 μmol/L; EC50: 26.7 μmol/L) as the positive control resveratrol (EC50: 21.2 μmol/L) using the 1,1-diphenyl-2-picrylhydrazyl （DPPH) free radical scavenging assays (Chen et al., 2013b).

Among the isolated compounds of the whole herbs of Monomeria barbata Lindl, compounds 169, 184, 190 and 197 showed antioxidant activity when using the DPPH radical scavenging assays (Yang et al., 2010, Yang et al., 2014). The antioxidant capacities of coelonin (6), flavidin (17) and imbricatin (20) were measured by DPPH radical-scavenging assays and •OH assays (IC50 values: 8.4, 6.6, and 8.5 μmol/L, DPPH assay; IC50 values: 0.03, 0.08, and 0.08 μmol/L, •OH assay) (Simmler, Antheaume & Lobstein, 2010).

In the above-mentioned compounds, it can be revealed that DPs with 2, 6-OCH3, 5, 7-OH groups show higher antioxidant activity. The structures and IC values of DPs from medicinal plants of Orchidaceae with significant anti-oxidant activities displayed in Fig. 12.

Fig. 12

DPs from medicinal plants of Orchidaceae with significant anti-oxidant activities.

Clinical applications

Over the years, medicinal plants of Orchidaceae showed a wide range of efficacy including clearing heat and resolving toxin, moistening lung and relieving cough and promoting blood circulation. DPs are the major bioactive ingredients of medicinal plants of Orchidaceae, which can prevent and treat diseases in clinic.

Silicosis is a chronic lung disease caused by long-term exposure to silica dust, characterized by progressive pulmonary fibrosis and lung inflammation (Guo, Zhang, & Shao, 2018). The innate immune response mediated by alveolar macrophage plays a key role in silicosis. Coelonin (6), a classical DP monomer was isolated from the tubers of B. striata can remarkably elevate the serum SOD level and lower the malondialdehyde, NO level; and it dose dependently decrease all the inflammatory cytokines, and lower hydroxyproline content. Therefore, coelonin (6) can effectively prevent lung fibrosis and through regulating the anti-oxidation system, immune system and cytokine level (Deng et al., 2016).

Summary

DPs from medicinal plants of Orchidaceae are responsible for the medicinal usage and attract more and more attention. DP structures, especially DP polymers have a lot of chiral centers and are the sources of diverse activities and stereoselectivities. In recent years, most studies on DPs are only focused on simple drug efficacy, more comprehensive pharmacological effects and mechanisms of action have not been fully elucidated. The further studies on the representative components of DPs are helpful to clarify the common material basis of medicinal plants of Orchidaceae and provide scientific basis for new drug development. As a kind of skeleton of active lead compounds, DPs can expand the structural diversity and provide a reference for the development of small molecule drugs by structural modifications, synthesis and other methods.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.