Chemical Studies of Cremanthodium (Asteraceae) Species;Sesquiterpenoids and Related Compounds

Abstract

Chemical constituents of Cremanthodium angustifolium, C. brunneopilosum, C. campanulatum, C. daochengense, C. discoideum, C. ellisii, C. helianthus, C. lineare, C. nobile, C. potaninii, C. principis, C. pulchrum, C. rhodocephalum, C. stenactinium, C. pleurocaule, and C. stenoglossum were reviewed. They produced mainly sesquiterpenoids–bicyclic and/or tricyclic eremophilanes, bisabolanes, bakkanes–and related compounds. Cremanthodium was shown to be close to Ligularia in chemical constituents.

Keywords

Asteraceae sesquiterpenoid eremophilane bisabolane bakkane oplopane eudesmane

Many sesquiterpenoids have been isolated from plants of family Asteraceae tribe Senecioneae, among which the genus Ligularia Cass. is known to be a rich source.^1,2 We are investigating chemical and genetic diversity of Ligularia and related species growing in the Hengduan Mountains area of China (usually more than 3000 m in elevation).^3,4 To date, we found the presence of intra-specific diversity in many species, and have isolated many sesquiterpenoids, such as eremophilanes, bisabolanes, bakkanes, oplopanes, and other related terpenoids. Among them, furanoeremophilanes were found in most of the major species, and we proposed a hypothesis that furanoeremophilane-producing species or intra-specific groups are ecologically advantageous than the species producing non-furanoeremophilanes.^3,4

The genus Cremanthodium Benth. is taxonomically very close to Ligularia.⁵ The morphological difference between Ligularia and Cremanthodium is recorded in the shape of involucre; cylindric for Ligularia and campanulate for Cremanthodium.⁶ While Ligularia species are found widely in Europe and Asia, distribution of Cremanthodium species are limited to the Tibetan and the adjacent area.⁶ Plants are mostly grown on alpine meadows of more than 3000 m (mostly around 4000 m) in elevation. Many species distribute from northwestern Yunnan Province to southeastern Xizang (Tibet) Autonomous Region. Due to their small plant size, it is difficult to collect kilograms of plants for chemical studies. Thus, not many studies on the chemical constituents have been reported. In this short review article, we describe chemical constituents of Cremanthodium species reported until today (Table 1), mainly our own works recently carried out. A photo of C. campanulatum is shown in Figure 1 as a representative example of Cremanthodium. Sesquiterpene skeletons appeared in this review and their numberings are shown in Figure 2. Compounds of each species are listed in Table 1. In the case of our own works, specimen numbers are listed (first 4 digits; the year of collection: the last 2 or 3 digits; specimen number of that year).

Figure 1

Cremanthodium campanulatum.

Figure 2

Major sesquiterpene skeletons and their numberings.

Table 1

Localities of 49 Samples of Cremanthodium and Isolated Compounds.

Sample no.	Specimen no.^a	Species	Locality^b	Elevation (m)	Isolated compounds					References
					Eremophilanes		Bakkanes	Bisabolanes	Others
					Bicyclic eremophilanes	Tricyclic eremophilanes	Bakkanes	Bisabolanes	Others
1	2005-36	Cremanthodium angustifolium	Daocheng (S)	4500	1, 13, 15					⁷
2	2007-94	C. angustifolium	Batang (S)	4500	13					⁸
3	2009-28	C. angustifolium	Daocheng (S)	4400		23, 24, 25				⁷
4	2002-19	C. angustifolium	Shangrila (Y)	3600	Nothing was identified					⁷
5	2002-49	C. angustifolium	Shangrila (Y)	3600	Nothing was identified					⁷
6	2009-58	C. brunneopilosum	Shiqu (S)	4400	13	30				⁹
7	2009-70	C. brunneopilosum	Shiqu (S)	4300		30				⁹
8	2010-17	C. brunneopilosum	Hongyuan (S)	3700	13, 16					⁹
9	2007	C. brunneopilosum	Lhasa (Tibet)	c)					63, 64, 68, 73, 74	¹⁰
10	2010-24	C. brunneopilosum	Hongyuan (S)	3500	Nothing was identified					⁹
11	2010-40	C. brunneopilosum	Jiuzhi (Q)	4100	Nothing was identified					⁹
12	2010-70	C. brunneopilosum	Xiahe (G)	3200	Nothing was identified					⁹
13	2007-56	C. campanulatum	Kangding (S)	4400				38, 41	77	¹¹
14	2007-120	C. campanulatum	Xiangcheng (S)	4300				38, 39, 41, 42	62, 77	¹¹
15	2008-12	C. campanulatum	Shangrila (Y)	4500				39, 40, 41, 43, 44, 45	77	¹¹
16	2005-37	C. daochengense	Xiangcheng (S)	4500					76	⁷
17	1994	C. discoideum	(Q)	c				46, 47, 48, 49, 50		^12 -14
18	1994	C. discoideum	(Q)	c				51, 52		¹⁵
19	c	C. ellisii	c	c					65	¹⁶
20	1991	C. ellisii	(G)	c	19				80, 87	¹⁷
21	1991	C. ellisii	Zhang (G)	c				53, 54, 55, 58		¹⁸
22	1990	C. ellisii	Zhang (G)	c					59, 60	¹⁹
23	c)	C. ellisii	Huzhu (Q)	c					78	²⁰
24	1994	C. ellisii	Huzhu (Q)	c				54, 55, 56, 57	78	²¹
25	1999	C. ellisii	Huzhu (Q)	c					78, 79, 81, 82, 84, 85	²²
26	2002-13	C. helianthus	Shangrila (Y)	3600	2, 3					⁷
27	2008-56	C. helianthus	Jianchuan (Y)	4000	2, 3, 8, 9, 11, 12, 14					²³
28	2009-03	C. helianthus	Shangrila (Y)	3700	2, 3, 13, 14				88	²³
29	2005-59	C. lineare	Kangding (S)	4200		27, 29			86	²⁴
30	2007-93	C. lineare	Batang (S)	4500	5					²⁴
31	2009-25	C. lineare	Daocheng (S)	4600		27, 28, 29				⁹
32	2009-63	C. lineare	Shiqu (S)	4200		20, 21, 22				²⁴
33	2009-64	C. lineare	Shiqu (S)	4200		26				²⁴
34	2009-72	C. lineare	Dege (S)	4000	2, 3, 4, 13, 17					²⁴
35	2009-83	C. lineare	Luhuo (S)	3700	3, 5		31, 32, 33			²⁴
36	2009-04	C. nobile	Shangrila (Y)	3600	2, 3				89	⁹
37	c	C. potaninii	c	c					66, 67, 68, 69, 75	²⁵
38	2007-119	C. principis	Xiangcheng (S)	4300			31			⁸
39	2007-55	C. pulchrum	Kangding (S)	4500	13, 15			36, 37		⁸
40	2008-13	C. pulchrum	Shangrila (Y)	4500	13					⁹
41	2002-54	C. rhodocephalum	Deqin (Y)	4400	Nothing was identified					⁷
42	2007-118	C. rhodocephalum	Xiangcheng (S)	4300				34, 35, 36, 37	61	²⁶
43	2009-38	C. stenactinium	Litang (S)	4400	10, 18				71, 72, 83	²⁷
44	2009-82	C. stenactinium	Luhuo (S)	3700	2, 3, 6, 7				83	²⁷
45	c	C. pleurocaule	c	c	Analyzed by gas chromatography					²⁸
46	2016-41	C. stenoglossum	Ganzi (S)	4700	14				70, 76	²⁹
47	2016-38	Ligularia (L.) nelumbifolia × C. stenoglossum	Ganzi (S)	4700	3, 13					²⁹
48	2016-39	L. nelumbifolia × C. stenoglossum	Ganzi (S)	4700	13					²⁹
49	2005-40	Unidentified	Daocheng (S)	4400			31			⁷

Specimen no. for our samples, and the year of collection for others.

County. Province in parenthesis; G = Gansu, Q = Qinghai, S = Sichuan, Y = Yunnan.

Not described.

Isolated Compounds From Cremanthodium Species

Eighty-nine compounds 1 to 89 have been isolated from 17 Cremanthodium species (Table 1). The most major sesquiterpenes are eremophilanes, which are grouped into 2: eremophilanes without a furan or a 12,8-olide moiety (bicyclic eremophilanes) 1 to 19 (Figure 3) and furanoeremophilanes and eremophilan-12,8-olides (tricyclic eremophilanes) 20 to 30 (Figure 4). Bakkanes (rearranged eremophilanes) 31 to 33 are also isolated (Figure 5). The second major group is bisabolanes (Figure 6). Twenty-five bisabolanes 34 to 58 are recorded, and most of them are highly oxygenated. The other compounds include oplopanes 59 to 62, germacranes 63 to 65, guaianes and a pseudoguaiane 66 to 68, a seco-guaiane (xanthane) 69, γ-humulene (70), eudesmanes 71 to 75, a triterpene (lupeol = 76), and lignans and related aromatics 77 to 89 (Figures 7 and 8).

Figure 3

Bicyclic eremophilanes (eremophilanes without a furan or a 12,8-olide moiety).

Figure 4

Tricyclic eremophilanes (furanoeremophilanes and eremophilan-12,8-olides).

Figure 5

Bakkanes (rearranged eremophilanes).

Figure 6

Bisabolanes. See text (section on “On the Structures of Bisabolanes”) for the drawings.

Figure 7

Other sesquiterpenoids (oplopanes, germacranes, guaianes, eudesmanes, and others). See text (section on “C. Potaninii C. w inkler and C. pleurocaule (Franchet) R. D. Good”) for the structure of 75.

Figure 8

Triterpene, lignans, and other compounds.

Cremanthodium angustifolium W. W. Smith

We collected 5 samples (samples 1-5) in Yunnan and Sichuan Provinces (Table 1).^7,8 From samples 1 and 2, eremophila-1(10),11-diene (1), petasin (13), and 3α-senecioyloxyeremophila-9,11-dien-8-one (15) were isolated, while 3 furanoeremophilanes 23, 24, and 25 were isolated from sample 3. This suggests the presence of intra-specific diversity as in many Ligularia species.^3,4 Unfortunately, no definitive compound was identified from samples 4 and 5.

Cremanthodium brunneopilosum S. W. Liu

This species is relatively large in plant size, as most of Ligularia species. From samples 6 to 8 (Table 1), petasin (13), 3α-(3-methylbutanoyloxy)eremophila-9,11-dien-8-one (16), and eremofarfugin A (30) were isolated.⁹ Unfortunately, samples 10 to 12 did not afford any decisive compound.⁹

He et al reported the chemical constituents of C. brunneopilosum collected in Lhasa (sample 9).¹⁰ Fourteen compounds were isolated from the petroleum ether soluble part of the MeOH extracts, 5 of which were terpenoids. Compound 68 was a pseudoguaianolide, compounds 73 and 74 were eudesmanes, and compounds 63 and 64 were germacranolides. Quite interestingly no eremophilane compound was isolated. This probably suggests the presence of at least 2 chemical lineages in this species. The other isolated compounds were 2 steroids and 7 flavonoids (not shown here).

Cremanthodium campanulatum Diels

The roots of samples 13 to 15 collected in Yunnan and Sichuan Provinces were extracted with EtOAc (Table 1). Bisabolane-type sesquiterpenoids were isolated as the major components.¹¹ From sample 13, compounds 38, 41, and 77 were isolated. From sample 14, compounds 38, 39, 41, 42, 62, and 77 were isolated. From sample 15, compounds 39, 40, 41, 43, 44, 45, and 77 were isolated. Bisabolane-type sequiterpenoids have been isolated from Ligularia and other genus.^1

-4 Recently, Hirota et al and Onuki et al reported that compounds 41 and 44 were isolated from L. lankongensis.^30,31 Interestingly, no eremophilane was detected in either C. campanulatum or L. lankongensis, suggesting that the 2 species belong to the same chemical lineage.

Because the absolute configuration of a 6-membered ring in a bisabolane was established,³² absolute configuration in the cyclohexane ring of our compound was drawn as depicted in the formula (see section on “On the Structures of Bisabolanes” for structure drawing of bisabolanes).

Cremanthodium helianthus (Franchet) W. W. Smith

Three samples (samples 26-28) were collected in Yunnan Province and analyzed (Table 1). Bicyclic eremophilanes were isolated from all the samples. Sample 26 produced both C-7 isomers of eremophila-9,11-dien-8-ones 2 and 3.⁷ Sample 27 produced 2, 3, 7βH-eremophila-9,11(13)-dien-12-ol (8), (E)-eremophila-7(11),9-dien-12-ol (9), 7βH-eremophila-9,11-dien-1α-ol (11), 7βH-eremophila-9,11-dien-1β-ol (12), and 3α-tigloyloxyeremophila-9,11-dien-8-one (14).²³ Compounds 2, 3, 13, 14, and isofraxidin (88) were isolated from sample 28.²³

Cremanthodium lineare Maximowicz

Seven samples (samples 29-35) were collected in Sichuan Province (Table 1). Sample 29 produced 1β,10β-epoxy-6β-(2-methylpropanoyloxy)furanoeremophilan-9-one (27) and 6β-(2-methylpropanoyloxy)furanoeremophil-1(10)-en-9-one (29) as well as p-hydroxybenzaldehyde (86).²⁴ Fukinone (5) was isolated from sample 30.²⁴ 6β-Propanoyloxyfuranoeremophil-1(10)-en-9-one (28) as well as 27 and 29 were isolated from sample 31.⁹ From sample 32, A/B-trans furanoeremophilanes, 20, 21, and 22, were isolated.²⁴ 6β-Acetoxy-1β,10β-epoxyfuranoeremophilane (26) was isolated from sample 33.²⁴ Sample 34 produced 2, 3, 4, petasin (13), and isopetasin (17).²⁴ Bakkenolide A (31), 32, and 33, as well as 3 and 5 were isolated from sample 35.²⁴ Four samples (samples 29, 31, 32, and 33) were found to produce tricyclic eremophilanes, while the others (samples 30, 34, and 35), bicyclic eremophilanes, indicating the presence of 2 subgroups, which was suggested by the genetical criteria.

Cremanthodium rhodocephalum Diels

Two samples were collected in 2002 and 2007 (Table 1). Although no decisive compound was isolated from sample 41,⁷ sample 42 was found to produce 2 bisabolane-type hydroperoxides 34 and 35, 2 bisabolane-type epoxy ketones 36 and 37, and oplopane compound 61.²⁶ The structure of compound 61 needs a comment. When Bohlmann et al first reported compound 61, it was drawn as 61a (Figure 9).³³ We isolated this compound, and the geometry of 3-methylpent-2-enoyloxy group at C-8 was revised from Z to E as 61b.²⁶ Later, after publication, we have carefully analyzed the 2-dimensional spectra and found that the positions of the ester groups at C-8 and C-9 should be exchanged. Thus, compound 61 should be formulated as shown in Figures 7 and 9.

Figure 9

Structure of 61.

Cremanthodium stenactinium Diels

Two samples were collected in 2009 in Sichuan Province (Table 1).²⁷ Sample 43 produced 7βH-13-(3-methylbutanoyloxy)eremophila-9,11-dien-8-one (10), 11,12,13-trinoreremophil-9-en-8-one (18), eudesmanes 71 and 72, and ferulaldehyde (83). Sample 44 produced 2, 3, both C-7 isomers of 8-oxoeremophila-9,11-dien-13-als 6 and 7, and 83.

Cremanthodium nobile (Franchet) Diels ex Léveillé, C. principis (Franchet) R. D. Good, C. pulchrum R. D. Good, and C. daochengense Y. Ling & S. W. Liu

We analyzed major chemical constituents of these species, all of which are very small in plant size. Eremophilanes were isolated from C. nobile and C. pulchrum. From the former (sample 36), bicyclic eremophilanes 2 and 3 were isolated together with coniferyl angelate (89),⁹ and from the latter (samples 39 and 40), 3-oxygenated eremophila-9,11-dien-8-ones 13 and 15 and biasbolanes 36 and 37 were isolated.^8,9 From C. principis (sample 38)⁸ and unidentified Cremanthodium sample 49,⁷ bakkenolide A (31) was isolated. From C. daochengense (sample 16), lupeol (76) was isolated.⁷

Cremanthodium ellisii (J. D. Hooker) Kitamura

In 1994 to 1997, Jia’s group reported isolation of 10 compounds from 4 samples (samples 19-22, Table 1).^16

-19 Compound 19, a germacrane 65, and aromatics 80 and 87 were isolated from samples 19 and 20.^16,17 Four bisabolanes 53 to 55 and 58 were isolated from sample 21.¹⁸ The structure of 53 was established by X-ray analysis. Although the configurations at C-8 and C-10 of other bisabolanes were also shown in the original paper, they were not confirmed and drawn in Figure 6 as they were undetermined. Two oplopanes 59 and 60 were isolated from sample 22.¹⁹

Jia’s group further studied the chemical constituents of the same species collected in Huzhu County, Qinghai Province (samples 23-25).^20
-22 Four bisabolanes 54 to 57 and an aromatic compound 78 were isolated together with some steroids from samples 23 and 24.^20,21 Although compound 78 was named ellisinin A,²⁰ it was later described as (–)-4′-O-methylnyasol.^21,22 Its demethyl derivative was known as cis-hinokiresinol (nyasol) and the absolute configuration was determined to be (–)-3R.³⁴ Therefore, the absolute configuration of compound 78 ([α]_D –34.5,²⁰ –42.2²¹) is likely to be 3R.

In contrast, completely different compounds were isolated from sample 25 collected in the same county.²² None of the terpenoids was isolated, instead many aromatic compounds 78, 79, 81, 82, 84, and 85 were isolated. Other compounds, for example, scopoletin, scopolin, scoporone, steroids, flavonoids, and glycerol derivatives were isolated but not shown here. These results indicated that there were at least 2 chemotypes in C. ellisii: bisabolane-producing type and no-sesquiterpenoid-producing type.

Cremanthodium discoideum Maximowicz

Jia’s group studied the chemical constituents of C. discoideum collected in Qinghai Province (samples 17 and 18, Table 1). There are 4 reports^12

-15 from the same group and these 2 samples seem to be based on the same extracts. Five bisabolanes 46 to 50 were isolated.¹³ The relative configurations of the corresponding acetate of compound 46 were determined by X-ray analysis. Later in 2004, the absolute configuration of 46 was established (vide infra).¹⁴ From sample 18, 2 more bisabolanes, 51 and 52, as well as steroids (not discussed in this review) were isolated.¹⁵

C. Potaninii C. Winkler and C. pleurocaule (Franchet) R. D. Good

A commercial sample of C. potaninii (sample 37) was analyzed (Table 1).²⁵ The chemical constituents were inuviscolide (66), its dihydro derivative 67, 2,3-dihydroaromaticin (68) (the major constituent), tomentosin (69), and inuloxin C (75). Inuloxin C (75) was a known compound, but its original literature drew a strange structure and called it eudesmane.³⁵ This compound is suspected most probably to be 75a or its isomer. One more paper is found isolating α-amyrin and other 6 triterpene 3-O-palmitates from C. potaninii.³⁶

The extracts of C. pleurocaule (sample 45) were analyzed by GC and 60 compounds were identified.²⁸ C. pleurocaule is identical to Ligularia pluerocaulis (Franchet) Handel-Mazzetti,⁶ from which various eremophilane sesquiterpenoids have been isolated.^37

-40

Hybrids Between C. stenoglossum Y. Ling & S. W. Liu and Ligularia nelumbifolia (Bureau & Franchet) Handel-Mazzetti

In the course of our search, we found a sample of C. stenoglossum (sample 46) and 2 morphologically intermediate samples between C. stenoglossum and Ligularia nelumbifolia (samples 47 and 48) at the same field in Sichuan Province.²⁹ Genetic analysis confirmed that samples 47 and 48 were hybrids. From sample 46, an eremophilane 14, γ-humulene (70), and lupeol (76) were isolated. From the hybrid samples, 3 and 13 were isolated. Liquid chromatography mass spectrometry (LC-MS) analysis indicated that 2, 3, 13, and 14 were included in both hybrid samples (samples 47 and 48). Compounds 2 and 3 were also detected in C. stenoglossum (sample 46), but not in the other parent sample, L. nelumbifolia. The results suggest that the eremophilane-producing ability in the hybrid samples is originated from C. stenoglossum.

On the Structures of Bisabolanes

Drawing the structures of bisabolanes needs a comment. The bisabolane skeleton has a plane of symmetry (Figures 2 and 6). Thus, compound 46, for example, can be expressed as A or B (Figure 10). Namely, the side chain attached to C-6α in A can be converted to C-6β as in B by rotation of the C(6)-C(7) single bond. The difference between A and B is not the configuration at C-6 but carbon numbering. Because the carbon numbering (C-1 to C-6) should follow anticlockwise, the numberings in A and B are different from each other, making the readers confusing. For example, the acetoxy group is located at C-2α in A and C-4β in B. Both styles A (C-6α substituent)^18,21 and B (C-6β substituent) are employed in the literatures.^11,30,31 Structure C is the enantiomer of A (=B). However, because it is not likely to occur enantiomeric carbon skeleton in nature, the difference between B and C can be attributed to the difference in substituents. In this review, all bisabolane structures are written with C-6β side chain as in B and C (Figure 6). We recommend this way for drawing bisabolanes.

Figure 10

Drawing bisabolanes. A = B = 46. C = enantiomer of A/B. D (wrong).

The ORTEP drawing of the acetate of 46 is shown in Ref.¹³ and the structure of the natural product is drawn as D (Figure 10). However, D is not correct, because the tracing is not following the configurations at C-8 and C-10 from the ORTEP results. The absolute configuration was later determined to be 1R,2R,3R,4R,6S,8S,10S in the original drawing (see A for the numbering) (=2R,3R,4R,5R,6S,8S,10S in drawing B),¹⁴ and thus we used the formula 46 (=B) in Figure 6.

The absolute configuration of highly oxygenated bisabolane sesquiterpenoids having a carbonyl group at C-2 position was discussed with ECD data⁴¹ or X-ray crystallography.⁴² Kuroda et al recently established the absolute configurations at C-8 and C-10 in a side chain of some bisabolane compounds by total synthesis.^43,44

Biological Activities

Finally, biological activities of compounds 38 to 45 against HeLa and HL60 cell lines are shown in Table 2. All the compounds were not active against HeLa cells. However, some were moderately active against HL60 cells. Compound 42 was the strongest (half-maximal inhibitory concentration 1.51 µM) among the 8 compounds 38 to 45.¹¹

Table 2

Biological Data of Compounds 38 to 45 (Half-Maximal Inhibitory Concentration [µM]).

Compound	HeLa	HL60
38	>100	30.8
39	57.4	>100
40	74.5	26.6
41	>100	45.4
42	5.9	1.5
43	>100	87.2
44	>100	38.6
45	>100	83.0

Conclusion

Although 69 species were listed in the genus Cremanthodium,⁶ only 17 species have been studied as shown in Table 1. This is partly because they grow mostly on alpine meadows of more than 4000 m in elevation and the size is rather small. The chemical constituents are mainly sesquiterpenoids of eremophilane and bisabolanes. They can be divided roughly into 3 groups (species with only 1 sample are not listed here); (i) eremophilane- and bakkane-producing species: C. angustifolium, C. brunneopilosum (samples 6-8), C. helianthus, C. lineare, C. pulchrum, and C. stenactinium, (ii) bisabolane-producing species: C. campanulatum, C. discoideum, and C. ellisii (samples 21 and 24), (iii) others: C. brunneopilosum (sample 9), C. ellisii (samples 22, 23, and 25). The close relationship between Ligularia and Cremanthodium was shown by the chemical constituents. More samples of Cremanthodium need to be analyzed in the future.

Footnotes

Acknowledgments

The authors wish to thank Kunming Institute of Botany for research coordination. The authors also thank all the collaborators in this project for their help in sample collection, valuable discussion, and measuring spectra.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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