Structural and bioactive studies of terpenes and cyclopeptides from the Genus Rubia
Chemistry Central Journal volume 7, Article number: 81 (2013)
Genus Rubia fell into about 70 species distributed widely around the world, a total of 36 species and 2 varieties were reported from China. The extracts and phytochemicals of Rubia plants had drawn considerable attention due to their potent bioactivities. As the two major ingredients from these plants, pentacyclic triterpenes and cyclopeptides were becoming a hot topic over the past twenty years for their remarkable anticancer, antioxidant and other effects. This paper compiled all 65 terpenes and 44 cyclopeptides with their distributions, physiological activities and melting points (or optical rotations) as reported in 85 references; besides, structure-activity relationships of these derivatives were briefly discussed. The information involved in this paper was expected to be meaningful for the further studies of the Genus Rubia.
Genus Rubia that belongs to the Rubiaceae is one kind of perennial herbs; it falls into about 70 species distributed widely around the world, such as Western Europe, Northern Europe, Mediterranean Coast, Temperate Asia, Africa, Himalaya, as well as the regions from Mexico to Tropical America. A total of 36 species and 2 varieties have been reported from China . Rubia species being one of the earliest plant resources possessed important commercial and medicinal values. Commercially, they were used as natural dye-stuffs in old days and improved commodity circulation; medically, these species being used as drugs were first recorded in the world famous pharmacy book of China, Divine Famer's Materia Medica, which has over 2000 years history . According to many medical books, the roots of Rubia plants being reputed for their satisfactory efficacy were wildly used for the treatment of cancers, tuberculosis, rheumatism, hematemesis, metrorrhagia, epistaxis, contusion and menoxenia in the Chinese traditional medicine [3, 4]. Besides, Indian folk medicine also comprised numerous prescriptions involved in Genus Rubia for healing wounds, inflammation, skin infections, and so on .
Within the last few decades, the extracts and phytochemicals of Rubia plants have drawn much attention due to their potent bioactivities. Studies on these plants led to the isolation of a series of bioactive ingredients including anthraquinones, naphthoquinones, terpenes, cyclopeptides and other constituents. Nine years ago, R. Singh etc. summarized a total of 33 terpenes and 19 cyclopeptides identified from 7 Rubia species . Since then, researches on phytochemicals of Genus Rubia have achieved a lot and the lack of a comprehensive and lately review on this subject prompted us to gather much more new information. The previous review of us has introduced 148 anthraquinones and naphthoquinones together with their structure-activity relationships; herein we continue a general presentation of Rubia terpenes and cyclopeptides that exhibited remarkable anticancer, antioxidant and other effects. The present paper is dedicated to summarizing and updating a total of 65 terpenes and 44 cyclopeptides whose structures, distributions and properties are listed in the following tables and figures; furthermore, structure-activity relationships of these derivatives are briefly discussed.
Terpenes and their glycosides isolated from the Genus Rubia
Terpenes were not generally considered as major effective ingredients existed in medicinal Rubia plants, but they were also the earliest phytochemicals isolated from Genus Rubia. To our knowledge, people have got 65 terpene derivatives including 5 monoterpenes and 60 pentacyclic triterpenes. Compared with the similar work in 2004, this paper supplemented 32 new terpenes; plant sources of several compounds were also extended. What’s more, we modified some previous information; for instance, β-sitosterol, daucosterol and stigmasterol should be classified under the steroids rather than the terpenes; three pentacyclic triterpenes named ‘Rubiprasins A-C’ were mistaken as ‘Rubiprassins A-C’ and Rubiprasin C’s structure was also wrongly described. All of the 65 terpenes and their glycosidic derivatives isolated from 8 Rubia species are listed in Table 1 together with melting points (or optical rotations); the structures of these compounds are described in Additional file 1: Figure S1.
Monoterpenes hold a relatively small proportion among Rubia terpenes. Up to 2012, researchers have identified 5 monoterpenes (1–5) distributed in 3 species including R. cordifolia, R. tinctorum and R. peregrina–; and it’s just the continuous studies of the ethyl acetate fraction of R. cordifolia that resulted in the isolation of the monoterpenoid (5). More detailed information of monoterpenes is involved in the following Table and Figure.
Most of Rubia pentacyclic triterpenes came from three species including R. schumanniana, R. peregrina, and R. yunnanensis, especially the latter. R. yunnanensis is known as “Xiao-Hong-Shen”, which is endemic to China and has been served as an alternative for R. cordifolia; it has a long history of medicinal application in China. The aforementioned three Rubia species were rich sources for pentacyclic triterpenes. No report could be available on triterpene derivatives of Genus Rubia until 1981, when S. K. Talapatra etc. got Rubiacoumaric acid (6) and Rubiafolic acid (7) from R. cordifolia. Several years after the discovery of the first two triterpenes, rubiprasins A-C and rubiarbonols A-F were identified from the same species [11, 12]. The subsequent reported pentacyclic triterpenes were mainly designated under a series of names such as rubiarbonol, rubiarbonone, rubiarboside, rubiprasin and rubianol. It seemed that compounds named rubiarbonones, rubiarbosides, rubianols and rubianosides mainly existed in R. yunnanensis–. Friedelinol-type triterpene (63) that belonged to arborinane-type derivatives was previously isolated from the family Rubiaceae, but it’s the first report for the isolation from the Genus Rubia. Further phytochemical studies of Genus Rubia have resulted in identification of another 16 new triterpenes –.
Except for compiling and summarizing the latest information, in the process of literature searching, we deem that some previous information is not credible. For instance, melting points of Rubiarbonone B (26) which roots in two different references should not be deviated too much [14, 16, 18]; it’s also doubted that the structure of Rubiarboside F (34) was describe as IV’s (49) [15, 21]. More detailed information of Rubia triterpenes is listed in the following Table and Figure, Mp refers to Melting point; [α] means to the Specific Rotation of the compounds (due to different test conditions, the data may be various).
Cyclopeptides isolated from the Genus Rubia
Studies on plant cyclopeptides have drawn considerable attention for their distinctive bicyclic structural features and significant antitumor activities. On the basis of the chemical skeletons and distributions in plants, N. H. Tan etc. proposed the systematic structural classification of plant cyclopeptides which were divided into two classes, five subclasses, and eight types . Followed by the rule, Rubia cyclopeptides should be classified under the Rubiaceae-type cyclopeptides formed with one α-D-alanine, one α-L-alanine, three N-methyl-α-L-tyrosines and one other proteinogenic α-L-amino acid . So far, people have got 44 cyclopeptide derivatives from the Genus Rubia. Compared with terpene derivatives, Rubia cyclopeptides have narrower sources and only existed in three species containing R. cordifolia, R. yunnanensis and R. akane. In general, according to these cyclopeptides’ names, we may deduce their distributions; for instance, the cyclopeptides named Rubiyunnanins and RYs were reported from R. yunnanensis while the structures whose names were designated as RAs or others mainly came from R. cordifolia.
At the end of the twentieth century, cyclopeptides called RA-I (66) and RA-II (67) were isolated from chloroform and methanol extracts of R. cordifolia as the minor constituents . It’s the first time to report that Genus Rubia contained cyclopeptides. Later, RAs III-VII (68, 70–74) were obtained from the methanol extract of R. cordifolia together with R. akane–. As far as we know, among the reported cyclopeptides, only RA-V (71) and RA-VII (74) existed in R. akane. Except for aglycone, further studies on the Genus Rubia have also confirmed many cyclopeptide glycosides; these known glucosides were just single substituted glucopyranoside derivatives. For example, RA-XII (79), RA-XIII (80) and RA-XIV (81) were discovered in higher plants for the first time ; RA-XV (82) and RA-XVI (83) that belonged to glucosides were identified from R. cordifolia; in addition, J. T. Fan etc. reported that Rubiyunnanins B (93), F (97), G (98), H (99), and RYs I-III (100–102) also contained glycosyl –. Beyond that mentioned skeleton, uncommonly, chloroform-soluble portion of methanol extracts from the roots of R. cordifolia gave a dimer named RA-dimer A (103), in which two molecules of deoxybouvardin were linked together via an ether linkage ; however, it’s a pity for us that chemical constructions of RA-700 and RC-18 haven’t been available [60, 61]. Just in last year, Y. Hitotsuyanagi etc. got a series of special cyclopeptides from the Genus Rubia[62, 63].
The complete list of cyclopeptides isolated from 3 Rubia species is summarized in Table 2 together with the physical properties; their structures are described in Additional file 2: Figure S2; herein Mp refers to Melting point, [α] means to the Specific Rotation (due to different test conditions, the data may be various), β-D-Gluc refers to β-D-glucopyranoside.
Biological activities of Rubia terpenes and Rubiacyclopeptides
Various crude fractions and purified compounds from the Genus Rubia exhibited a relatively wide range of biological activities –. Numerous experimental data verified that pentacyclic triterpenes possessed potent advantage on the aspects of antitumor, antiinflammatory, protecting liver, anti-HIV effects , while the most significant advantage of plant cyclopeptides was their underlying mechanisms of antitumor effects. As the two major ingredients existed in those Rubia plants, pentacyclic triterpenes and cyclopeptides were becoming a hot topic over the past twenty years for their remarkable effects. The following contents aims to offer the detailed statements of pharmacological activities of Rubia terpenes and cyclopeptides, especially their anticancer and antioxidant effects. Finally, all the bioactive terpenes and cyclopeptides together with the sketchy mechanisms are collected in Table 3.
Anticancer effects of Rubia terpenes and Rubiacyclopeptides
Cytotoxicity and inhibitory on cell lines
Rubiarbonols A (16) and F (21), rubiarbonone C (27), and rubianol-c (42) exhibited cytotoxic effects in the MTT assay and they could also inhibit NO production . Compounds 7–9, 11–13, 23 and 50–52 had been evaluated for cytotoxicity against three human cancer cell lines including Hela, BGC-823 and A549; then compounds 8–9, 11, 50 and 52 showed cytotoxicity with the IC50 values of 10.75~18.87 μg/ml . Compounds 22, 54, 55, 58 and 62 had inhibition on A549, Hela and SMMC-7721; however, the data were not very satisfactory . Rubiarbonol A (16) was reported to have relatively strong cytotoxicity against HT-29; compared rubiarbonols A and B, introduction of the hydroxyl group on C-28 seemed to enhance cytotoxicity, especially on HT-29. Besides, compound 15 exhibited potent bioactivities against A549, SK-OV-3, SK-MEL-2, MES-SA and HCT-15 .
Different from pentacyclic triterpenes’ wide bioactivities, the effects of Rubia cyclopeptides mainly focused on inhibitory against tumors; and it’s available to identify bioactive cyclopeptides. An efficient isolation method for antitumor cyclopeptides from Genus Rubia had been established by following the activity against murine tumor P388 leukemia that was successfully used to purify RAs I-IV (66–70) . In a similar way, H. Itokawa etc.  found that the methanolic extract prepared from roots of R. cordifolia had a significant antitumor activity against Sarcoma 180 ascites and P388 leukemia in mice, from which RAs-III, -IV, -V (71) and -VII (74) were obtained. Recent years, monoclonal antibodies against RA-VII (74) had been also generated for screening of antitumor cyclopeptides. T. Hasuda etc. proved that they were useful for checking of the RA series compounds in the roots of R. cordifolia and R. akane.
Various data exhibited that different structural residues of Rubia cyclopeptides seemed to be closely related with their anticancer effects. Studies on the effect of RA-XVII (84) on cytotoxicity and conformation showed that although the structure exhibited little effect on the conformation of the molecule, it might decrease the activity as the side chain of residue 1 grew longer . On the basis of several cyclopeptide derivatives, the typical type II β-turn structure and the aromatic side chain of Tyr-3 over this turn were also considered to play a very important role in its antitumor activities . RA-X (77) containing a glutamic acid at residue 2 possessed strong antitumour effect on P388 while RA-IX (76) with conformation restricted to a type II β-turn at residues 2 and 3 showed almost no antitumour activities . RAs XI-XIV (78–81) had potent antitumor activity against P388, especially the compound 79 whose residue 2 was methyl. The conformation of cis N-methyl amide bond between residues 2 and 3 also played an important role in the antitumour activities of RAs . RA-XVIII (85) was another natural peptide of the RA-series in which the benzene ring of Tyr-6 was hydroxylated and its cytotoxicity against P-388 was 0.012 μg/ml . RA-XIX, -XX, -XXI and -XXII (86–89) had been evaluated for their cytotoxicity against P388, with RA-VII (74) as reference; for the compounds having a methoxyl group in Tyr-6, the order of cytotoxicity was 74 > 87 > 86. Compound 89 possessing a hydroxyl group in its Thr-2 was less cytotoxic than 88. It seemed that the cytotoxicity decreased with increased in the length of the carbon side chain or introduction of a polar functionality at this location . RA-XXIII (90) and RA-XXIV (91) exhibited just moderate cytotoxicity against P-388 with IC50 values of 0.16 and 0.48 mg/ml, respectively . T. Koizumi etc. had ever applied RA-VII (74) for the treatment of tumors in mice; daily intraperitoneal injection of RA-VII (1.5 or 3 mg/kg/day) had no toxic effects on those animals, but significantly and dose dependently inhibited the growth of Lewis lung carcinoma cells previously inoculated into the mice .
Compared with the various sources and remarkable effects of RAs, cyclopeptides named after Rubiyunnanin only existed in R. yunnanensis and their efficacies on tumors were relatively weaker. Cytotoxicities of Rubiyunnanin A (92) and B (93) against the 11 cancer cell lines were measured by SRB assay, but only 93 possessed moderate cytotoxicities . Rubiyunnanins C-H (94–99) and RA-V, RA-I, RA-XXIV, RA-XII, RY-II not only exhibited cytotoxicities against the same cell lines with IC50 values ranging from 0.001 to 56.24 μM, but also exerted inhibitions against NO production in LPS and IFN-c-induced RAW 264.7 murine macrophages with IC50 values ranging from 0.05 to 12.68 μM . RYs I-III (100–102), RA-700 (104), and RC-18 (105) possessed only medium activities against P388 –[58, 60, 61]. The newly identified compounds 106–108, and RA-V, VII were evaluated for their cytotoxic activities against HL-60 and HCT-116 while only the latter had potent cytotoxicities . Moreover, compound 109 exhibited cytotoxic effects on HL-60 cells, but which was much weaker than those of RA-XXIV and RA-VII .
Inducing cell apoptosis
Researchers paid much attention on anticancer mechanisms of maslinic acid (9), ursolic acid (11) and oleanolic acid (12) over the past decade years. No obvious correlation could be observed between cytotoxicity and inhibitory activity of DNA relaxation and decatenation by DNA topoisomerases I and II . Oleanolic acid had selective inhibitory activity against DNA topoisomerase II compared with DNA topoisomerase I but weak cytotoxicity against HT-29, MCF-7 and HepG2 . Maslinic acid was able to induce caspase-dependent apoptosis in human colon-cancer cells via the intrinsic mitochondrial pathway [73, 74]; it could also potentiate anti-tumor activities of TNF-α and inhibit pancreatic tumor growth and invasion by activating caspase-dependent apoptotic pathway and by suppressing NF-κB activation and its downstream gene expression . Inhibition of Protein kinase C (PKC) that was related to the tumor development might lead to inhibition of cells growth and spreading of cancer cells, while maslinic acid acted as a PKC inhibitor. Ursolic acid potentiated TRAIL-induced apoptosis through activation of reactive oxygen species and JNK-mediated up-regulation of death receptors and down-regulation of decoy receptor 2 and cell survival proteins [76, 77]; it was also considered as a novel blocker of STAT3 activation that might have a potential in prevention and treatment of multiple myeloma and other cancers . Ursolic acid and oleanolic acid possessed markedly apoptotic effects on four cell lines via increasing DNA fragmentation, decreasing mitochondrial membrane potential, lowering Na+-K+-ATPase activity and elevating caspase-3 and caspase-8 activities; they could suppress cell adhesion and reduce the production of VEGF and ICAM-1 in these cell lines .
Compared with the inhibition of Rubia cyclopeptides on cell lines, antiangiogenic effect of them were rarely involved. Sato and his coworkers demonstrated the antiangiogenic activity of RA-VII (74) on the proliferation, migration, stress fiber formation of BAEC and effects on mouse corneal angiogenesis . Last year, G. G. L. Yue etc. discovered RA-V (71) also possessed the activity in HUVEC and HMEC-1 with changes in function of these endothelial cells. The underlying mechanisms of action involved the ERK1/2 signalling pathway; however, RA-V might regulate different signalling pathways in various endothelial cells .
Antioxidant effects of Rubia terpenes and Rubiacyclopeptides
Free radical NO was reported to be implicated in lots of physiological and pathological processes including vasodilation, nonspecific host defense and chronic or acute inflammation. It was produced by the oxidation of L-arginine under NO synthase (NOS). In the family of NOS, iNOS was particularly involved in pathological aspects with overproduction of NO, which could be expressed in response to pro-inflammatory agents such as interleukin-1β, tumor necrosis factor-a and lipopolysaccharide (LPS) in various cell types such as macrophages, endothelial cells and smooth muscle cells .
The bioactivities of rubianols on NO production from LPS-activated macrophages had been examined. Rubianol-d (43) and rubianol-e (44) exhibited the inhibition without cytotoxicity in the MTT assay whose efficacy was equivalent to L-NMMA’s; rubianol-c (42), rubiarbonols A (16) and F (21), rubiarbonone C (27) showed both cytotoxic and inhibitory activities on NO production . RA-V (71) and RA-XII (79) were demonstrated to possess potent effects on iNOS induction, and the suppression was closely related to their inhibitions of NO . Inhibitory effects of Rubiyunnanin A-H (92–99) and RA-V, RA-I, RA-XXIV, RA-XII, RY-I were also evaluated; all of the compounds except 92 exhibited activity against NO production in LPS .
Other effects of Rubiatriterpenes
Antiplatelet aggregation effect
Among compounds 16, 17 and 25, Rubiarbonol B (17) exhibited the most potent inhibition against arachidonic acid-induced and collagen-induced platelet aggregation at 150 μM, while Rubiarbonol A (16) and Rubiarbonone A (25) promoted platelet aggregation at the high doses and possessed antiplatelet aggregation activity at the lower concentrations. This result might be consistent with a basic tenet of Traditional Chinese Medicine, in that variations of the dose of prescriptions induced either stimulatory or inhibitory effects .
Antibacterial activity against Staphylococcus aureus and antifungal activity against Candida albicans of triterpenes from R. yunnanensis were evaluated using the turbidimetric method; compound 22 exhibited inhibition on both of the two strains . Besides, ursolic acid (11) and oleanolic acid (12) possessed fairly high antimicrobial activities but were weaker than clinical antimicrobial drugs’; however, both of them exhibited low toxicity and might be used for treatment of infections by Vancomycin-Resistant Enterococci .
Excess visceral adiposity might predispose to chronic diseases like hypertension and type-II diabetes with a high risk for coronary artery disease. Adipose tissue secreted cytokines and oxidative stress played an important role in the chronic disease progression. Triterpene derivatives had abilities to regulate glucose and lipid metabolism. C. L. Melo etc.  verified that oleanolic acid (12) could ameliorate visceral adiposity and improve glucose tolerance in mice and had an antiobesity potential through modulation of carbohydrate and fat metabolism. Much attention was also focused on food that might be beneficial in preventing diet-induced body fat accumulation and possibly reducing the risk of diabetes and heart disease; then ursolic acid (11) was demonstrated to have potent bioactivities improving certain metabolic parameters associated with diets high in saturated fats and obesity .
As a natural and low toxic compound, maslinic acid (9) elicited excellent outcomes without inducing the side effects. It exhibited significant glucose-lowering and hypoinsulinemic effects in KK-Ay mice and might hold great promise as a natural therapeutic agent for treatment of type-II diabetes . Furthermore, both ursolic acid (11) and oleanolic acid (12) markedly suppressed renal aldose reductase activity and enhanced the activity of glyoxalase I, which contributed to decrease renal AGEs formation and improve renal functions; therefore, supplement of oleanolic acid and ursolic acid or foods rich in these compounds might be helpful for the prevention or treatment of diabetic kidney diseases .
Two triterpenes, maslinic acid (9) and ursolic acid (11), were reported to possess inhibition on the human immunodeficiency virus (HIV-1) protease .
To our knowledge, the reported Rubia terpenes distributed in 8 species and most of them derived from R. yunnanensis. The triterpenes were designated under a series of names including rubiarbonol, rubiarbonone, rubiarboside, rubiprasin and rubianol; among them, oleanane-type and fernane-type triterpenes accounted for overwhelming majority. Rubia cyclopeptides had narrower sources and existed in only 3 species including R. cordifolia, R. yunnanensis and R. akane. These terpenes and cyclopeptides, especially the latter, possessed excellent anticancer effects; maslinic acid, ursolic acid, oleanolic acid and several cyclopeptides containing RA-V and RA-VII drew relatively more attention than any other compound. From Table 3 and Additional file 1: Figure S1, it may be inferred that the Rubia triterpenes owning a free hydroxyl group on third carbon atom exhibited relatively strong inhibitory on cell lines; besides, fernane-type triterpenes possessed promising antioxidant effects. As for Rubia cyclopeptides, increase in the length of carbon side chain at residues 1, 2 and introduction of polar groups at residue 2 might decrease structure’s cytotoxicity; N-methyl amide bond between residues 2 and 3, together with aromatic side chain of residue 3 over β-turn played pivotal role in the antitumor activities. Beyond that, the orientation of one or both of the Tyr-5 and Tyr-6 phenyl rings was also essential to express activities, while structures possessing two rings formed between Tyr-5 and residue 6 via a phenolic oxygen linkage and a new carbon bond only possessed moderate cytotoxicities.
Up to now, phytochemical investigations of the Genus Rubia have resulted in identification of various chemical components including anthraquinones, naphthoquinones, terpenes and cyclopeptides. This paper dedicated to compiling all 65 terpenes derivatives and 44 cyclopeptides derivatives from 8 Rubia species. Together with the previous work, we have already finished summarizing a total of 257 compounds from 12 Rubia species with their bioactivities. However, taking into account the fact that 70 species belong to the Genus Rubia spreading around the world, only 17% of them have been phytochemically investigated, the Genus Rubia still remains to be a potential resource to research. Furthermore, as one kind of natural dyestuffs, resource exploration of Genus Rubia is also an asset to economic development and waits for its full exploitation.
Chen WQ, Luo XR, Gao YZ, Ruan YZ: Flora of China: Rubiaceae. Beijing. 1999, 71 (1): 287-318.
Xu K, Wang PL, Wang L, Liu CM, Xu SX, Cheng YT, Wang YH, Li Q, Lei HM: Quinone derivatives from Genus Rubia plants and their bioactivities. Chem Biodivers. 10.1002/cbdv.201200173. in press
Zhao SM, Kuang B, Fan JT, Yan H, Xu WY, Tan NH: Antitumor cyclic hexapeptides from Rubia plants: history, chemistry, and mechanism (2005–2011). CHIMIA Int J Chem. 2011, 65 (12): 952-956. 10.2533/chimia.2011.952.
Chinese Pharmacopoeia Commission: Chinese Pharmacopoeia. Part I. 2010, Beijing, 218-219.
Meena AK, Pal B, Panda P, Sannd R, Rao MM: A review on Rubia cordifolia: its phyto constituents and therapeutic uses. Drug Invention Today. 2010, 2 (5): 244-246.
RamSingh G, Chauhan SMS: 9, 10-anthraquinones and other biologically active compounds from the Genus Rubia. Chem Biodivers. 2004, 1 (9): 1241-1242. 10.1002/cbdv.200490088.
Wu LJ, Wang SX, Hua HM, Li X, Zhu TR, Miyase T, Ueno A: 6-methoxygeniposidic acid, an iridoid glycoside from Rubia cordifolia. Phytochemistry. 1991, 30 (5): 1710-1711. 10.1016/0031-9422(91)84241-J.
EI-Emary NA, Backheet EY: Three hydroxymethylanthraquinone glycosides from Rubia tinctorum. Phytochemistry. 1998, 49 (1): 277-279. 10.1016/S0031-9422(97)01121-7.
Ozgen U, Kazaz C, Secen H, Calis I, Coskun M, Houghton PJ: A novel naphthoquinone glycoside from Rubia peregrina L. Turk J Chem. 2009, 33: 561-568.
Talapatra SK, Sarkar AC, Talapatra B: Two pentacyclic triterpenes from Rubia cordifolia. Phytochemistry. 1981, 20 (8): 1923-1927. 10.1016/0031-9422(81)84036-8.
Itokawa H, Qiao YF , Takeya K : New arborane type triterpenoids from Rubia cordifolia var. pratensis and R. oncotricha. Chem Pharm Bull. 1990, 38 (5): 1435-1437. 10.1248/cpb.38.1435.
Itokawa H, Qiao YF, Takeya K, Iitaka Y: New triterpenoids from Rubia cordifolia var. pratensis (Rubiaceae). Chem Pharm Bull. 1989, 37 (6): 1670-1672. 10.1248/cpb.37.1670.
Zou C, Hao XJ, Chen CX, Zhou J: New arborane type triterpenoids from Rubia yunnanensis (I). Acta Botanica Yunnanica. 1993, 15 (1): 89-91.
Zou C, Hao XJ, Chen CX, Zhou J: Structures of Rubiarbonone B and C. Acta Botanica Yunnanica. 1999, 21 (2): 256-259.
Liou MJ, Wu TS: Triterpenoids from Rubia yunnanensis. J Nat Prod. 2002, 65 (9): 1283-1287. 10.1021/np020038k.
Xu XY, Zhou JY, Fang QC: Chemical constituents of Rubia yunnanensis root. J Chin Pharmaceut Sci. 1995, 4 (3): 157-160.
Arisawa M, Ueno H, Nimura M, Hayashi T, Morita N: Rubiatriol, a new triterpenoid from the Chinese Drug Qián Cáo Gén. Rubia cordifolia. J Nat Prod. 1986, 49 (6): 1114-1116. 10.1021/np50048a027.
Xu XY, Zhou JY, Fang QC: Study on the chemical constituents of Rubia Yunnanensis Diels. Acta Pharmaceutica Sinica. 1994, 29 (3): 237-240.
Morikawa T, Tao J, Ando S, Matsuda H, Yoshikawa M: Absolute stereostructures of new arborinane-type triterpenoids and inhibitors of nitric oxide production from Rubia yunnanensis. J Nat Prod. 2003, 66 (5): 638-645. 10.1021/np0205710.
Kuang B, Han J, Zeng GZ, Chen XQ, He WJ, Tan NH: Three new triterpenoids from Rubia schumanniana. Nat Prod Bioprospect. 2012, 2: 166-169. 10.1007/s13659-012-0038-8.
Tao J, Morikawa T, Ando S, Matsuda H, Yoshikawa M: Bioactive constituents from Chinese natural medicines. XI.1) Inhibitors on NO production and degranulation in RBL-2H3 from Rubia yunnanensis: structures of Rubianosides II, III, and IV, Rubianol-g, and Rubianthraquinone. Chem Pharm Bull. 2003, 51 (6): 654-662. 10.1248/cpb.51.654.
Fan JT, Kuang B, Zeng GZ, Zhao SM, Ji CJ, Zhang YM, Tan NH: Biologically active arborinane-type triterpenoids and anthraquinones from Rubia yunnanensis. J Nat Prod. 2011, 74 (10): 2069-2080. 10.1021/np2002918.
Ibraheim ZZ, Gouda YG: Minor constituents from Rubia Cordifolia L. root. Bull Pharm Sci. 2010, 33 (2): 225-233.
Son JK, Jung JH, Lee CS, Moon DC, Choi SW, Min BS, Woo MH: DNA Topoisomerases I and II inhibition and cytotoxicity of constituents from the roots of Rubia cordifolia. Bull Korean Chem Soc. 2006, 27 (8): 1231-1234.
Jeong SY, Zhao BT, Lee CS, Son JK, Min BS, Woo MH: Constituents with DNA Topoisomerases I and II inhibitory activity and cytotoxicity from the roots of Rubia cordifolia. Planta Med. 2012, 78 (2): 177-181. 10.1055/s-0031-1280265.
Son JK, Jung SJ, Jung JH, Fang Z, Lee CS, Seo CS, Moon DC, Min BS, Kim MR, Woo MH: Anticancer constituents from the roots of Rubia cordifolia L. Chem Pharm Bull. 2008, 56 (2): 213-216. 10.1248/cpb.56.213.
Liou MJ, Teng CM, Wu TS: Constituents from Rubia ustulata Diels and R. yunnanensis Diels and their Antiplatelet Aggregation Activity. J Chin Chem Soc. 2002, 49 (6): 1025-1030.
Chung MI, Jou SJ, Cheng TH, Lin CN, Ko FN, Teng CM: Antiplatelet constituents of formosan Rubia akane. J Nat Prod. 1994, 57 (2): 313-316. 10.1021/np50104a020.
Khan MA, Rahman A: Karachic acid: A new triterpenoid from Betula utilis. Phytochemistry. 1975, 14 (3): 789-791. 10.1016/0031-9422(75)83036-6.
Zou C, Hao XJ, Chen CX, Zhou J: A new antitumor glycocyclohexapeptide and arborane type new triterpenoids Rubia yunnanensis. Acta Botanica Yunnanica. 1992, 14 (1): 114-
Melo CL, Queiroz MGR, Fonseca SGC, Bizerra AMC, Lemos TLG, Melo TS, Santos FA, Rao VS: Oleanolic acid, a natural triterpenoid improves blood glucose tolerance in normal mice and ameliorates visceral obesity in mice fed a high-fat diet. Chem-Biol Interact. 2010, 185 (1): 59-65. 10.1016/j.cbi.2010.02.028.
Chen LS, Lv Y, Xu SW, Xin Y: Study on the triterpene acids in fruit of Crataegus pinnatifida. Lishizhen Med Mater Med Res. 2008, 19 (12): 2909-2910.
Peng JN, Feng XZ, Li GY, Liang XT: Chemical investigation of Genus Hedyotis II. Isolation and identification of iridoids from Hedyotis Chrysotricha. Acta Pharmaceutica Sinica. 1997, 32 (12): 908-913.
Xie RR, Guo J, Zhang DZ, Yan CY: Study on chemical constituents of compound ZhenzhuTiaozhi. Journal of Guangdong Pharmaceutical College. 2010, 26 (4): 332-333.
Siddiqui BS, Firdous , Begum S: Two triterpenoids from the leaves of Plumeria obtuse. Phytochemistry. 1999, 52 (6): 1111-1115. 10.1016/S0031-9422(99)00270-8.
Kim MR, Lee HH, Hahm KS, Moon YH, Woo ER: Pentacyclic triterpenoids and their cytotoxicity from the stem bark of Styraxjaponica S. et Z. Arch Pharm Res. 2004, 27 (3): 283-286. 10.1007/BF02980060.
Ngouela S, Nyasse B, Tsamo E, Sondengam BL, Connollya JD: Spathodic acid: a triterpene acid from the stem bark of Spathodea campanulata. Phytochemistry. 1990, 29 (12): 3959-3961. 10.1016/0031-9422(90)85376-Q.
Tan NH, Zhou J: Plant cyclopeptides. Chem Rev. 2006, 106 (3): 840-895. 10.1021/cr040699h.
Zhao SM, Kuang B, Fan JT, Yan H, Xu WY, Tan NH: Antitumor cyclic hexapeptides from Rubia Plants: History, Chemistry, and Mechanism (2005–2011). CHIMIA. 2011, 65 (12): 952-956. 10.2533/chimia.2011.952.
Itokawa H, Takeya K, Mori N, Sonobe T, Mihashi S, Hamanaka T: Studies on Antitumor cyclic hexapeptides RA obtained from Rubiae Radix Rubiaceae. VI: minor antitumor constituents. Chem Pharm Bull. 1986, 34 (9): 3762-3768. 10.1248/cpb.34.3762.
Itokawa H, Takeya K, Mihara K, Mori N, Hamanaka T, Sonobe T, Iitaka Y: Studies on the antitumor cyclic hexapeptides obtained from Rubiae Radix. Chem Pharm Bull. 1983, 31 (4): 1424-1427. 10.1248/cpb.31.1424.
Itokawa H, Morita H, Takeya K, Tomioka N, Itai A, Iitaka Y: New antitumor bicyclic hexapeptides, RA-VI and -VIII from Rubia cordifolia; conformation-activity relationship II. Tetrahedron. 1991, 47 (34): 7007-7020. 10.1016/S0040-4020(01)96155-1.
Itokawa H, Yamamiya T, Morita H, Takeya K: New antitumour bicyclic hexapeptides, RA-IX and-X from Rubia cordifolia. Part 3. Conformation–antitumour activity relationship. J Chem Soc, Perkin Trans 1. 1992, 4: 455-459.
Itokawa H, Takeya K, Mori N, Hamanaka T, Sonobe T, Mihara K: Isolation and antitumor activity of cyclic hexapeptides isolated from Rubiae Radix. Chem Pharm Bull. 1984, 32 (1): 284-290. 10.1248/cpb.32.284.
Morita H, Yamamiya T, Takeya K, Itokawa H: New antitumor bicyclic hexapeptides, RA-XI, -XII, -XIII and -XIV from Rubia cordifolia. Chem Pharm Bull. 1992, 40 (5): 1352-1354. 10.1248/cpb.40.1352.
Takeya K, Yamamiya T, Morita H, Itokawa H: Two antitumour bicyclic hexapeptides from Rubia cordifolia. Phytochemistry. 1993, 33 (3): 613-615. 10.1016/0031-9422(93)85458-4.
Hitotsuyanagi Y, Ishikawa H, Hasuda T, Takeya K: Isolation, structural elucidation, and synthesis of RA-XVII, a novel bicyclic hexapeptide from Rubia cordifolia, and the effect of side chain at residue 1 upon the conformation and cytotoxic activity. Tetrahedron Lett. 2004, 45 (5): 935-938. 10.1016/j.tetlet.2003.11.112.
Itokawa H, Morita H, Takeya K, Tomioka N, Itai A: RAI-III and VI, conformational isomers of antitumor cyclic hexapeptides, RA-III and VI from Rubia cordifolia. Chemistry Lett. 1991, 20 (12): 2217-2220.
Morita H, Yamamiya T, Takeya K, Itokawa H, Sakuma C, Yamada J, Suga T: Conformational recognition of RA-XII by 80S Ribosomes: a differential line broadening study in 1H NMR spectroscopy. Chem Pharm Bull. 1993, 41 (4): 781-783. 10.1248/cpb.41.781.
Itokawa H, Morita H, Kondo K, Hitotsuyanagi Y, Takeya K, Iitaka Y: Isomerization of antitumour bicyclic hexapeptide, RA-VII from Rubia cordifolia. Part 4. conformation– antitumour activity relationship. J Chem Soc, Perkin Trans 2. 1992, 9: 1635-1642.
Lee JE, Hitotsuyanagi Y, Kim IH, Hasuda T, Takeya K: A novel bicyclic hexapeptide, RA-XVIII, from Rubia cordifolia: structure, semi-synthesis, and cytotoxicity. Bioorg Med Chem Lett. 2008, 18 (2): 808-811. 10.1016/j.bmcl.2007.11.030.
Lee JE, Hitotsuyanagi Y, Takeya K: Structures of cytotoxic bicyclic hexapeptides, RA-XIX, -XX, -XXI, and -XXII, from Rubia cordifolia L. Tetrahedron. 2008, 64 (18): 4117-4125. 10.1016/j.tet.2008.01.094.
Lee JE, Hitotsuyanagi Y, Fukaya H, Kondo K, Takeya K: New cytotoxic bicyclic hexapeptides, RA-XXIII and RA-XXIV, from Rubia cordifolia L. Chem Pharm Bull. 2008, 56 (5): 730-733. 10.1248/cpb.56.730.
Fan JT, Chen YS, Xu WY, Du LC, Zeng GZ, Zhang YM, Su J, Li Y, Tan NH: Rubiyunnanins A and B, two novel cyclic hexapeptides from Rubia yunnanensis. Tetrahedron Lett. 2010, 51 (52): 6810-6813. 10.1016/j.tetlet.2010.07.066.
Fan JT, Su J, Peng YM, Li Y, Li J, Zhou YB, Zeng GZ, Yan H, Tan NH: Rubiyunnanins C–H, cytotoxic cyclic hexapeptides from Rubia yunnanensis inhibiting nitric oxide production and NF-κB activation. Bioorg Med Chem. 2010, 18 (23): 8226-8234. 10.1016/j.bmc.2010.10.019.
Zou C, Hao XJ, Zhou J: Antitumor glycocyclohexapeptide from Rubia yunnanensis. Acta Botanica Yunnanica. 1993, 15 (4): 399-402.
He M, Zou C, Hao XJ, Zhou J: A new antitumor cyclic hexapeptide glycoside from Rubia yunnanensis. Acta Botanica Yunnanica. 1993, 15 (4): 408-
He M, Zou C, Hao XJ, Zhou J: New antitumor glycocyclohexapeptide from Rubia yunnanensis. Chinese Chem Lett. 1993, 4: 1065-
Hitotsuyanagi Y, Aihara T, Takeya K: RA-dimer A, a novel dimeric antitumor bicyclic hexapeptide from Rubia cordifolia L. Tetrahedron Lett. 2000, 41 (32): 6127-6130. 10.1016/S0040-4039(00)01029-7.
Hamanaka T, Ohgoshi M, Kawahara K, Yamakawa K, Tsuruo T, Tsukagoshi S: A novel antitumor cyclic hexapeptide (RA-700) obtained from Rubiae radix. Pharmaceutical Society of Japan. 1987, 10 (11): 616-623.
Adwankar MK, Chitnis MP: In vivo anti-Cancer activity of RC-18. Chemotherapy. 1982, 28 (4): 291-293. 10.1159/000238092.
Hitotsuyanagi Y, Odagiri M, Kato S, Kusano JI, Hasuda T, Fukaya H, Takeya K: Isolation, structure determination, and synthesis of Allo-RA-V and Neo-RA-V, RA-Series bicyclic peptides from Rubia cordifolia L. Chem Eur J. 2012, 18 (10): 2839-2846. 10.1002/chem.201103185.
Hitotsuyanagi Y, Kusano JI, Kim IH, Hasuda T, Fukaya H, Takeya K: O-Seco-RA-XXIV, a possible precursor of an antitumor peptide RA-XXIV, from Rubia cordifolia L. Phytochem Lett. 2012, 5 (2): 335-339. 10.1016/j.phytol.2012.02.014.
Krishnaiah VC, Ishaq BM, Kumar CH, Kumar JGS: Antidiarrhoeal activity of root extracts of Rubia cordifolia Linn. JGTPS. 2011, 2 (4): 476-488.
Patel PR, Raval BP, Karanth HA, Patel VR: Potent antitumor activity of Rubia cordifolia. International Journal of Phytomedicine. 2011, 2 (1): 44-46.
Joharapurkar AA, Zambad SP, Wanjari MM, Umathe SN: In vivo evaluation of antioxidant activity of alcoholic extract of Rubia cordifolia Linn. and its influence on ethanol-induced immunosuppression. Indian J Pharmacol. 2003, 35 (4): 232-236.
Baskar R, Bhakshu LM, Bharathi GV, Reddy SS, Karuna R, Reddy GK, Saralakumari D: Antihyperglycemic activity of aqueous root extract of Rubia cordifolia in streptozotocin- induced diabetic rats. Pharm Biol. 2006, 44 (6): 475-479. 10.1080/13880200600798593.
Charde RM, Charde MS, Fulzele SV, Satturwar PM, Joshi SB: Wound healing activity of ethanolic extract of Rubia Cordifolia roots. J Pharm Res. 2010, 3 (12): 3070-3071.
Deoda RS, Kumar D, Bhujbal SS: Gastroprotective effect of Rubia cordifolia Linn. on aspirin plus pylorus-ligated ulcer. Evid base Compl Alternative Med. 2011, 2011 (Article ID 541624): 5-10.1155/2011/541624. http://www.hindawi.com/journals/ecam/2011/541624/abs/,
Cheng XH, Xiong YQ: Advances in studies on pharmacological activities of pentacyclic triterpenoid saponins. Chinese Traditional and Herbal Drugs. 2007, 38 (5): 792-795.
Hasuda T, Hitotsuyanagi Y, Takeya K: Production of monoclonal antibodies against antitumor cyclohexapeptide RA-VII from Rubia cordifolia and their characterization. J Nat Med. 2011, 65 (3): 588-593.
Koizumi T, Abe M, Yamakuni T, Ohizumi Y, Hitotsuyanagi Y, Takeya K, Sato Y: Metronomic scheduling of a cyclic hexapeptide Ra-VII for anti-angiogenesis, tumor vessel maturation and anti-tumor activity. Cancer Sci. 2006, 97 (7): 665-674. 10.1111/j.1349-7006.2006.00229.x.
Reyes-Zurita FJ, Rufino-Palomares EE, Lupianez JA, Cascante : Maslinic acid, a natural triterpene from Olea europaea L., induces apoptosis in HT29 human colon-cancer cells via the mitochondrial apoptotic pathway. Cancer Lett. 2009, 273 (1): 44-54. 10.1016/j.canlet.2008.07.033.
Juan ME, Planas JM, RuizGutierrez V, Daniel H, Wenzel U: Antiproliferative and apoptosis inducing effects of maslinic and oleanolic acids, two pentacyclic triterpenes from olives, on HT29 colon cancer cells. Brit J Nutr. 2008, 100 (1): 36-43.
Li CH, Yang ZF, Zhai CY, Qiu WW, Li DL, Yi ZF, Wang L, Tang J, Qian M, Luo J, Liu MY: Maslinic acid potentiates the anti-tumor activity of tumor necrosis factor a by inhibiting NF-κB signaling pathway. Mol Cancer. 2010, 9: 73-85. 10.1186/1476-4598-9-73.
Mooi LY, Yew WT, Hsum YW, Soo KK, Hoon LS, Chieng YC: Suppressive effect of maslinic acid on PMA-induced Protein Kinase C in Human B-Lymphoblastoid Cells. Asian Pac J Cancer P. 2012, 13: 1177-1182. 10.7314/APJCP.2012.13.4.1177.
Prasad S, Yadav VR, Kannappan R, Aggarwal BB: Ursolic Acid, a pentacyclic triterpene, potentiates TRAIL-induced apoptosis through p53-independent up-regulation of death receptors. J Biol Chem. 2011, 286 (7): 5546-5557. 10.1074/jbc.M110.183699.
Pathak AK, Bhutani M, Nair AS, Ahn KS, Chakraborty A, Kadara H, Guha S, Sethi G, Aggarwal BB: Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol Cancer Res. 2007, 5 (9): 943-955. 10.1158/1541-7786.MCR-06-0348.
Yan SL, Huang CY, Wu ST, Yin MC: Oleanolic acid and ursolic acid induce apoptosis in four human liver cancer cell lines. Toxicol in Vitro. 2010, 24 (3): 842-848. 10.1016/j.tiv.2009.12.008.
Yue GGL, Fan JT, Lee JKM, Zeng GZ, Ho TWF, Fung KP, Leung PC, Tan NH, Lau CBS: Cyclopeptide RA-V inhibits angiogenesis by down-regulating ERK1/2 phosphorylation in HUVEC and HMEC-1 endothelial cells. Brit J Pharmacol. 2011, 164 (7): 1883-1898. 10.1111/j.1476-5381.2011.01458.x.
Horiuchi K, Shiota S, Hatano T, Yoshida T, Kuroda T, Tsuchiya T: Antimicrobial activity of oleanolic acid from Salvia officinalis and related compounds on Vancomycin-Resistant Enterococci (VRE). Biol Pharm Bull. 2007, 30 (6): 1147-1149. 10.1248/bpb.30.1147.
Jayaprakasam B, Olson LK, Schutzki RE, Tai MH, Nair MG: Amelioration of obesity and glucose intolerance in High-Fat-Fed C57BL/6 mice by anthocyanins and ursolic acid in Cornelian Cherry (Cornus mas). J Agric Food Chem. 2006, 54 (1): 243-248. 10.1021/jf0520342.
Liu J, Sun HB, Duan WG, Mu DY, Zhang LY: Maslinic acid reduces blood glucose in KK-Ay mice. Biol Pharm Bull. 2007, 30 (11): 2075-2078. 10.1248/bpb.30.2075.
Wang ZH, Hsu CC, Huang CN, Yin MC: Anti-glycative effects of oleanolic acid and ursolic acid in kidney of diabetic mice. Eur J Pharmacol. 2010, 628 (1–3): 255-260.
Xu HX, Zeng FQ, Wan M, Sim KY: Anti-HIV triterpene acids from Geum japonicum. J Nat Prod. 1996, 59 (7): 643-645. 10.1021/np960165e.
This part of work is partially supported by the National Natural Science Foundation of China (No.81073017; No. 81173519), and the Innovation Team Project Foundation of Beijing University of Chinese Medicine named ‘Lead Compounds Discovering and Developing Innovation Team Project Foundation’ (No. 2011-CXTD-15).
The authors declare that they have no competing interests.
KX, PW, HL have all been involved in drafting this review. BY, YC, and QL read and approved the final manuscript. All authors read and approved the final manuscript.
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.
About this article
Cite this article
Xu, K., Wang, P., Yuan, B. et al. Structural and bioactive studies of terpenes and cyclopeptides from the Genus Rubia. Chemistry Central Journal 7, 81 (2013). https://doi.org/10.1186/1752-153X-7-81