Ethnobotany, Phytochemistry, and Biological Activities of the Genus Cordyline

Cordyline species have a long history in traditional medicine as a basis of treatment for various ailments such as a bloody cough, dysentery, and a high fever. There are about 26 accepted species names in this genus distributed worldwide, including C. fruticosa, C. autralis, C. stricta, C. cannifolia, and C. dracaenosides. This work presents a comprehensive review of the traditional uses of plants of the genus Cordylie and their chemical constituents and biological activities. A bibliographic search was conducted to identify available information on ethnobotany, ethnopharmacology, chemical composition, and biological activities. A total of 98 isolated compounds potentially responsible for most of the traditional medicinal applications have been reported from eight species of Cordyline and are characterised as flavonoid, spirostane, furostane, and cholestane glycosides. Some of these pure compounds, as well as extracts from some species of Cordyline, have exhibited noteworthy anti-oxidant, antiproliferative, antimicrobial, and hypolipidemic activities. Although many of these species have not yet been investigated phytochemically or pharmacologically, they remain a potential source of new bioactive compounds.


Introduction
Traditional medicine frequently relies on medicinal plants for the treatment of various ailments and diseases.In developing countries, traditional medicine plays a significant role in delivering primary health care.Scientists have relied on the wealth of the floral kingdom for nearly half of all new drug discoveries to date [1,2].Even ornamental plant species can contain a vast wealth of bioactive compounds valuable to medicine [3].For example, drugs currently in clinical use for cancer treatment include paclitaxel, derived from Taxus brevifolia L., vincristine, derived from Catharanthus roseus (L.) G. Don., and epigallocatechin-3-gallate, a phenolic catechin from Camellia sinensis [4], all of which are better known as ornamental rather than medicinal plants.
Natural products and their derivatives are a significant source for novel drug development in modern medicine, and many of these derivatives form the active ingredient of drugs approved by the U.S. Food and Drug Administration (FDA) [5].Dependency on direct medicinal plant derivatives is particularly marked in developing countries, where

Botany and Taxonomy
The name Cordyline is derived from the Greek kordyle, which means club, which refers to the plants' thick underground stems or rhizomes.Royen was the first to report the name Cordyline in 1740 and to propose a classification, but due to the presence of Yucca and Dracaena in his classification, Adanson gave the plant a new generic classification in 1763 [15].The genus Cordyline, one of the so-called 'tree lilies', was placed in the family Laxmanniaceae according to the Angiosperm Phylogeny Group (APG) in 2003, then in the Asparagaceae family in 2009.Also called Agavaceae, this family contains 128 genera, with more than 3000 species [16].The genus Cordyline contains 26 species alone, of which C. fruticosa, C. australis, C. stricta, C. annifolia, C. rubra, and C. dracaenoside appear to have been the most researched.Cordyline australis, commonly called the cabbage tree and known as 'ti kouka' by the Maori people, is the most widespread of this genus and occurs in open places and at forest margins on the three main islands [17].Cordylines form small trees or shrubs and have leathery leaves, which are often clustered and palm-like in appearance.Cordyline species have creamish white roots that often form root suckers starting from their rhizomes [18][19][20].Cordyline belongs to the few genera of monocots in which a cambium is present in the stem.The most well-known ornamental and medicinal plant of this genus is Cordyline fruticosa L. (Chev.)(Figure 1), with its beautiful and attractive decorative foliage.
Plants of the genus Cordyline generally reach up to 3 m high and are remarkable for their colourful foliage and varied heights, colours, and the shape of their leaves [21][22][23].Several hybrid combinations of the Cordyline species have been recorded.The species is believed to have originated in Southeast Asia and Papua New Guinea.The plants of the genus Cordyline are not always easy to distinguish from those of the Dracaena.However, the petiole of the former is generally larger than that of the latter (10 to 30 cm versus 1 to 8 cm).Plants of the genus Cordyline generally reach up to 3 m high and are remarkable for their colourful foliage and varied heights, colours, and the shape of their leaves [21][22][23].Several hybrid combinations of the Cordyline species have been recorded.The species is believed to have originated in Southeast Asia and Papua New Guinea.The plants of the genus Cordyline are not always easy to distinguish from those of the Dracaena.However, the petiole of the former is generally larger than that of the latter (10 to 30 cm versus 1 to 8 cm).

Traditional Uses of the Genus Cordyline
Several plants of the genus Cordyline, and particularly their leaves, are used in traditional medicines throughout the tropical and subtropical regions for the treatment of various diseases such as dysentery, skin infection, rheumatism, inflammations, and periodic fever [24,25].
Cordyline dracaenoides is used as a traditional medicine in the south of Brazil as an anti-inflammatory preparation for the treatment of rheumatoid and related diseases [26].Cordyline stricta is an evergreen shrub native to Australia, and an extract of its leaves is used as a hemostatic in traditional Chinese medicine [9].Cordyline fruticosa, commonly known as the good luck plant, is grown in tropical and subtropical regions as an ornamental plant.In Polynesia, it is used for both cultural purposes and as a food crop [27].The plant is widely utilised in both everyday life and as a source of traditional medicine.The leaves are used for costumes, decorations, clothing, sandals, packaging, and cooking.The rhizomes can be baked into a molasses-like food product and eaten [28].In addition, the plant is used for the treatment of various diseases.The leaves are used to treat sore throat and neck pain [29], as a hemostatic [30,31], and to induce abortion [32], and the roots are used for toothache, laryngitis, and to treat infections of the mammary glands [31,33].
In Sabah, the Kadazan-Dusun people, who are the largest ethnic group in Malaysia, use the roots of C. terminalis L. Kunth (also known as C. fruticosa) (locally called Pipisokalaganan) as part of their local medicine for curing cough, bloody cough, dysentery, high fever, difficulties in urinating, bloody urine, kidney diseases, headaches, inflammation in the digestive tract, scurf, and joint pain.For example, the roots are pounded into a paste and applied to the stomach to relieve stomach pain [34].In Hawaii, local people use the purple flowers of C. fruticosa to treat asthma and growths in the nose [35].

Traditional Uses of the Genus Cordyline
Several plants of the genus Cordyline, and particularly their leaves, are used in traditional medicines throughout the tropical and subtropical regions for the treatment of various diseases such as dysentery, skin infection, rheumatism, inflammations, and periodic fever [24,25].
Cordyline dracaenoides is used as a traditional medicine in the south of Brazil as an anti-inflammatory preparation for the treatment of rheumatoid and related diseases [26].Cordyline stricta is an evergreen shrub native to Australia, and an extract of its leaves is used as a hemostatic in traditional Chinese medicine [9].Cordyline fruticosa, commonly known as the good luck plant, is grown in tropical and subtropical regions as an ornamental plant.In Polynesia, it is used for both cultural purposes and as a food crop [27].The plant is widely utilised in both everyday life and as a source of traditional medicine.The leaves are used for costumes, decorations, clothing, sandals, packaging, and cooking.The rhizomes can be baked into a molasses-like food product and eaten [28].In addition, the plant is used for the treatment of various diseases.The leaves are used to treat sore throat and neck pain [29], as a hemostatic [30,31], and to induce abortion [32], and the roots are used for toothache, laryngitis, and to treat infections of the mammary glands [31,33].
In Sabah, the Kadazan-Dusun people, who are the largest ethnic group in Malaysia, use the roots of C. terminalis L. Kunth (also known as C. fruticosa) (locally called Pipisokalaganan) as part of their local medicine for curing cough, bloody cough, dysentery, high fever, difficulties in urinating, bloody urine, kidney diseases, headaches, inflammation in the digestive tract, scurf, and joint pain.For example, the roots are pounded into a paste and applied to the stomach to relieve stomach pain [34].In Hawaii, local people use the purple flowers of C. fruticosa to treat asthma and growths in the nose [35].

Other Important Uses of Plants of the Genus Cordyline
Ornamental plants are characterized by attractive foliage and/or flowers that can survive and grow indoors and/or outdoors.Cordyline fruticosa, with its attractive red decorative foliage, is one of India's most economically important ornamental houseplants [36].The economic value of ornamental plants of the genus Cordyline has risen perceptibly worldwide and is still increasing to meet the steady demand of the floriculture industry.Reports that the roots of Cordyline australis may contain more than 60% fructofuranan suggest that the species could become a commercial source of fructose [37].Cordyline australis has been used extensively by the Maori people in Australia, both as a source of fibre and as a food, and there is strong evidence to suggest that the plant was translocated extensively in pre-European times [38].
Cordyline fruticosa is often used ornamentally as a low-growing border shrub [39].C. fruticosa is associated with cultural, material, and religious uses among the peoples of Oceania [18,40].There is some evidence that the early Polynesians used Cordyline fruticosa for its importance in costume making, for wrapping food, for religious uses, and as a food source [41].A hedge of C. fruticosa around the house was believed to ward off evil spirits and bring good luck [42].The fleshy rhizome contains up to 20% sugar, mainly fructose, and is used as a natural sweetener in New Zealand and for the production of an alcoholic beverage in Hawaii [43].In Hawaii, the fibre from the leaves of the 'Ti' plant (a common name for any plant of the genus in Hawaii) was used for making sandals, baskets, bird snares, sieves, and thatch for roofs, rope, and cord.The leaves of the plant (known as 'rau ti' in the Cook Islands) or the tender young shoots were eaten raw or roasted in the embers of a fire.Pith (commonly called Ti) was dried in the sun and cooked to make porridge [43].Roots of Ti were used for making sweet drinks.Sugar was extracted by cooking the roots in an earth oven called an 'umu-ti'.Large pits were used to steam the roots.Long hedges of Cordyline fruticosa are planted by locals to guard the gardens against pigs.The handling of 'Ti' was often accompanied by ceremonial protocols [43].
The New Zealand cabbage tree, known as Cordyline australis, is internationally rated as one of their most famous indigenous plants.Its popularity is based not only on its characteristic habit, shape, and deliciously fragrant flowers but also on the relatively recent progress of coloured foliage forms [44].Other species, also known as cabbage trees, include C. kaspar, C. indivisa (Ti toi), C. banksii (Ti ngahere), and C. pumilio (Ti rauriki) [45].

Chemical Constituents
A thorough review of the literature, based on the widespread uses of different parts of the plants of the Cordyline genus in traditional medicine, has resulted in considerable chemical analysis of their active compounds.A bibliographic investigation has revealed the isolation and identification of two principal classes of compounds with various structural skeletons.The process of isolating some of these compounds was carried out using simple column chromatography.In contrast, others used vacuum liquid chromatography on reversed-phase RP-18 silica gel medium-pressure liquid chromatography on silica gel 60.The structures of isolated compounds were established based on 1D and 2D NMR data, mass spectrometry, and chemical methods.Phytochemical studies have been mainly focused on the following eight Cordyline species: C. australis, C. fruticosa, C. manners-suttoniae, C. stricta, C. rubra, C. dracaenoides, C. cannifolia, and C. indivisa.The structures of the isolated secondary metabolites are grouped in Figures 2-5.
The following figures summarise all reported compounds from the Cordyline genus.

Biological Activities
Phytochemical investigations have revealed the presence of several constituents belonging to different classes of compounds.Due to their antibacterial, antifungal, antiparasitic, and antioxidant activities, the genus Cordyline has mainly been investigated for its properties already observed in the natural environment.Bioactivities reported for Cordyline plant extracts and their pure compounds are summarised by activity in this section.
All the steroidal saponins presented here align with the results reported from studies on the Agavaceae family.In fact, this family is known to produce mainly steroidal saponins, as reviewed by Boyce and Tinto in 2006 [58].In addition, one of the most widely studied genus of this family (the Agave) is reported to mostly contain steroidal saponins and sapogenins [59], and we noticed that the structures with ∆ 25(27) are even more common in the genus Cordyline than in the genus Agave.The genus Yucca is also reported to produce such compounds [58].This review presented several flavonoids isolated from plants of the genus Cordyline, while some research only highlighted the flavonoid profiles in the genus Agave [60].

Cordyline dracaenoides
Chemical analysis of C. dracaenoides revealed the presence of steroidal saponins and anthocyanidins in the stem, rhizome and root.Small amounts of tannins were also detected in its stem and rhizome.Other studies conducted on this plant have shown the existence of steroidal saponins, including brisbagenin (5) and brisbenone (96) [63,64].
The following figures summarise all reported compounds from the Cordyline genus.

Biological Activities
Phytochemical investigations have revealed the presence of several constituents belonging to different classes of compounds.Due to their antibacterial, antifungal, antiparasitic, and antioxidant activities, the genus Cordyline has mainly been investigated for its properties already observed in the natural environment.Bioactivities reported for Cordyline plant extracts and their pure compounds are summarised by activity in this section.

Antimicrobial Activity
The antimicrobial activity of fruticoside H (18), fruticoside I (19), and fruticoside J (20) was assessed against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, and Candida albicans.The three isolated saponins, even at the highest concentration used in the test (256 mg/L), were not able to inhibit growth except for compound 19 (Fructicoside I) against E. faecalis.In this case, the minimum inhibitory concentration (MIC) value was 128 mg/L, which, although still high, is indicative of a specific antibacterial activity.The minor structural difference between 18 and 19 suggested that the presence of the SO 3 H group at C-4' and the absence of the double bond at C-5(∆ 5,6 ) can significantly decrease the MIC value (more than 256 µg/mL for 18 and 128 µg/mL for 19) of the molecules against the enterococcal species [7].The n-hexane, ethyl acetate, and methanol extracts of C. fruticosa were evaluated for their antibacterial capacity against Gram-negative Escherichia coli and Salmonella typhi as Staphylococcus aureus and Grampositive Bacillus subtilis by the microdilution method.The ethyl acetate fraction was found to be the most active against Salmonella typhi (inhibition diameter ID 15.2 mm) and S. aureus (ID 14.2 mm) in comparison to penicillin (ID 83.5 and 73.2 mm), tetracycline (ID 76.8 and 72.1 mm) and streptomycin (ID 77.2 and 71.4 mm) used as standards [14].The crude methanol extract of C. fruticosa showed a faint zone of inhibition against E. fecalis [13].Firoj et al. (2003) reported antibacterial activity in methanol, chloroform, acetone, and hexane extracts of Cordyline fruticosa.
The anticandidal activity of C. fruticosa leaf extracts was examined using agar well diffusion against Candida albicans.N-hexane, ethyl acetate, and ethanol extracts showed weak inhibition zones of 13, 8 and 12 mm, respectively, at a concentration of 400 µg/well, compared to 100 mm of the Chloramphenicol [69].

Antioxidant Activity
Antioxidant activity measured using the 2,2-diphenyl-1-picryl-hydrazyl (DPPH) method of crude extract of C. fruticosa purple flowers and isolated compounds showed the potential to scavenge free radicals.In fact, the methanol crude extract displayed an IC 50 of 13.1 µg/mL, while isolated compounds (39)(40)(41)(42)(43) showed IC 50 in the range of 13.8 to 16.4 µg/mL compared to that of quercetin (4.5 µg/mL) used as a positive control [54].Antioxidant activity of encapsulated (with sodium caseinate beads) and unencapsulated phenolic content of C. fruticosa methanolic extract were assessed for their free radical scavenging capacity per gram of ascorbic acid equivalent (AAE).The encapsulated extracts showed good antioxidant activity after one year of conservation (EC 50 27.38 mg/g AAE) in comparison to the unencapsulated extracts (EC 50 13.4mg/g AAE) [70].A similar method was investigated on the methanol extract of C. fruticosa leaves; this extract was combined with copper oxide to form nanoparticles.Both crude extract and nanoparticles exhibited antioxidant activity following the DPPH method, with ascorbic acid used as a positive control [71].As has been reported with several medicinal [72,73], this antioxidant activity is linked to the flavonoid content of Cordyline fruticosa.

Antiproliferative Activity
The antiproliferative effect of steroidal saponins is well reported and is known to affect cancer cell lines following several mechanisms such as apoptosis, differentiation, senescence, autophagy, oncosis, and other pathways [74][75][76].The effect of fruticoside H-J (18-20) on the viability of the MDA-MB 231 human breast adenocarcinoma cell line, HCT 116 human colon carcinoma cell line and A375 human malignant melanoma cell line were evaluated in vitro using the MTT assay.Fruticoside H and I (18 and 19) showed moderate antiproliferative activity, with IC 50 values ranging from 37.83 to 69.68 µM for 18 on A375 and MDA-MB 231 cells, respectively, and from 46.59 to 59.97 µM for 19 on A375 and HCT116 cells, respectively.Fruticoside J (20) was inactive on the three tumour cell lines tested [7].Using the same method against the same cell lines, investigators found that the steroidal saponins Fruticoside K and M (26 and 28) displayed weak cytotoxicity against melanoma (A375), breast adenocarcinoma (MDA-MB-231), and colon carcinoma (HCT116) human tumour cell lines [11].
Cytotoxicity of compounds 6, 60, and 69 was also evaluated against the cancer cell lines of human keratinocytes and human dermal fibroblasts.They all exhibited cytotoxicity with IC 50 values ranging from 18.2 to 74.9 µM for human keratinocyte cells and 4.2 to 16.5 µM for human dermal fibroblast cells [8].
Compounds 49-59 were evaluated for their cytotoxicity using the MTS method [3-(4,5dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] against the 4T1 cell line from a mouse mammary gland tissue, an animal model for stage IV human breast cancer.Compounds 49, 54, and 55 displayed good cytotoxic activity with the respective IC 50 values of 1.39, 1.52, and 3.24 µM, compared to 5-FU (IC 50 6.70 Mm) [58].The results obtained for 49, 54, 55, and 69 seem to contradict those of Zhu et al. (2015), who reported that anticancer activity increased with the number of sugars.Several compounds tested with a high number of sugars exhibited low activity, and it is possible that the aglycone moieties could have contributed to this activity (likely the double bonds ∆ 5−6 and ∆ 25(27) ).Additionally, the hydroxyl at C-3 could have had an effect [77].This is in alignment with compound 20, which had no activity, and the presence of the double bond ∆ 5−6 and the absence of the double bond ∆ 25(27) ) could explain this inactivity.

Hypolipidemic Potential, Antiparasitic Activity, Nephrotoxicity and Hepatotoxicity Preventions
The methanol extract of the rhizomes of C. fruticosa has been investigated for its hypolipidemic potential in Wistar rats.Intake of 30 mg/Kg and 70 mg/Kg was found to lower lipid plasma levels in mice [78].This extract showed the potential to lower blood fatty acid, glucose, and triglyceride levels in obese Wistar rats [79].The n-butanolsoluble fraction of the methanol extract of senescent leaves of C. australis was assessed for its antiparasitic activity; it displayed a weak inhibition against Plasmodium falciparum, Tripanosoma brucei, and Tripanosoma cruzi, with an IC 50 of 12, 23 and 32 µM, respectively, relative to 0.018 µM of Chloroquine [10].The aqueous extract of C. fruticosa also displayed antitrypanosomial activity by slowing the mitotic cycle in Trypanosoma evansi, with an IC 50 of 48.1 µg/mL [80].
The effect of C. fruticosa leaf extract against doxorubicin-cisplatin-induced nephrotoxicity and hepatotoxicity in rats was assessed.Administration of C. fruticosa extract induced a significant decrease in the aspartate aminotransferase, alanine amino transferase, alkaline phosphatase, urea and creatinine in doxorubicin-treated rats.It protected the renal tissues from necrosis induced by doxorubicin.The administration of the extract 10 days before cisplatin ingestion in the preventive process contributed to a pronounced protection against hepatic injury induced by cisplatin [55].
The effect of C. fruticosa leaves' methanol extract was studied on castor oil-induced diarrhoea and magnesium sulphate-induced diarrhoea.The extract significantly reduced the frequency of magnesium sulphate-induced diarrhoea at the dose of 800 mg/Kg of body weight [81].
Based on the number of studies that have reported the biological activities of steroidal saponins, we recommend that future biological assays address their effect on inflammatory cells, nervous cells, and fungi.The study of the action mechanism of the double bond ∆ 25(27) could be carried out to shed light on their effect on cancer cells.

Toxicology
In a brine shrimp lethality test after 24 h, surviving brine shrimp nauplii were counted, and LC50 was assessed.The methanol extract of C. fruticosa exhibited considerable toxicity, with an LC50 value of 355.7 µg/mL, compared to a standard of vincristine sulfate (LC50 of 3.8 µg/mL).This result indicates that the methanol extract has a cytotoxicity effect and it could have antitumour molecules [81].

Conclusions
Due to their versatile traditional uses, Cordyline species have been extensively studied for their phytoconstituents as well as for their biological activities.Flavonoid, spirostane, furostane, and cholestane glycosides have been isolated from seven Cordyline species, while C. indivisa remains largely unstudied.In summary, the plant extracts and some of their pure compounds possess a broad spectrum of biological activities such as antibacterial, antifungal, antiproliferative, antiparasitic, and hypolipidemic effects.Saponins, sapogenins, and flavonoids are the most frequently isolated and identified classes of compounds in the species C. australis, C. fruticosa, C. manners-suttoniae, C. stricta, C. rubra, C. cannifolia, and C. dracaenoides, and currently constitute the only investigated and identified phytochemicals.Cordyline plants have been and continue to be used in traditional medicine against certain infections caused by bacteria, fungi, and parasites.This review of all available literature reveals that steroidal saponins, steroidal sapogenins, and flavonoids are the biomarkers of plants belonging to the Cordyline genus and present in one view the wide opportunities for the use of Cordyline plants in drug discovery with regard to bioactive molecules not yet characterised from this genus.The bioassay-guided isolation and identification of the bioactive components of plants of the genus Cordyline remain un-investigated, and more detailed in silico studies are required to propose detailed structure-activity relationships in order to determine the mechanisms of action of saponin and flavonoid constituents.
Although some compounds isolated from plants of the genus Cordyline have exhibited interesting biological activities, much more work is needed to exploit them in the pharmaceutical industry, as they were generally obtained in small amounts.Synthesis of some of these secondary metabolites from readily available reactants should be considered by pharmacochemists in order to obtain amounts sufficient for use in drug development.

Figure 2 .
Figure 2. Structures of steroidal saponins isolated from some plants of the genus Cordyline.

Figure 3 .
Figure 3. Main sapogenins isolated from plants of the genus Cordyline.

Figure 3 .
Figure 3. Main sapogenins isolated from plants of the genus Cordyline.

Figure 4 .
Figure 4. Flavonoids isolated from some plants of the genus Cordyline.

Figure 4 .
Figure 4. Flavonoids isolated from some plants of the genus Cordyline.

Figure 4 .Figure 5 .
Figure 4. Flavonoids isolated from some plants of the genus Cordyline.