Flavonoids and Stilbenoids of the Genera Dracaena and Sansevieria: Structures and Bioactivities

The genera Dracaena and Sansevieria (Asparagaceae, Nolinoideae) are still poorly resolved phylogenetically. Plants of these genera are commonly distributed in Africa, China, Southeast Asia, and America. Most of them are cultivated for ornamental and medicinal purposes and are used in various traditional medicines due to the wide range of ethnopharmacological properties. Extensive in vivo and in vitro tests have been carried out to prove the ethnopharmacological claims and other bioactivities. These investigations have been accompanied by the isolation and identification of hundreds of phytochemical constituents. The most characteristic metabolites are steroids, flavonoids, stilbenes, and saponins; many of them exhibit potent analgesic, anti-inflammatory, antimicrobial, antioxidant, antiproliferative, and cytotoxic activities. This review highlights the structures and bioactivities of flavonoids and stilbenoids isolated from Dracaena and Sansevieria.


Introduction
The taxonomic boundaries of the dracaenoid genera Dracaena and Sansevieria have long been debated. In the APG IV system of flowering plant classification, the two genera are still differentiated; both have been placed in the subfamily Nolinoideae of the family Asparagaceae, in the order Asparagales [1]. However, recent molecular phylogenetic studies showed that Sansevieria was nested within Dracaena, rendering the latter paraphyletic unless Dracaena was expanded to include species formerly placed in Sansevieria [2][3][4]. In this paper we have maintained the historical division in the two genera because the chemical literature is mainly based on the former botanical classification. However, known Dracaena synonyms for Sansevieria species are also reported.
The genus Dracaena consists of more than 100 accepted species which are mainly distributed in the tropics and subtropics, especially in Africa, Australia, and Southern Asia [5]. They are mainly succulent shrubs and trees, and a few are commonly grown as shrubby houseplants, especially the variegated forms. The complete chloroplast (CP) genomes of six species have recently been reported, showing that can be used as a super-barcode for Dracaena spp. identification [6]. "Dragon's blood" is a non-specific name for deep red resinous exudates that are obtained from cut stems of different plant taxa endemic to various regions around the globe and belonging to the families of Asparagaceae, Arecaceae, Chamaesyce (Euphorbiaceae), and Fabaceae [7,8]. About six Dracaena plants, This review describes the most characteristic flavonoids and stilbenes isolated from Dracaena and Sansevieria species that have been investigated so far; the main biological activities are also reported. Compounds found in each species have been divided according to the plant organ from which they have been isolated. The literature has been retrieved from the databases Reaxys and Google Scholar until February 2020. A few papers written in Chinese (see reference [8]) could not be reviewed.

Dracaena usambarensis Engl. (synonym for Dracaena mannii Baker)
The plant is distributed from Senegal to Angola along the African west coast; it is widespread in tropical Africa and grows along the African east coast from Kenya to Kosi Bay in northern KwaZulu-Natal. Separation of a root extract afforded 4,4′-dihydroxy-2,3-dimethoxydihydrochalcone, the homoisoflavonoid 7-O-methyl-8-demethoxy-3-hydroxy-3,9-dihydropunctatin, and the homoisoflavanones 99 and (3S)-3,5,6,4′-tetrahydroxy-7-methoxyhomoisoflavanone (structure 104 in Figure 16) [76]. Compound 104 showed moderate cytotoxic effects against drug sensitive human lymphoblastic leukemia CCRF-CEM T cells; instead, it was inactive against all the other tested cell lines, including leukemia (CEM/ADR5000), human breast adenocarcinoma (MDA-MB-231-pcDNA3 and MDA-MB-231-BCRP clone 23), human glioblastoma (U87.MG and the resistant subline U87.MGΔEGFR), human hepatocyte carcinoma (Hep G2), and healthy hepatocyte (AML12) cell lines [76].  The bioactivities of loureirin B (94) are worthy of note. The compound can modulate the TTX-R sodium channel in DRG neurons via an AC/cAMP/PKA pathway that involves the activation of AC and PKA [73]. Another study confirmed that compound 94 promotes insulin secretion and lowers blood glucose level mainly through increasing mRNA level of Pdx-1, MafA, and intracellular ATP level, and inhibiting KATP current and influx of intracellular Ca 2+ [74]. Experiments on Crohn's disease (CD) rat model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) indicated that loureirin B (94) can be beneficial for ameliorating the damage to colon length in a dose dependent manner. Moreover, loureirin B remarkably ameliorated TNBS-induced inflammatory response via regulation of cytokines in the colonic tissues, and inhibited apoptosis through regulation of IL-6/STAT3/NF-κB signaling pathway. This finding may represent a novel approach to treat CD and provides an alternative choice for disorders associated with CD [70]. Homoisoflavans 69 and 7,10-dihydroxy-11methoxydracaenone (structure 103 in Figure 15) were isolated from a CHCl3 extract of the plant. They were inactive against S. aureus, Bacillus subtilis, and Escherichia coli (MIC > 250 μg/mL) [75].   It is worth noting that the names cochinchinenenes G and H, at first attributed to compounds 67 and 62, respectively [44], were later also used for naming "compounds" 68 and 34, respectively [42].
The bioactivities of loureirin B (94) are worthy of note. The compound can modulate the TTX-R sodium channel in DRG neurons via an AC/cAMP/PKA pathway that involves the activation of AC and PKA [73]. Another study confirmed that compound 94 promotes insulin secretion and lowers blood glucose level mainly through increasing mRNA level of Pdx-1, MafA, and intracellular ATP level, and inhibiting K ATP current and influx of intracellular Ca 2+ [74]. Experiments on Crohn's disease (CD) rat model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) indicated that loureirin B (94) can be beneficial for ameliorating the damage to colon length in a dose dependent manner. Moreover, loureirin B remarkably ameliorated TNBS-induced inflammatory response via regulation of cytokines in the colonic tissues, and inhibited apoptosis through regulation of IL-6/STAT3/NF-κB signaling pathway. This finding may represent a novel approach to treat CD and provides an alternative choice for disorders associated with CD [70]. Homoisoflavans 69 and 7,10-dihydroxy-11-methoxydracaenone (structure 103 in Figure 15) were isolated from a CHCl 3 extract of the plant. They were inactive against S. aureus, Bacillus subtilis, and Escherichia coli (MIC > 250 µg/mL) [75].

Colorants of Dragon's Blood Resins
Different red colorants, namely, dracaenin A (79) [42,54] (Figure 12), nordrachorhodin (105), dracorhodin (106), dracoflavilium (107/108), and dracorubin (109) (Figure 17), have been isolated from dragon's blood resins obtained from different Dracaena trees [79]. The compounds share a common chromophore constituted by three conjugated rings forming a 2-phenyl-1-benzopyran moiety. These compounds undergo multiple structural transformations in aqueous acidic and basic solution, following the same basic mechanisms, that were completely characterized in the case of 7,4′dihydroxy-5-methoxyflavilium, called dracoflavilium (107/108) [79]. This colorant was isolated from a resin extracted from D. draco centenary trees existing in the region of Lisbon and Madeira island; the structure was confirmed by total synthesis [79]. Dragon's blood is yellow in strongly acidic aqueous solutions, because the species present is the flavylium cation 108. At moderately acidic pH values, the red quinoid base 107 is formed which absorbs at about 550 nm. This base is the major species (63%) at biological pH (ca. 6) and gives the resin the characteristic red color (Figure 1a). The remaining species (37%) in the equilibrium is the pale-yellow (E)-chalcone 110. Ionized (E)-chalcone 111 and the predominant pink deprotonated quinoid base 112 are present at pH = 8-9, whereas the double deprotonated base 113 is the only species occurring at pH = 12 ( Figure 18) [79].  These compounds undergo multiple structural transformations in aqueous acidic and basic solution, following the same basic mechanisms, that were completely characterized in the case of 7,4 -dihydroxy-5-methoxyflavilium, called dracoflavilium (107/108) [79]. This colorant was isolated from a resin extracted from D. draco centenary trees existing in the region of Lisbon and Madeira island; the structure was confirmed by total synthesis [79]. Dragon's blood is yellow in strongly acidic aqueous solutions, because the species present is the flavylium cation 108. At moderately acidic pH values, the red quinoid base 107 is formed which absorbs at about 550 nm. This base is the major species (63%) at biological pH (ca. 6) and gives the resin the characteristic red color (Figure 1a). The remaining species (37%) in the equilibrium is the pale-yellow (E)-chalcone 110. Ionized (E)-chalcone 111 and the predominant pink deprotonated quinoid base 112 are present at pH = 8-9, whereas the double deprotonated base 113 is the only species occurring at pH = 12 ( Figure 18) [79].

Colorants of Dragon's Blood Resins
Different red colorants, namely, dracaenin A (79) [42,54] (Figure 12), nordrachorhodin (105), dracorhodin (106), dracoflavilium (107/108), and dracorubin (109) (Figure 17), have been isolated from dragon's blood resins obtained from different Dracaena trees [79]. The compounds share a common chromophore constituted by three conjugated rings forming a 2-phenyl-1-benzopyran moiety. These compounds undergo multiple structural transformations in aqueous acidic and basic solution, following the same basic mechanisms, that were completely characterized in the case of 7,4′dihydroxy-5-methoxyflavilium, called dracoflavilium (107/108) [79]. This colorant was isolated from a resin extracted from D. draco centenary trees existing in the region of Lisbon and Madeira island; the structure was confirmed by total synthesis [79]. Dragon's blood is yellow in strongly acidic aqueous solutions, because the species present is the flavylium cation 108. At moderately acidic pH values, the red quinoid base 107 is formed which absorbs at about 550 nm. This base is the major species (63%) at biological pH (ca. 6) and gives the resin the characteristic red color (Figure 1a). The remaining species (37%) in the equilibrium is the pale-yellow (E)-chalcone 110. Ionized (E)-chalcone 111 and the predominant pink deprotonated quinoid base 112 are present at pH = 8-9, whereas the double deprotonated base 113 is the only species occurring at pH = 12 ( Figure 18) [79].

Sansevieria roxburghiana
The homoisoflavanone (-)-(3R)-cambodianol (20) was claimed to have been isolated from a MeOH extract of S. roxburghiana [86]. However, recent careful examination of the NMR spectra of the compound led to a revision of the structure. In fact, the correct structure corresponds to that of compound 125 (Figure 20), that is the enantiomer of homoisoflavanone 119 isolated from S. cylindrica [82,83]. compound led to a revision of the structure. In fact, the correct structure corresponds to that of compound 125 (Figure 20), that is the enantiomer of homoisoflavanone 119 isolated from S. cylindrica [82,83].  (Figure 21), from the EtOAc soluble fraction of a methanol extract of S. trifasciata [87]. Dihydrochalcone (+)-(8S)-trifasciatine C (114) was isolated from the aerial parts [88].
Among flavonoid families, dihydrochalcones, flavans, homoisoflavans, meta-homoisoflavans, and oligomers appear to be diagnostic chemical clusters in Dracaena species. Loureins A (36) and B (37) are often used as the chemical markers for the quality control of dragon's blood.
In contrast to the wide variety of Dracaena flavonoids, the chemical families mostly occurring in Sansevieria species are only flavones (e.g., 121) and homoisoflavanones (e.g., 116). This finding may depend on the fact that, compared with Dracaena species, less phytochemical studies have been  (Figure 21), from the EtOAc soluble fraction of a methanol extract of S. trifasciata [87]. Dihydrochalcone (+)-(8S)-trifasciatine C (114) was isolated from the aerial parts [88]. compound led to a revision of the structure. In fact, the correct structure corresponds to that of compound 125 (Figure 20), that is the enantiomer of homoisoflavanone 119 isolated from S. cylindrica [82,83].  (Figure 21), from the EtOAc soluble fraction of a methanol extract of S. trifasciata [87]. Dihydrochalcone (+)-(8S)-trifasciatine C (114) was isolated from the aerial parts [88].
Among flavonoid families, dihydrochalcones, flavans, homoisoflavans, meta-homoisoflavans, and oligomers appear to be diagnostic chemical clusters in Dracaena species. Loureins A (36) and B (37) are often used as the chemical markers for the quality control of dragon's blood.
In contrast to the wide variety of Dracaena flavonoids, the chemical families mostly occurring in Sansevieria species are only flavones (e.g., 121) and homoisoflavanones (e.g., 116). This finding may depend on the fact that, compared with Dracaena species, less phytochemical studies have been
Among flavonoid families, dihydrochalcones, flavans, homoisoflavans, meta-homoisoflavans, and oligomers appear to be diagnostic chemical clusters in Dracaena species. Loureins A (36) and B (37) are often used as the chemical markers for the quality control of dragon's blood.
In contrast to the wide variety of Dracaena flavonoids, the chemical families mostly occurring in Sansevieria species are only flavones (e.g., 121) and homoisoflavanones (e.g., 116). This finding may depend on the fact that, compared with Dracaena species, less phytochemical studies have been devoted to Sansevieria spp. Moreover, Dracaena flavonoids have mostly been isolated from red resins, while those identified in Sansevieria have been found in extracts of aerial parts and rhizomes. Interestingly, the pterocarpan 124 and the 8-hydroxymethyldihydrochalcones (1,2-seco-homoisoflavanones) 114 and 115, isolated from two Sansevieria spp., are the only examples of such structures occurring in the two groups of plants. In addition to flavones, homoisoflavanones are the only flavonoids isolated from both Sansevieria and Dracaena species, although they display different substitution patterns. In fact, compared with Dracaena homoisoflavanones, the structures of the corresponding derivatives from Sansevieria spp. usually contain more Oand C-alkyl substituents; moreover, a hydroxy group is often bonded to C3. Enantiomeric trifasciatines B (116 and 127) and C (114 and 115), and homoisoflavanones 119 and 125 are examples of antipodal congeners occurring in different species of the same genus. More interesting is the isolation of enantiomeric compounds from different parts of the same plant. Thus, (+)-(8S)-trifasciatine C (114) was isolated from aerial parts of S. cylindrica [80], while the (8R)-enantiomer (115) was isolated from rhizomes [82]. Two different biosynthetic routes have been proposed to explain the formation of such antipodal flavonoids. Enantiodivergent biosynthetic reactions are involved that stem from achiral intermediates [82,87]. The isolation of homoisoflavonoids appears to have chemotaxonomic significance, because the largest number have been associated with Asparagaceae, Fabaceae and, to a minor extent, Liliaceae and Orchidaceae families [89].

Conclusions
The field of natural product chemistry has greatly contributed to the progress of pharmacology and medicine. The wide range of bioactive compounds isolated from different plants still motivate many research groups worldwide to find new bioactive constituents and to determine their structures and biological activities. In this review we have reported the most characteristic structures and bioactivities of flavonoids and stilbenes isolated from Dracaena and Sansevieria species. These plants have revealed to be rich sources of compounds having unprecedented structures and exhibiting a wide range of biological and pharmacological properties. More attention has been devoted to Dracaena than Sansevieria flavonoids, possibly due to the very well-known effects of the red resin dragon's blood, that is collected from some Dracaena species and is widely used in several Asian traditional medicines. Indeed, the number and diversity of flavonoids isolated from Dracaena dragon's blood are impressive, encompassing a great number of chemical families. In addition, the potential therapeutic effects of the drug and individual constituents on different diseases are attractive, such as the remarkable activities on cardiovascular, inflammatory, and cerebrovascular diseases. However, more in vitro and in vivo scientific experiments must be programmed and carried out before the effective material may be qualified as a suitable candidate for clinical trials.
Compared to the phytochemical investigations conducted on Dracaena spp., those concerning Sansevieria species are less numerous and isolated flavonoids are chemically less diverse. However, the structural similarities of flavonoids isolated from Sansevieria and Dracaena plants seem to justify, on a chemotaxonomic basis, the recent inclusion of Sansevieria species inside the genus Dracaena.