Sea Cucumber Glycosides - MDPI

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Sea Cucumber Glycosides: Chemical Structures, Producing Species and Important Biological Properties Muhammad Abdul Mojid Mondol 1 , Hee Jae Shin 2, *, M. Aminur Rahman 3 and Mohamad Tofazzal Islam 4, * 1 2 3 4

*

School of Science and Technology, Bangladesh Open University, Board Bazar, Gazipur 1705, Bangladesh; [email protected] Marine Natural Products Laboratory, Korea Institute of Ocean Science and Technology, 787 Haeanro, Ansan 427-744, Korea World Fisheries University Pilot Programme, Pukyong National University (PKNU), 45 Yongso-ro, Nam-gu, Busan 48513, Korea; [email protected] Department of Biotechnology, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur 1706, Bangladesh Correspondence: [email protected] (H.J.S.); [email protected] (M.T.I.); Tel.: +82-31-400-6172 (H.J.S.); +880-2920-5310-14 (ext. 2252) (M.T.I.); Fax: +82-31-400-6170 (H.J.S.); +880-2920-5333 (M.T.I.)

Received: 27 June 2017; Accepted: 11 October 2017; Published: 17 October 2017

Abstract: Sea cucumbers belonging to echinoderm are traditionally used as tonic food in China and other Asian countries. They produce abundant biologically active triterpene glycosides. More than 300 triterpene glycosides have been isolated and characterized from various species of sea cucumbers, which are classified as holostane and nonholostane depending on the presence or absence of a specific structural unit γ(18,20)-lactone in the aglycone. Triterpene glycosides contain a carbohydrate chain up to six monosaccharide units mainly consisting of D-xylose, 3-O-methy-D-xylose, D-glucose, 3-O-methyl-D-glucose, and D-quinovose. Cytotoxicity is the common biological property of triterpene glycosides isolated from sea cucumbers. Besides cytotoxicity, triterpene glycosides also exhibit antifungal, antiviral and hemolytic activities. This review updates and summarizes our understanding on diverse chemical structures of triterpene glycosides from various species of sea cucumbers and their important biological activities. Mechanisms of action and structural–activity relationships (SARs) of sea cucumber glycosides are also discussed briefly. Keywords: holostane; nonholostane; cucumarioside; cytotoxic; antifungal; glycosides

1. Introduction Nature is the largest source of pharmaceutical lead drugs for the remedies of many diseases. Earlier scientists mainly focused on terrestrial samples (plants and microorganisms) for the discovery of lead bioactive compounds. With the passage of time, the search for new drugs or agrochemicals has been switching from land to ocean due to re-isolation of known natural products from terrestrial samples. Marine organisms produce diversified bioactive compounds because of large species biodiversities and living in extremely harsh environment. Among so many sources, numerous bioactive metabolites have been isolated from marine invertebrates such as echinoderms with a broad spectrum of biological activities [1]. The echinoderms are divided into five classes, i.e., Holothuroidea (sea cucumbers), Asteroidea (starfishes), Echinoidea (sea urchins), Crinoidea (sea lilies), and Ophiuroidea (brittle stars and basket stars), which live exclusively in the marine habitat, distributed in almost all depths and latitudes, as well as reef Mar. Drugs 2017, 15, 317; doi:10.3390/md15100317

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environments or shallow shores [2,3]. The importance of these echinoderms as a potential source of bioactive compounds for the development of new therapeutic drugs/agrochemicals has been growing rapidly [1]. Compounds isolated from echinoderms showed numerous biological activities including antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, anti-tuberculosis, anti-inflammatory, antitumor, and antiviral activities [1]. Sea cucumber traditionally has been used as tonic food in China and other Asian countries for thousands of years. Besides being used as food, sea cucumbers are also promising source of bioactive natural products which predominantly belong to triterpene glycosides exhibiting antifungal, cytotoxic, hemolytic, cytostatic, and immunomodulatory and antiviral activities [4]. Several monographs concerning the structures and biological properties of triterpene glycosides obtained from sea cucumbers have been published but not presented in a systematic way [5,6]. This report comprehensively reviews in depth structural features of sea cucumber glycosides with corresponding producing species. Important biological activities, mechanism of action, and structure–activity relationships (SARs) of the diverse glycosides produced by the different species of sea cucumber are also discussed briefly. 2. Taxonomy, Distribution and Nutritive Value of Sea Cucumbers One of the predominant invertebrate lives in marine environment is sea cucumber, which belong to the class Holothuroidea under the phylum Echinodermata. Holothuroidea has been divided into three subclasses, Aspidochirotacea, Apodacea and Dendrochirotacea, and further into six orders, Apodida, Elasipodida, Aspidochirotida, Molpadida, Dendrochirotida and Dactylochirotida [7]. Majority of the harvestable species of sea cucumbers belong to three families, viz., Holothuriidae (genera Holothuria and Bohadschia), Stichopodidae (genera Stichopus, Actinopyga, Thelenota, Parastichopus and Isostichopus), and Cucumariidae (genus Cucumaria) [8]. Sea cucumbers are elongated tubular or flattened soft-bodied marine benthic invertebrates, typically with leathery skin, ranging in length from a few millimeters to a meter [9]. Holothuroids encompass 14,000 known species occur in most benthic marine habitats worldwide, in both temperate and tropical oceans, and from the intertidal zone to the deep sea, and are considered as the very important parts of oceanic ecosystem [10]. Economically, sea cucumbers are important in two reasons: first, some species produce triterpene glycosides that are interested to pharmaceutical companies finding their medical use and second, use as food item. About 70 species of sea cucumbers have been exploited worldwide; out of which 11 species have been found to be commercially important [11]. Sea cucumbers have been well recognized as a tonic and traditional remedy in Chinese and Malaysian literature for their effectiveness against hypertension, asthma, rheumatism, cuts and burns, impotency and constipation [12,13]. Nutritionally, sea cucumbers have an impressive profile of valuable nutrients such as vitamin A, vitamin B1 (thiamine),vitamin B2 (riboflavin), vitamin B3 (niacin), and minerals, especially calcium, magnesium, iron and zinc [14,15]. 3. Extraction, Purification and Characterization To extract glycosides, first sea cucumbers will be freeze dried, then cut into pieces and extracted twice with refluxing EtOH. The combined extracts will be concentrated under reduced temperature and the residue will be dissolved in H2 O. Desalting will be carried out by passing this fraction through a Polychrom column (Teflon), eluting first the inorganic salts and crude polar impurities with H2 O and then the glycosides fraction with 50% EtOH. The fraction will be sub-fractionated by silica gel column chromatography using suitable gradient solvent system. The glycosides from each sub-fraction can be purified by reverse phase HPLC developing suitable solvent system (MeOH-H2 O). Triterpene glycosides have two parts: carbohydrate and triterpene. The number of monosaccharide units present in the carbohydrate chain can be deduced by observing the number of anomeric carbons (~103 ppm) and protons (~5 ppm, d) resonances in 13 C and 1 H NMR spectra, respectively. The sequence

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of monosaccharide units in the carbohydrate chain can be established by the analysis of anomeric H/C correlations in the HMBC spectrum which can also be confirmed by NOE corrections between anomeric protons and MALDI-TOF mass spectroscopic data analysis. The position of attachment of glycone with aglycone can be confirmed by the HMBC experiment. The presence of diverse types of monosaccharide units and their repetitions in the carbohydrate chain can be established by acid hydrolysis followed by GC-MS analysis of the corresponding aldononitrile peracetates [16]. The site of attachment of sulfate group at monosaccharide units can be determined by observing chemical shift of esterification carbon atoms. The chemical shifts of α (esterification) and β-carbons are shifted ~5 ppm downfield and ~2 ppm up field, respectively, compare to their corresponding nonsulfated derivatives. The structure of the aglycone can be established based on its spectroscopic data (1 H NMR, 13 C NMR, COSY, HMBC, HSQC, and TOCSY) and by comparing with the literature data. Configuration can be determined by the analysis of NOE data, stable conformers, coupling constants and comparing chemical shifts of chiral centers with literature. 4. Structural Features of Triterpene Glycosides Isolated from Sea Cucumbers Triterpene glycosides, also known as holothurins or saponins, are secondary metabolites typically produced by sea cucumbers (class Holothuroidea). These glycosides are amphiphilic in nature having two parts: aglycone (lipophilic, lipid-soluble) and glycone (hydrophilic, water-soluble). The majority of the glycosides contain so called holostane type aglycone comprise of lanostane-3β-ol with a γ(18,20)-lactone in the E-ring of the pentacyclic triterpene [(3β,20S-dihydroxy-5α-lanostanoγ(18,20)-lactone] (Figure 1). A few of the glycosides contain nonholostane type aglycone which do not have γ(18,20)-lactone in the tetracyclic triterpene. The glycone parts may contain up to six monosaccharide units covalently connected to C-3 of the aglycone. The sugar moieties mainly consist of D-xylose (Xyl), D-quinovose (Qui), D-glucose (Glc), 3-O-methyl-D-glucose (MeGlc), 3-O-methyl-D-xylose (MeXyl) (Figure 2) and sometimes 3-O-methyl-D-quinovose (MeQui), 3-O-methyl-D-glucuronic acid (MeGlcA) and 6-O-acetyl-D-glucose (AcGlc). In the carbohydrate chain, the first sugar unit is always a xylose and a majority case second is quinovose, whereas 3-O-methyl-D-glucose and/or 3-O-methyl-D-xylose are always the terminal monosaccharide units. The presence of two quinovose residues in a carbohydrate chain is unique for sea cucumber and starfish glycosides. In glycone part, the sugar units are generally arranged in a straight or branched chain (Figure 3). The majority of tetrasaccharides show a linear chain with the most common 3-O-Me-Glc-(1→3)-Glc-(1→4)-Qui-(1→2)-Xyl. Hexaglycosides are generally nonsulfated with a linear 3-O-Me-Glc (1→3)-Glc (1→4)-Xyl (2→1)-Qui (4→1)-Glc (3→1)-3-O-MeGlc unit. Pentasaccharides have a linear chain like tetrasaccharides but a branching at C-2 of quinovose (Figure 3). Sixty percent of the triterpene glycosides isolated so far from sea cucumbers have sulfate groups linked to the monosaccharide units of the carbohydrate chain. Most of them are monosulfsated, but many di- and trisulfated glycosides have also been isolated. Most tetrasaccharides and pentasaccharides are sulfated at C-4 of xylose unit. In both the cases, additional sulfate groups at C-6 of the 3-O-methylglucose and glucose units have also been found. The term “Ds” stands for desulfated. Sea cucumber triterpene glycosides are chemotaxonomic markers specific for groups of genera within each family.

Sixty percent of the triterpene glycosides isolated so far from sea cucumbers have sulfate groups linked to the monosaccharide units of the carbohydrate chain. Most of them are monosulfsated, but many di- and trisulfated glycosides have also been isolated. Most tetrasaccharides and pentasaccharides are sulfated at C-4 of xylose unit. In both the cases, additional sulfate groups at C-6 of the 3-O-methylglucose and glucose units have also been found. The term Mar. Drugs 2017, 317 for desulfated. Sea cucumber triterpene glycosides are chemotaxonomic markers “Ds”15, stands specific for groups of genera within each family. 21 18 19

1

11 9

10

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4 30

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20S-hydroxy-5α-lanostano-γ(18,20)-lactone (Holostane)

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C 13 H D

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26 20

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3β,20S-dihydroxy-5α-lanostano-γ(18,20)-lactone (Holostanol)

Figure 1. Structures of lanostane, holostane and holostanol.

Figure 1. Structures of lanostane, holostane and holostanol.

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HO HO O OH HO O OH O OH HO HO HO O OH MeO O OH HO HO O OH HO HO HO HO OH OH OH HO MeO HO D-xylose D-glucose 3-O-methyl-D-glucose OH OH Mar. Drugs 2017, 15, 317 OH D-xylose D-glucose 3-O-methyl-D-glucose

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O OH O OH HO O OH HO MeO O OH HO HO HO OH OH MeO HO 3-O-methyl-D-xylose OH D-quinovose OH 4 of 35 3-O-methyl-D-xylose D-quinovose

Figure 2. Common sugar units present in sea cucumber glycosides.

FigureFigure 2. HO Common sugar units present in sea cucumber glycosides. 2. Common sugar units present in sea cucumber glycosides.

HO HO MeGlc HO HO 6

O OH O OH O OH O OH HO OH HO HO HO Glc MeO MeO1 Xyl HO HO 1 O HO 5 HO 5 1 O O O HOOH O OH MeGlc O Glc OH HO OH OH Xyl HO HO O O 6 5 O HO HO 1 O O HOD-glucose HO 5 O MeO HO D-xylose O HO 1 O O HO 3 D-quinovose 3-O-methyl-D-glucose O HO O HO 1 3-O-methyl-D-xylose OH HO 4 O OH OH 2 O OO O HO HO HO O O O O

OO O HO HO O O HO HO 3 OH HO 2 HO 3 OH HO 2 HO HO HO 4 O 3O O HO 4 2 O O O MeO O O HO O OOH O OHO O HO OH HO OH HO O in sea cucumber O HO O O5 O O 2. Common sugar units present glycosides. O 3 Figure 3 HO HO 4 O HO 2 O 2 O MeO O HO MeO O HO O HO O O HO HO OH OH OH OH OH HO OH OH HO OH O O Glc Qui O HO 5 O O O HO OH HO 1 O OH HO 1 OMeO OH OH HO 3 1 O OH MeGlc Glc Glc OH HO Qui OH O HO HO Xyl MeGlc HO 1 O O HO 5 1 O O HO 6 5O O OH 3 HO 1 1 HO HO HO HO O HO HO 3O O O O 1 O 1 OO HO HO O 4 HO HO OH 2 HO HO 2 O OO HO HO HO O O OO O O O O 2O O O O HO HO HO O O O O HO O HO OHO MeO HO HO HO HO 4 HO HO 3 3 HO HO HO OH OH HO HO O 4 OH HO 2 OO O OH OH 2O O 2 O OOHO O MeO O HO HO O HO 2 O O HO HO OH O OH OH O HO O HO OH 4 HO O 3 3 OH HO HO 4 HO 2 O HO HOO OH MeO O HO O MeO O HO O O OH HO 2 O HO OH HO OH HO O HO OH OH HO O OH 5 O O O OH O MeO MeO HO HO OH OH HO OH OH OH OH Figure 3. Some common carbohydrate architectures found in sea cucumber glycosides. Glc Qui HO MeGlc 1 O carbohydrate HO 3 architectures Figure 3. Some common in sea 1cucumber glycosides.OH O 1 O found HO O HO Figure 3. Some common carbohydrate architectures found in sea cucumber glycosides. HO O O O O HO can be classified HO 3 Triterpene glycosides as holostaneO type HO having HO HO HO 4 OH HO 2O O 2 O O3β-hydroxy-5α-lanostanoO O O HO 2 O O HO HO O HO Triterpene Oglycosides can be and classified as type having 3β-hydroxy-5α-lanostanoHO holostane OH but have γ(18,20)-lactone structural feature nonholostane type do not have a γ(18,20)-lactone MeO HO HO HO OH OH OH OH OH γ(18,20)-lactone structural feature and nonholostane type do not have a γ(18,20)-lactone but have MeO HO 4 HO HO 4 MeO HO MeGlc MeO

other structural features likebe holostane type glycosides. Triterpene glycosides can classified as holostane type having 3β-hydroxy-5α-lanostanoother structural like holostane type glycosides. Figurefeatures 3. Some common architectures found in sea cucumber glycosides. γ(18,20)-lactone structural feature andcarbohydrate nonholostane type do not have a γ(18,20)-lactone but have other 4.1. Holostane Type Triterpene Glycosides structural 4.1. features like holostane type glycosides. Holostane Type Triterpenecan Glycosides Triterpene glycosides be classified as holostane type having 3β-hydroxy-5α-lanostanoDepending on the position of double bond in the B and C ring of the aglycone (Figure 1), γ(18,20)-lactone featureofand nonholostane typeB do notC have but have Depending structural on the position double bond in the and ring aofγ(18,20)-lactone the aglycone (Figure 1),

holostane type glycosides can be further subdivided into three groups: glycosides with 4.1. Holostane Type Triterpene Glycosides other structural like 3β-hydroxyholost-9(11)-ene, holostane glycosides. holostane type features glycosides can be type further subdivided three groups: glycosides with 3β-hydroxyholost-7(8)-ene, andinto 3β-hydroxyholost-8(9)-ene aglycone 3β-hydroxyholost-7(8)-ene, 3β-hydroxyholost-9(11)-ene, 3β-hydroxyholost-8(9)-ene aglycone(Figure 1), skeletons.on There are eight pentacyclic triterpene and 30 and alkane side chain aglycone architectures Depending the position of double bond in the B and C ring of the aglycone 4.1. Holostane Type Triterpene Glycosides triterpene and 30 alkane side chain aglycone architectures skeletons. There eight pentacyclic commonly foundare in holostane type glycosides (Figure 4). In these architectures, certain functional holostane commonly type glycosides can be further subdivided intoarchitectures, three groups: glycosides with holostane glycosides (Figure In these certain functional Depending oninthe positiontype double bond in the4).B and C ring of the groups aglycone 1), groups are found generally attached toofthe specific carbons: keto and β-acetoxy at (Figure C-16, and 3β-hydroxyholost-7(8)-ene, 3β-hydroxyholost-9(11)-ene, and 3β-hydroxyholost-8(9)-ene groups are generally attached to the specific carbons: keto and β-acetoxy groups at C-16, and aglycone holostane type glycosides α-hydroxy group at C-12 and can C-17.be further subdivided into three groups: glycosides with α-hydroxy group at C-12 and3β-hydroxyholost-9(11)-ene, C-17. triterpene and 30 skeletons.3β-hydroxyholost-7(8)-ene, There are eight pentacyclic alkane side chain aglycone architectures and 3β-hydroxyholost-8(9)-ene aglycone 21 skeletons. There are eight pentacyclic triterpene and 30 alkane side chain aglycone architectures commonly found in holostane (Figure 4). InOthese certain functional O O architectures, O 21 type glycosides O O O O commonly found type glycosides (Figure 4). In these certain functional 18 holostane 20 O architectures, O in O O to O carbons: O at C-16, O O groups are generally11attached the specific keto and β-acetoxy groups and α-hydroxy 17 20 groups are generally attached to the specific carbons: keto and β-acetoxy groups at C-16, and 13 18 1 16 9 17 11 group at C-12 and C-17. 13at C-12 and C-17. α-hydroxy group O O 21 O 3 O 31 6 O 32 O 4 I 30 Sugar O O 18 20 31 Sugar I O Sugar 30 11 HO 13 O 17 Sugar O 1 O16 9 HO O 10 8 3

3

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O Sugar O Sugar Sugar

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OH OAc OH O III Sugar O O O VII O HO Sugar VII Sugar (a) OH

(a) O Sugar

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O Sugar

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O O O Sugar Sugar OH OH O O O Sugar O O Sugar Sugar OH

O O

IV O IV O HO O HO

(a)

Figure 4. Cont.

O Sugar

O O O

IV O VIII HO VIII

OH OH OAc OAc

O OH OAc

O VII

O

VIII

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OH OAc

OAc OnBu

OEt

OH

OH

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OH

OAc

OAc

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OAc

O

OAc (b)

Figure 4. Pentacyclic triterpene and alkane side chain skeletons are commonly found in holostane

Figure 4. type Pentacyclic triterpene and alkane side chain skeletons are commonly found in holostane glycosides. (a) Pentacylic triterpene skeletons. Substitution by selective functional groups and type glycosides. (a) Pentacylic Substitution by selective groups and unsaturation generally taketriterpene place in theskeletons. alkane side chain (2-methylpentane) attachedfunctional to C-20 of the E-ring of aglycone. (b) Alkane sidethe chain architectures. unsaturation generally take place in alkane side chain (2-methylpentane) attached to C-20 of the E-ring of aglycone; (b) Alkane side chain architectures. 4.1.1. 3β-Hydroxyholost-7(8)-ene Skeleton Containing Holostane Glycosides

Substantial number of triterpene glycosides in this category is produced by sea cucumbers. The 4.1.1. 3β-Hydroxyholost-7(8)-ene Skeleton Containing Holostane Glycosides

species Eupentacta fraudatrix, Holothuria lessoni, Bohadschia marmorata, Stichopus chloronotus and Staurocucumis liouvillei mostglycosides of the compounds in category this group. is Forproduced convenience,by thesea large Substantial number of produce triterpene in this cucumbers. number of compounds in this category can be further subdivided into four groups depending on species Eupentacta fraudatrix, Holothuria lessoni, Bohadschia marmorata, Stichopus chloronotus and the number of sugar units.

The Staurocucumis liouvillei produce most of the compounds in this group. For convenience, the large Glycosides with 3β-Hydroxyholost-7(8)-ene Skeleton and Six Sugar Units number ofHolostane compounds in this category can be further subdivided into four groups depending on the number of sugar The units. name of the compounds in this group, their producing species, chemical structures and references are summarized in Table 1 and Figure 5. The most common features of glycosides in this are the presence of α-acetoxy group at C-23,Skeleton double bond C-25(C-26) and terminal Holostanecategory Glycosides with 3β-Hydroxyholost-7(8)-ene andatSix Sugar Units 3-O-methyl-D-glucose in carbohydrate chain. An interesting point to be noted in here is that the

The name of theis compounds group, their producing species, chemical structures and sulfate group totally absent inin thisthis group of compounds. references are summarized in Table 1 and Figure 5. The most common features of glycosides in Table 1. Name and producing species of glycosides with 3β-hydroxyholost-7(8)-ene and sixs ugar this category units. are the presence of α-acetoxy group at C-23, double bond at C-25(C-26) and terminal 3-O-methyl-D-glucose in carbohydrate chain. An interesting point to be noted in here is that the sulfate Compound Name Producing Species Reference Compound Name Producing Species Reference group is totally absent in thisThelenota groupanax of compounds. Stichoposide C (1) Stichoposide D (2) [17] Thelenota anax [18] Stichoposide E (3)

Stichopus chloronotus

[19]

Stichloroside A1 (4)

S. chloronotus

[20]

(5) Stichloroside B1 (6) A2 producing S. chloronotus [20] S. chloronotus Table Stichloroside 1. Name and species of glycosides with 3β-hydroxyholost-7(8)-ene and sixs[20] ugar units.

Stichloroside B2 (7) S. chloronotus Stichloroside C2 (9) S. chloronotus Compound Name ProducingS.Species Synallactoside B1 (11) nozawai Holotoxin S. japonicus Stichoposide C (1) E (13) Thelenota anax

Stichoposide E (3) Stichloroside A2 (5) Stichloroside B2 (7) Stichloroside C2 (9) Synallactoside B1 (11) Holotoxin E (13)

Stichopus chloronotus S. chloronotus S. chloronotus S. chloronotus S. nozawai S. japonicus

[20] [20] Reference [16] [22] [17]

[19] [20] [20] [20] [16] [22]

Stichloroside C1 (8) S. chloronotus [20] Synallactoside A2 (10) Synallactes nozawai [16] Compound Name Producing Species Variegatuside F (12) S. variegates [21]

Stichoposide D (2) Stichloroside A1 (4) Stichloroside B1 (6) Stichloroside C1 (8) Synallactoside A2 (10) Variegatuside F (12)

Thelenota anax S. chloronotus S. chloronotus S. chloronotus Synallactes nozawai S. variegates

Reference [18] [20] [20] [20] [16] [21]

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O

1 Stichoposide C R1 = CH3, R2 = H, R3 = CH2OH 2 Stichoposide D R1 = R3=CH2OH, R2 = H 3 Stichoposide E R1 = H, R2 = R3 = CH2OH R3

HO MeO HO HO MeO

6

4

HO 5 O HO O OH R2 3 O HO O OH

O

O O O OH HO O R1 2 O O O OHHO OH

O

23

25

H OAc 16 7

1

H

4 Stichloroside A1 R1 = H, R2 = CH2OH, R3 = CH2OH 5 Stichloroside A2 R1 = H, R2 = CH2OH, R3 = CH2OH, Δ25(26) 6 Stichloroside B1 R1 = CH2OH, R2 = H, R3 = CH2OH 7 Stichloroside B2 R1 = CH2OH, R2 = H, R3 = CH2OH, Δ25(26) 8 Stichloroside C1 R1 = CH3, R2 = H, R3 = CH2OH 9 Stichloroside C2 R1 = CH3, R2 = H, R3 = CH2OH, Δ25(26) 10 Synallactoside A2 R1 = CH3, R2 = H, R3 = H, Δ25(26) 11 Synallactoside B1 R1 = CH3, R2 = CH3OH, R3 = H, Δ25(26)

12 Variegatuside F R1=R3=CH2OH, R2=H, 2313 Holotoxin E R1=CH3, R2=H, R3=CH2OH, 16-

OH instead of OAc O, 23-H instead of OAc, sugar unit 6=Glc, Δ25(26)

Figure 5. 5. Chemical Chemical structures structures of of holostane holostane glycosides with 3β-hydroxyholost-7(8)-ene and six sugar units.

Holostane Glycosides Glycosides with with 3β-Hydroxyholost-7(8)-ene 3β-Hydroxyholost-7(8)-ene Skeleton Skeleton and and Five Five Sugar Sugar Units Units Holostane The name name of of the the compounds compounds in in this this group, group, their their producing producing species, species, chemical chemical structures structures and and The references are aresummarized summarizedininTable Table 2 and Figure 6. The common structural features this references 2 and Figure 6. The mostmost common structural features in thisin group group are the sulfate groups at C-4 of xylose and C-6 of glucose and methylglucose with either are the sulfate groups at C-4 of xylose and C-6 of glucose and methylglucose with either β-acetoxy β-acetoxy or keto groupand at C-16 and C-25(26) doubleAbond. quite number of compounds contain or keto group at C-16 C-25(26) double bond. quiteAnumber of compounds contain a ketoa keto group at C-23.The rare structural of triterpene glycoside are the of group at C-23.The rare structural features features of triterpene glycoside are the presence of presence 16,22-epoxy 16,22-epoxy group (33), ethoxy group (29) and methylglucuronic acid (51). Cucumarioside A 1-2 (17) group (33), ethoxy group (29) and methylglucuronic acid (51). Cucumarioside A1 -2 (17) is the is theexample only example of triterpene glycosides containing an acetate the terminal only of triterpene glycosides containing an acetate groupgroup at C-6atofC-6 theofterminal sugarsugar unit. unit. Carbohydrate chain can be one branched (14–48 and52–54) or straight (49–51). Carbohydrate chain can be one branched (14–48 and 52–54) or straight (49–51). 3-O-methyl-D-xylose 3-O-methyl-xylose as a terminal monosaccharide unit feature that is of a characteristic feature of allfrom the as a terminalDmonosaccharide unit that is a characteristic all the glycosides isolated glycosides fraudatrix. isolated from Eupentacta fraudatrix. Eupentacta Table 2. 2. Name Table Name and and producing producing species species of of glycosides glycosides with with 3β-hydroxyholost-7(8)-ene 3β-hydroxyholost-7(8)-eneand andfive fivesugar sugarunits. units. Compound Name Producing Species Reference Compound Name Producing Species Reference Compound Name Producing Species Reference Compound Name Producing Species Reference Cucumarioside A0-1 (14) Cucumaria japonica Cucumarioside A0-2 (15) [23] C. japonica [23] Cucumarioside A0 -1 (14) Cucumaria japonica [23] Cucumarioside A0 -2 (15) C. japonica [23] Cucumarioside A0-3 (16) Cucumarioside A1-2 (17) C. japonica [23] C. japonica [24] Cucumarioside A0 -3 (16) C. japonica [23] Cucumarioside A1 -2 (17) C. japonica [24] 2 -2 (18) Cucumarioside A 2 -3 (19) Cucumarioside A C. japonica [25] C. japonica Cucumarioside A2 -2 (18) C. japonica [25] Cucumarioside A2 -3 (19) C. japonica [24] [24] Cucumarioside (20) C. japonica japonica [24] Cucumarioside A2A -52(21) conicospermium 2-4 Cucumarioside -5 (21) C. C. Cucumarioside AA C. [24] conicospermium [26] [26] 2 -4(20) Cucumarioside (22) C. japonica japonica [24] Cucumarioside A6A -26(23) [27] [27] 4 -2(22) 4-2 Cucumarioside -2 (23) C. japonica Cucumarioside AA C. [24] C. japonica Cucumarioside A7 -1 (24) C. japonica [28] Cucumarioside A7 -2 (25) C. japonica [28] 7-1 (24) Cucumarioside 7-2 (25) Cucumarioside AA C. [28] C. japonica Cucumarioside C. japonica japonica [28] Cucumarioside HA(27) E. fraudatrix [29] [28] 7 -3 (26) -32 (26) Cucumarioside (27) Cucumarioside A7H C. japonica [28] E. fraudatrix Cucumarioside (28) E. fraudatrix [30] Cucumarioside H4 H (29) E. fraudatrix [30] [29] CucumariosideHH (30) fraudatrix [29] Cucumarioside H6H (31) E. fraudatrix [29] [30] 2 5(28) Cucumarioside 4 (29) Cucumarioside E.E.fraudatrix [30] E. fraudatrix Cucumarioside H7 (32) E. fraudatrix [29] Cucumarioside H8 (33) E. fraudatrix [29] 5 (30) Cucumarioside H 6 (31) Cucumarioside H E. fraudatrix [29] E. fraudatrix [29] Cucumarioside I1 (34) E. fraudatrix [31] Cucumarioside I2 (35) E. fraudatrix [32] 7 (32) Cucumarioside H 8 (33) Cucumarioside H E. fraudatrix [29] E. fraudatrix Cucumarioside I3 (36) E. fraudatrix [31] Frondoside A (37) C. frondosa [33] [29] Frondoside BI1(38) frondosa [34] Frondoside A2 -1 (39) C. E. frondosa [35] [32] (34) Cucumarioside I2 (35) Cucumarioside E.C.fraudatrix [31] fraudatrix Frondoside A2 -2 (40) frondosa [35] Frondoside A2 -3 (41) C. frondosa [35] Frondoside A (37) Cucumarioside I3 (36) E.C.fraudatrix [31] C. frondosa [33] Frondoside A2 -4 (42) C. frondosa [36] Calcigeroside C2 (43) P. calcigera [37] 2 -1 (39) Frondoside B (38) Frondoside A C. frondosa C. frondosa [34] Calcigeroside D2 (44) P. calcigera [38] Calcigeroside E (45) P. calcigera [38] [35] Colochiroside (46) anceps [39] Cucumarioside E. fraudatrix [40] [35] Frondoside AC21-3(47) (41) Frondoside A2-2A(40) C.C.frondosa [35] C. frondosa Cucumarioside E. fraudatrix [40] Synallactoside B (49) S. nozawai [16] [37] 2 (48) 2 Calcigeroside C 2 (43) Frondoside A2-4C(42) C. frondosa [36] P. calcigera Synallactoside C (50) S. nozawai [16] Synaptoside A (51) Synapta maculata [41] Calcigeroside (45) Calcigeroside D2-1(44) P. calcigera [38] P. calcigera Okhotoside A C. okhotensis [42] Frondoside A7 -1 E (53) C. frondosa [43] [38] 2 (52) Colochiroside (46) Cucumarioside C1(47) E. fraudatrix [40] C. frondosa anceps [39] Frondoside AA (54) C. [43] 7 -2 Synallactoside B2 (49) Cucumarioside C2 (48) E. fraudatrix [40] S. nozawai [16] Synaptoside A (51) Synallactoside C (50) Synapta maculata [41] S. nozawai [16] Frondoside A7-1 (53) Okhotoside A2-1 (52) C. okhotensis [42] C. frondosa [43] Frondoside A7-2 (54) C. frondosa [43]

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O

R7

O

R6 O O R1O HO O O O HO O O HO4 O HO RO OH OH O R5 O HO HO OH 14 Cucumarioside A0-1 R1=SO3Na, R2=H, R3=CH2OH, R4=CH3, R5=H, R6=

OAc, R7=

15 Cucumarioside A0-2 R1=SO3Na, R2=H, R3=CH2OH, R4=CH3, R5=H, R6=

OAc, R7=

16 Cucumarioside A0-3 R1=SO3Na, R2=H, R3=CH2OH, R4=CH3, R5=H, R6=

O, R7=

R3

R2

O

O, R7=

17 Cucumarioside A1-2 R1=SO3Na, R2=CH2OH, R3=CH2OAc, R4=H, R5=H, R6= 18 Cucumarioside A2-2 R1=SO3Na, R2=CH2OH, R3=CH2OH, R4=CH3, R5=H, R6=

O, R7=

19 Cucumarioside A2-3 R1=SO3Na, R2=CH2OH, R3=CH2OH, R4=CH3, R5=H, R6=

O, R7=

20 Cucumarioside A2-4 R1=SO3Na, R2=CH2OH, R3=CH2OH, R4=CH3, R5=H, R6= H, R7= 21 Cucumarioside A2-5 R1=SO3Na, R2=CH2OH, R3=CH2OH, R4=CH3, R5=H, R6=

OAc, R7=

22 Cucumarioside A4-2 R1=SO3Na, R2=CH2OH, R3=CH2OH, R4=CH3, R5=H, R6=

O, R7=

23 Cucumarioside A6-2 R1=SO3Na, R2=CH2OH, R3=CH2OSO3Na, R4=CH3, R5=H, R6=

O

O, R7=

24 Cucumarioside A7-1 R1=SO3Na, R2=CH2OSO3Na, R3=CH2OSO3Na, R4=CH3, R5=H, R6=

O, R7=

25 Cucumarioside A7-2 R1=SO3Na, R2=CH2OSO3Na, R3=CH2OSO3Na, R4=CH3, R5=H, R6=

O, R7=

26 Cucumarioside A7-3 R1=SO3Na, R2=CH2OSO3Na, R3=CH2OSO3Na, R4=CH3, R5=H, R6=H, R7= 27 Cucumarioside H R1=R5=H, R2=R3=CH2OH, R4=Me, R6=

OAc, R7=

28 Cucumarioside H2 R1=SO3Na, R2=CH2OH, R3=R5=H, R4=Me, R6=

OAc, R7=

29 Cucumarioside H4 R1=SO3Na, R2=CH2OH, R3=R5=H, R4=Me, R6=

OAc, R7=

30 Cucumarioside H5 R1=SO3Na, R2=CH2OH, R3=H, R4=CH3, R5=H, R6=

OAc, R7=

31 Cucumarioside H6 R1=SO3Na, R2=CH2OH, R3=H, R4=CH3, R5=H, R6=

OAc, R7=

32 Cucumarioside H7 R1=SO3Na, R2=CH2OH, R3=H, R4=CH3, R5=H, R6=

OAc, R7=

33 Cucumarioside H8 R1=SO3Na, R2=CH2OH, R3=H, R4=CH3, R5=H, R6=

OAc, R7=

OH OEt

OH , 16,22-epoxy

34 Cucumarioside I1 R1=SO3Na, R2=CH2OSO3Na, R3=H, R4=CH3, R5=H, R6=

OAc, R7=

35 Cucumarioside I2 R1=SO3Na, R2=CH2OSO3Na, R3=H, R4=CH3, R5=H, R6=

OAc, R7=

36 Cucumarioside I3 R1=SO3Na, R2=CH2OSO3Na, R3=H, R4=CH3, R5=H, R6=

OAc, R7=

37 Frondoside A R1=SO3Na, R2=R5=H, R3=CH2OH, R4=CH3, R6=

OAc, R7=

38 Frondoside B R1=SO3Na, R2=CH2OSO3Na, R3=CH2OH, R4=CH3, R5=R6=H, R7= 39 Frondoside A2-1 R1=SO3Na, R2=R3=CH2OH, R4=CH3, R5=H, R6=

O, R7=

O

40 Frondoside A2-2 R1=SO3Na, R2=R3=CH2OH, R4=CH3, R5=R6=H, R7= 41 Frondoside A2-3 R1=SO3Na, R2=R3=CH2OH, R4=CH3, R5=R6=H, R7= 42 Frondoside A2-4 R1=SO3Na, R2=R3=CH2OH, R4=CH3, R5=R6=H, R7=

Figure 6. Cont.

OH

OH

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43 Calcigeroside C2 R1=SO3Na, R2=CH2OH, R3=H, R4=CH3, R5=CH2OH, R6=H, R7= O 44 Calcigeroside D2 R1=SO3Na, R2=CH2OSO3Na, R3=H, R4=CH3, R5=CH2OH, R6=H, R7= OAc, R7=

45 Calcigeroside E R1=SO3Na, R2=R5=CH2OH, R3=CH2OSO3Na, R4=CH3, R6=

46 Colochiroside A R1=SO3Na, R2=CH2OSO3Na, R3=CH2OH, R4=CH3, R5=H, R6= 47 Cucumarioside C1 R1=R5=H, R2=R3=CH2OH, R4=CH3, R6=

OAc, R7=

48 Cucumarioside C2 R1=R5=H, R2=R3=CH2OH, R4=CH3, R6=

OAc, R7=

O

22

O

R3 HO MeO

O

O OH HO O O HO OH

OH

O

O

26

49 Synallactoside B2 R1=R2=R3=H, R4=

OAc,Δ25(26)

50 Synallactoside C R1=R2=H, R3=CH2OH, R4=

O

O

OH

O, R7=

25

R4 R1O HO HO R2 HO O O

O

OAc,Δ25(26)

51 Synaptoside A R =SO3Na, R =CH2OH, R =COONa, R4= 1

OH

O

O

2

22

3

O

26 25

R3

R2 O HO MeO

R2O O HO O OH

NaO3SO HO R1 O O OH HO HO HO

O

O

O O O O

52 Okhotoside A2-1 R1=OH, R2=H, R3=

OAc, Δ25(26)

53 Frondoside A7-1 R1=H, R2=SO3Na, R3=

O, Δ24

54 Frondoside A7-2 R1=R2=H, R2=SO3Na, Δ24

OH

Figure 6. structures of holostane glycosides with 3β-hydroxyholost-7(8)-ene and fiveand sugar Figure 6. Chemical Chemical structures of holostane glycosides with 3β-hydroxyholost-7(8)-ene five units. sugar units.

Holostane Glycosides with 3β-Hydroxyholost-7(8)-ene Skeleton and Four Sugar Units Holostane Glycosides with 3β-Hydroxyholost-7(8)-ene Skeleton and Four Sugar Units Several compounds in this group were isolated from the species of Staurocucumis liouvillei and Several compounds in this group were isolated from the species of Staurocucumis liouvillei and Eupentacta fraudatrix (Table 3). The most common characteristic of glycosides in the group is the Eupentacta fraudatrix (Table 3). The most common characteristic of glycosides in the group is the presence of sulfate at C-4 of xylose and either keto or β-acetoxy group at C-16 (Figure 7). Some of presence of sulfate at C-4 of xylose and either keto or β-acetoxy group at C-16 (Figure 7). Some of the compounds in this series, especially liouvillosides, violaceusosides and cucumechinosides, may the compounds in this series, especially liouvillosides, violaceusosides and cucumechinosides, may contain up to three sulfates in their carbohydrate chain. The presence of α-hydroxy at C-12 and C-17 contain up to three sulfates in their carbohydrate chain. The presence of α-hydroxy at C-12 and C-17 (78 and 79), artifact n-butoxy (113) and ethoxy (114) groups at C-25, and three consecutive xylose (78 and 79), artifact n-butoxy (113) and ethoxy (114) groups at C-25, and three consecutive xylose sugar units in carbohydrate chain (72) are rare structural features in this category. Cucumariosides sugar units carbohydrate chain (72) rare structural features this category. Cucumariosides A1 (111), A5in(115) and A11 (118) are theare desulfated derivatives of in cucumariosides G1 (123), G3 (124)A1 (111), A (115) and A (118) are the desulfated derivatives of cucumariosides G 5 11 1 (123), G3 (124) and and G4 (125), respectively. G4 (125), respectively. Table 3. Name and producing species of glycosides with 3β-hydroxyholost-7(8)-ene and four sugar Table units. 3. Name and producing species of glycosides with 3β-hydroxyholost-7(8)-ene and four sugar units. Compound Name Compound Name Liouvilloside A (55) Liouvilloside A (55) Liouvilloside A2 (57) Liouvilloside A2 (57) Liouvilloside A5 (59) Liouvilloside A5 (59) Liouvilloside B1 (61) Liouvilloside B1 (61) Violaceuside A (63) Violaceuside A (63) Violaceuside I (65) Violaceuside I (65) Violaceuside III (67) Intercedenside B (67)

Producing Species Reference Producing Species Reference Staurocucumis liouvillei [44] Staurocucumis liouvillei [44] S. S. liouvillei [45] liouvillei [45] liouvillei [46] S. S. liouvillei [46] liouvillei [45] S. S. liouvillei [45] P. violeceus [47] P. violeceus [47] P. violeceus [48] P. violeceus [48] P. violeceus [48] Mensamria intercedens [49]

CompoundName Name Compound Liouvilloside 1 (56) Liouvilloside AA 1 (56) LiouvillosideAA 3 (58) Liouvilloside 3 (58) Liouvilloside LiouvillosideBB(60) (60) Liouvilloside LiouvillosideB2B(62) 2 (62) Violaceuside B (64) Violaceuside B (64) Violaceuside II (66) Violaceuside II (66) Intercedenside A (68) Intercedenside C (70)

Producing SpeciesReference Reference Producing Species S. liouviellei S. liouviellei S. liouvillei S. liouvillei S. liouvillei S. liouvillei S. liouvillei S. liouvillei P. violeceus P. violeceus P. violeceus

P. violeceus M. intercedens M. intercedens

[45] [45] [45] [45] [44] [44] [45] [45] [47] [47] [48]

[48] [49] [49]

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Intercedenside D (71) M. intercedens Intercedenside F (73) M. intercedens Intercedenside H (75) M. intercedens Compound Name Producing Species Patagonicoside A (77) Psolus patagonicus Violaceuside III (67) P. violeceus Patagonicoside C (79) P. patagonicus Intercedenside B (67) Mensamria intercedens Philinopside B (81) Pentacta Intercedenside D (71) M.quadrangularis intercedens Philinopside F (83)F (73) P. quadrangularis Intercedenside M. intercedens Intercedenside M. intercedens Mollisoside B2 (85)H (75) Australostichopus mollis Patagonicoside (77) Pseudostichopus Psolus patagonicus Pseudostichoposide AA (87) trachus Patagonicoside C (79) P. patagonicus Cucumarioside F2 (89) E. fraudatrix Philinopside B (81) Pentacta quadrangularis Typicoside A1 (91)F (83) Actinocucumis typica Philinopside P. quadrangularis Mollisoside B2 (85) Australostichopus Typicoside B1 (93) A. typica mollis Pseudostichoposide Typicoside C2 (95) A (87) Pseudostichopus A. typica trachus Cucumarioside F (89) E. fraudatrix Okhotoside A1-1 (97)2 Cucumaria okhotensis Typicoside A1 (91) Actinocucumis typica Okhotoside B2 (99) C. okhotensis Typicoside B1 (93) A. typica Colochiroside A1 (101) Colochirus robustus Typicoside C2 (95) A. typica Okhotoside Cucumaria okhotensis 1 -1 (97) (103) Colochiroside A3 A C. robustus Okhotoside B2 (99) okhotensis Colochiroside B2 (105) C.C.robustus Colochiroside A1 (101) Colochirus robustus Violaceusosides C (107) P. C. violaceus Colochiroside A3 (103) robustus Violaceusosides E (109) P. C. violaceus Colochiroside B2 (105) robustus Violaceusosides C (107) P. violaceus Cucumarioside A1 (111) E. fraudatrix Violaceusosides E (109) P. violaceus Cucumarioside A3 (113) E. fraudatrix Cucumarioside A1 (111) E. fraudatrix 5 (115) Cucumarioside A E. fraudatrix Cucumarioside A3 (113) E. fraudatrix Cucumarioside A7 (117) E. E. fraudatrix Cucumarioside A5 (115) fraudatrix Cucumarioside A7 (117) fraudatrix Cucumarioside A12 (119) E. E. fraudatrix Cucumarioside A12 (119) fraudatrix Cucumarioside A14 (121) E. E. fraudatrix Cucumarioside A14 (121) E. fraudatrix Cucumarioside G1 (123) C. fraudatrix Cucumarioside G1 (123) C. fraudatrix Cucumarioside G4 (125) E. E. fraudatrix Cucumarioside G4 (125) fraudatrix Pentactaside C (127) P. quadrangularis Pentactaside C (127) P. quadrangularis Variegatuside A (129) variegates Variegatuside A (129) S. S. variegates Synallactoside A1 (131) nozawai Synallactoside A1(131) S. S. nozawai Thelenotoside B (133) T. ananas Thelenotoside B (133) T.C.ananas Cucumechinoside B (135) echinata Cucumechinoside B (135) C.C. echinata Cucumechinoside D (137) echinata Cucumechinoside F (139) echinata Cucumechinoside D (137) C.C. echinata LefevreosideFA(139) lefevrei 2 (141) Cucumechinoside C. C. echinata Lefevreoside D (143) C. lefevrei Lefevreoside A2 (141) C. lefevrei Lefevreoside D (143) C. lefevrei

Intercedenside E (72) [50] 3. Cont. Table

[50] [50] Reference [51] [48] [52] [49] [53] [50] [54] [50] [50] [55] [51] [57] [52] [58] [53] [60] [54] [55] [60] [57] [60] [58] [61] [60] [62] [60] [63] [60] [61] [63] [62] [64] [63] [65] [63] [65] [64] [65] [66] [65] [66] [66] [66] [66] [67] [66] [67] [66] [66] [67] [67] [68] [68] [70] [70] [71] [71] [73] [73] [16] [16] [74] [74] [75] [75] [75] [75] [75] [76] [75] [76] [76] [76]

R8

O

M. intercedens [50] Intercedenside G (74) M. intercedens [50] Intercedenside I (76) M. intercedens [50] Compound Name Producing Species Reference Patagonicoside B (78) P. patagonicus [52] Intercedenside A (68) M. intercedens [49] Philinopside A (80) P. quadrangularis [53] Intercedenside C (70) M. intercedens [49] PhilinopsideE E (82) quadrangularis [50] [54] Intercedenside (72) M.P. intercedens MollisosideGA(74) (84) A. mollis Intercedenside M. intercedens [50] [55] Intercedenside (76) M. intercedens [50] [56] EximisosideI A (86) P. eximius Patagonicoside B (78) P. patagonicus [52] [58] Cucumarioside F1 (88) E. fraudatrix Philinopside A (80) P. quadrangularis [53] Pseudocnoside A (90) P. leoninus Philinopside E (82) P. quadrangularis [54] [59] Typicoside 2 (92) A. typica Mollisoside AA (84) A. mollis [55] [60] Eximisoside (86) P. eximius [56] [60] TypicosideA C 1 (94) A. typica Cucumarioside E. fraudatrix [58] [61] 1 1(88) FrondosideFA (96) C. okhotensis Pseudocnoside A (90) P. leoninus [59] Okhotoside B1 (98) C. okhotensis [62] Typicoside A2 (92) A. typica [60] Okhotoside 3 (100) okhotensis Typicoside C1 B(94) A. C. typica [60] [62] Colochiroside A2 (102) C. robustus Frondoside A1 (96) C. okhotensis [61] [63] Okhotoside B1 (98) C. okhotensis [62] [64] Colochiroside B1 (104) C. robustus Okhotoside B3 (100) C. okhotensis [62] Colochiroside B3 (106) C. robustus [64] Colochiroside A2 (102) C. robustus [63] Violaceusosides D (108) P. violaceus Colochiroside B1 (104) C. robustus [64] [65] Violaceusosides G (110) P. violaceus Colochiroside B3 (106) C. robustus [64] [65] Violaceusosides DA (108) P. violaceus [65] [67] Cucumarioside 2 (112) E. fraudatrix Violaceusosides GA (110) P. violaceus [65] [66] Cucumarioside 4 (114) E. fraudatrix Cucumarioside A2 (112) E. fraudatrix [67] Cucumarioside A 6 (116) E. fraudatrix [66] Cucumarioside A4 (114) E. fraudatrix [66] Cucumarioside 11 (118) E. fraudatrix Cucumarioside A6A (116) E. fraudatrix [66] [67] Cucumarioside A11A(118) E. fraudatrix [67] [67] Cucumarioside 13 (120) E. fraudatrix Cucumarioside A13A(120) E. fraudatrix [67] [66] Cucumarioside 15 (122) E. fraudatrix Cucumarioside A15 (122) E. fraudatrix [66] Cucumarioside G3 (124) E. fraudatrix [69] Cucumarioside G3 (124) E. fraudatrix [69] Pentactaside B (126) P. quadrangularis [71] [71] Pentactaside B (126) P. quadrangularis Pseudostichoposide B (128) P. trachus Pseudostichoposide B (128) P. trachus [72] [72] Variegatuside C (130) S. variegates [21] [21] Variegatuside C (130) S. variegates Thelenotoside A (132) Thelenota ananas Thelenotoside A (132) Thelenota ananas [74] [74] Cucumechinoside A (134) C. echinata [75] Cucumechinoside A (134) C. echinata [75] Cucumechinoside C (136) C. echinata [75] Cucumechinoside C (136) C. echinata Cucumechinoside E (138) C. echinata [75] [75] Lefevreoside A1 (140) C. lefevrei [76] [75] Cucumechinoside E (138) C. echinata Lefevreoside C (142) C. lefevrei [76] [76] Lefevreoside A1 (140) C. lefevrei Lefevreoside C (142) C. lefevrei [76]

O

R7 R6 R5

O

R 1O

R4 HO MeO

HO R2 O O OH HO

R3 O HO O OH 1

O

O O

OH 2

55 Liouvilloside A R =SO3Na, R =CH3, R3=R4=CH2OSO3Na, R5=

OAc, R6=H, R7=

56 Liouvilloside A1 R1=SO3Na, R2=CH3, R3=CH2OSO3Na, R4=CH2OH, R5=

O, R6=H, R7=

57 Liouvilloside A2 R1=SO3Na, R2=CH3, R3=CH2OSO3Na, R4=CH3, R5=

O, R6=H, R7=

58 Liouvilloside A3 R1=SO3Na, R2=CH3, R3=CH2OSO3Na, R4=CH3, R5=

OAc, R6=H, R7=

Figure Figure 7. 7. Cont. Cont.

, R8=H , R8=H , R8=H , R8=H

Mar. Drugs 2017, 15, 317 Mar. Drugs 2017, 15, 317

10 of 35 10 of 35

, R8=H OH , R8=H

OAc, R6=H, R7=

59 Liouvilloside A5 R1=SO3Na, R2=CH3, R3=CH2OSO3Na, R4=CH3, R5= 60 Liouvilloside B R1=H, R2=CH3, R3=CH2OSO3Na, R4=CH2OSO3Na, R5=

OAc, R6=H, R7=

61 Liouvilloside B1 R1=SO3Na, R2=CH3, R3=CH2OSO3Na, R4=CH2OSO3Na, R5=

O, R6=H, R7=

62 Liouvilloside B2 R1=SO3Na, R2=CH3, R3=CH2OSO3Na, R4=CH2OSO3Na, R5=

OAc, R6=H, R7=

, R8=H

, R8=H

OAc, R6=H, R7=

63 Violaceuside A R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5=

, R8=H

, R8=H

64 Violaceuside B R1=SO3Na, R2=CH2OH, R3=H, R4=CH2OH, R5=

OAc, R6=H, R7=

65 Violaceuside I R1=SO3Na, R2=CH2OH, R3=H, R4=CH2OH, R5=

O , R6=H, R7=

, R8=

7

8

1

2

3

4

5

6

1

2

3

4

5

6

1

2

3

4

1

2

3

4

6

8

7

8

O, R =H, R =

67 Violaceuside III R =SO3Na, R =CH3, R =H, R =CH2OSO3Na, R =

OH

,R = 5

7

68 Intercedenside A R =SO3Na, R =CH3, R =H, R =CH2OH, R =H, R =

OH

,R =

O, R =H, R =

66 Violaceuside II R =SO3Na, R =CH3, R =H, R =CH2OSO3Na, R =

OH

OAc

,R =

H, R = 6

H, R =

,R =

OAc

70 Intercedenside C R1=SO3Na, R2=CH2OH, R3=H, R4=CH2OH, R8=H, R6=

OH, R7=

, R5=

OAc

8

69 Intercedenside B R =SO3Na, R =CH3, R =H, R =CH2OSO3Na, R =H, R =

1

2

4

1

2

3

3

8

6

8

6

7

71 Intercedenside D R =SO3Na, R =R =CH2OH, R =H, R =H, R = 4

OH, R = OH, R =

6

4

3

8

OH, R =

6

,R =

OH, R7=

76 Intercedenside I R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R8=H, R6=

OH, R7=

3

4

5

, R8=

H, R7=

81 Philinopside B R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5=

OAc, R6=

H, R7=

82 Philinopside E R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5=

O, R6=

3

4

5

, R8=H, additional OSO3Na at C-2 of Xyl , R8=H , R8=H

H, R7=

84 Mollisoside A R1=SO3Na, R2=CH3, R3=CH2OH, R4=CH2OH, R5=H, R6=H, R7=

, R8=H

O

, R8=H

O, R6=H, R7= 6

7

86 Eximisoside A R =H, R =CH2OH, R =H, R =CH2OH, R =OAc, R =H, R =

OH

7 87 Pseudostichoposide A R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5=H, R6=H, R =

88 Cucumarioside F1 R1=SO3Na, R2=CH3, R3=CH2OSO3Na, H, R4=H, R5=

O OAc, R6=H, R7=

89 Cucumarioside F2 R1=SO3Na, R2=CH3, R3=CH2OSO3Na, H, R4=H, R5=

OAc, R6=H, R7=

90 Pseudocnoside A R1=SO3Na, R2=CH3, R3=CH2OSO3Na, R4=CH2OH, R5= 91 Typicoside A1 R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5=

OAc, R6=

92 Typicoside A2 R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5=H, R6=

O, R6=

93 Typicoside B1 R1=SO3Na, R2=CH3, R3=CH2OH, R4=CH2OH, R5=H, R6=

, R8=H , R8=H , R8=H , R8=H

H, R7=

OAc OAc

H, R7=

94 Typicoside C1 R1=SO3Na, R2=CH3, R3=CH2OSO3Na, R4=CH2OH, R5=H, R6=

H, R7=

95 Typicoside C2 R1=SO3Na, R2=CH3, R3=CH2OSO3Na, R4=CH2OH, R5=H, R6=

H, R7=

Figure Figure 7. 7. Cont. Cont.

, R8=H

, R8=H

H, R7=

H, R7=

OH

, R8=H

H, R7=

OAc, R6=

OH , R8=

OH, R7=

OAc, R6=

2

, R8=H

OH, R =

80 Philinopside A R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5=

1

OAc

7

OH, R7=

79 Patagonicoside C R1=SO3Na, R2=CH3, R3=CH2OH, R4=CH2OH, R5= H, R6=

OAc

, R5=

6

78 Patagonicoside B R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5= H, R6=

85 Mollisoside B2 R1=SO3Na, R2=CH2OH, R3=H, R4=CH2OH, R5=

OAc , R5=

77 Patagonicoside A R =SO3Na, R =CH3, R =CH2OSO3Na, R =CH2OH, R = H, R =

83 Philinopside F R1=SO3Na, R2=CH2OH, R3=H, R4=CH2OH, R5=

OAc

5

75 Intercedenside H R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R8=H, R6=

2

OAc

5

,R =

7

74 Intercedenside G R1=SO3Na, R2=R4=CH2OH, R3=H, R8=H, R =H, R =

1

OAc

5

,R =

7

73 Intercedenside F R =SO3Na, R =R = CH2OH, R =H, R =H, R = 2

5

,R =

7

72 Intercedenside E R =SO3Na, R =R = H, R =CH2OH, R =H, R = 1

5

7

, R8=H OH OAc

, R8=H , R8=H , R8=H

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11 of 35 11 of 35

96 Frondoside A1 R1=SO3Na, R2=CH3, R3=R6=H, R4=CH2OH, R5=

, R8=H

OAc, R7=

, R8=H

OAc, R7=

97 Okhotoside A1-1 R1=SO3Na, R2=CH3, R3=R6=H, R4=CH2OH, R5=

O 98 Okhotoside B1 R1=SO3Na, R2=R3=R4=CH2OH, R6=H, R5=

OAc, R7=

101 Colochiroside A1 R1=SO3Na, R2=R4=CH2OH, R3=H, R5=

, R8=H

OAc, R7=

99 Okhotoside B2 R1=SO3Na, R2=R4=CH2OH, R3=CH2OSO3Na, R6=H, R5= 100 Okhotoside B3 R1=OH, R2=CH2OH, R3=R4=CH2OSO3Na, R6=H, R5=

, R8=H

, R8=H

OAc, R7=

, R8=H

H, R7=

OAc, R6=

102 Colochiroside A2 R1=SO3Na, R2=R4=CH2OH, R3= R5=H, R6=

H, R7=

, R8=H

103 Colochiroside A3 R1=SO3Na, R2=R4=CH2OH, R3= R5=H, R6=

H, R7=

, R8=H

104 Colochiroside B1 R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5=

OAc, R6=

H, R7=

105 Colochiroside B2 R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5=

OAc, R6=

H, R7=

106 Cloochiroside B3 R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5=

OAc, R6=

H, R7=

107 Violaceusoside C R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5=

O, R6=

OH , R8=H

, R8=H , R8=H

H, R7=

108 Violaceusoside D R1=SO3Na, R2=CH3, R3=CH2OSO3Na, R4=CH2OH, R5=

OAc, R6=

HO MeO

HO O HO O OH

O

HO HO O

O OH HO HO

117 Cucumarioside A7 R=

O

R

111 Cucumarioside A1 R=

H

112 Cucumarioside A2 R=

OAc

113 Cucumarioside A3 R=

115 Cucumarioside A5 R=

OH

116 Cucumarioside A6 R=

118 Cucumarioside A11 R=

120 Cucumarioside A13 R=

OH

O

OAc

HO MeO

HO O HO O OH

O

O

124 Cucumarioside G3 R=

HO HO MeO

O HO O OH

O

O O

OH

R

R 127 Pentactaside C R1= O

O

123 Cucumarioside G1 R=

2

1

NaO3SO HO O O OH HO

OEt

122 Cucumarioside A15 R=

H 126 Pentactaside B R1=

OH

OnBu

125 Cucumarioside G4 R=

O

O O

OAc

R H

O

, R8=H

OH OH 119 Cucumarioside A12 R=

121 Cucumarioside A14 R= O

NaO3SO HO O O OH HO

, R8=H

114 Cucumarioside A4 R=

O

O O

O

, R8=H

H, R7=

6 H, R7= 109 Violaceusoside E R1=SO3Na, R2=CH3, R3=H, R4=CH2OH, R5= O, R = (additional OSO3Na at C-3 of Qui) 110 Violaceusoside G R1=SO3Na, R2=CH3, R3=H, R4=CH2OSO3Na, R5= OAc, R6= H, R7= (additional OSO3Na at C-3 of Qui)

O

, R8=H OH

O

OAc, R2= OAc, R2= 2

128 Pseudostichoposide B R1 =H, R =

OSO3Na

Figure Figure 7. 7. Cont. Cont.

O

Mar. Drugs 2017, 15, 317 Mar. Drugs 2017, 15, 317

12 of 35 12 of 35

O

R2

O

129 Variegatuside A R1=OH, R2=

H

130 Variegatuside C R1=OH, R2=

OH OH

HO HO MeO

HO HO R1 HO O O

O HO O OH

O

O

131 Synallactoside A1 R1=H, R2=

H

132 Thelenotoside A R1=H, R2=

O

O

OH

OAc OAc

133 Thelenotoside B R1=OH, R2=

OH O

OAc

O O R

R1O HO R4O HO MeO

O O

3

R O HO O OH

O

O HO 2 OR

H 134 Cucumechinoside A R=O, R1=SO3Na, R2=R4=H, R3=CH2OSO3Na

O

O

135 Cucumechinoside B R=H2, R1=SO3Na, R2=R4=H, R3=CH2OSO3Na 136 Cucumechinoside C R=O, R1=R2=R4=SO3Na, R3=H

OH

137 Cucumechinoside D R=O, R1=R2=SO3Na, R3= R4=H 138 Cucumechinoside E R=O, R1=R4=SO3Na, R2=H, R3=CH2OSO3Na 139 Cucumechinoside F R=H2, R1=R4=SO3Na, R2=H, R3=CH2OSO3Na O

O

24

H OAc

HO HO MeO

O HO O OH

R1O HO O O HO OH

O

O

H

OO

26 25

140 Lefevreoside A1 R1=H 141 Lefevreoside A2 R1=SO3Na 142 Lefevreoside C R1=SO3Na, Δ24(25) 143 Lefevreoside D R1=SO3Na, Δ25(26)

OH

Chemical structures of holostane glycosides with 3β-hydroxyholost-7(8)-ene and units. four Figure 7.7.Chemical structures of holostane glycosides with 3β-hydroxyholost-7(8)-ene and four sugar sugar units.

Holostane Glycosides with 3β-Hydroxyholost-7(8)-ene Skeleton and 1–3 Sugar Units Holostane Glycosides with 3β-Hydroxyholost-7(8)-ene Skeleton and 1–3 Sugar Units The name of the compounds in this group, their producing species, chemical structures and The name of the compounds thisFigure group, producing species, structures and references are summarized in Table 4inand 8. their The most common featurechemical of triterpene glycosides references are summarized in Table 4 and Figure 8. The most common feature of triterpene is the presence of double bond at C-25(26). Cucumarioside B1 (146) is the geometric isomer of glycosides is the presence of double bond at C-25(26). Cucumarioside 1(146) is the geometric and pentactaside III (148) is the positional isomer of Bstichoposide A (153). cucumarioside B2 (142) isomer of cucumarioside B2 (142) and pentactaside III (148) is the positional isomer of stichoposide A (153). Table 4. Name and producing species of glycosides with 3β-hydroxyholost-7(8)-ene and 1–3 sugar units. Table 4. Name and producing species of glycosides with 3β-hydroxyholost-7(8)-ene and 1–3 sugar Compound Name Producing Species Reference Compound Name Producing Species Reference units. Pentactaside I (144)

Pentacta quadrangularis

[77]

Pentactaside II (145)

P. quadrangularis

[77]

Compound Name Species Reference Compound Name Producing Reference Cucumarioside B1 (146) Producing E. fraudatrix [78] Cucumarioside B2 (147) E. fraudatrix Species[78] Pentactaside III (148) Pentacta P. quadrangularis [77] Stichoposide A (149) cloronotus Pentactaside I (144) Pentactaside II (145) S.P. quadrangularis [77] quadrangularis [79] [77] Stichoposide B (150) Stichopus cloronotus [79] Stichorrenoside A (151) Stichopus horrens [80] Cucumarioside B1 (146) Cucumarioside B2 (147) S. horrens E. fraudatrix [78] E. fraudatrix [80] [78] Stichorrenoside B (152) S. horrens [80] Stichorrenoside C (153) Stichorrenoside D (154) S. horrens [80] Hillaside A (155) H.S. hilla Pentactaside III (148) Stichoposide A (149) P. quadrangularis [77] cloronotus [81] [79] Stichoposide B (150) Stichorrenoside A (151) Stichopus horrens Stichopus cloronotus [79] [80] Stichorrenoside B (152) Stichorrenoside C (153) S. horrens [80] S. horrens [80] Stichorrenoside D (154) Hillaside A (155) S. horrens [80] H. hilla [81]

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13 of 35 13 of 35

144 Pentactaside I R =SO3Na, Δ24 145 Pentactaside II R =SO3Na, Δ25(26)

O

22

O

H

22Z,25(26)

146 Cucumarioside B1 R =H, Δ 147 Cucumarioside B2 R =H, Δ22E,25(26) O

RO HO

O

R1O HO R2 HO HO

O O

O O OH HO

HO HO

OAc

OH

O

25

O

O H R4 R3

O

1 2 4 3 24 O O 148 Pentactaside III R =SO3Na, R =R =H, R =OAc, Δ 149 Stichoposide A R1=SO3Na, R2=R3=H, R4=OAc, Δ25(26) OH 150 Stichoposide B R1=R3=H, R2=OH, R4=OAc, Δ25(26)

R3 O

O

26 25 27 H R4 151 Stichorrenoside A R1=CH2OH, R2=R4=H, R3=OH

HO HO R1 2 RO HO

152 Stichorrenoside B R1=CH2OH, R2=SO3Na, R3=OH, R4=H

O

O

153 Stichorrenoside C R1=CH2OH, R2=R3=H, R4=OAc, Δ25(26) 154 Stichorrenoside D R1=R2=R3=H, R4=OAc, Δ25(26)

O O O

OH

O OH

HO HO

O

O

OH

H

155 Hillaside A

Figure 8. 8. Chemical Chemicalstructures structuresofof holostane glycosides 3β-hydroxyholost-7(8)-ene andsugar 1–3 sugar holostane glycosides withwith 3β-hydroxyholost-7(8)-ene and 1–3 units. units.

4.1.2. 3β-Hydroxyholost-9(11)-ene Skeleton Containing Holostane Glycosides 4.1.2. 3β-Hydroxyholost-9(11)-ene Skeleton Containing Holostane Glycosides The species Holothuria lessoni, Bohadschia marmorata and Bohadschia bivittata produce most of the The species Holothuria lessoni, Bohadschia and Bohadschia bivittata produce most ofalso the compounds in this group. For convenience, themarmorata large number of compounds in this category can compounds in this group. For convenience, the large number of compounds in this category can be further subdivided into four groups depending on the number of sugar units also be further subdivided into four groups depending on the number of sugar units Holostane Glycosides with 3β-Hydroxyholost-9(11)-ene Skeleton and Six Sugar Units Holostane Glycosides with 3β-Hydroxyholost-9(11)-ene Skeleton and Six Sugar Units Similar to 3β-hydroxyholost-7(8)-ene skeleton with six sugar units (Figure 5), 3β-hydroxyholostSimilar to 3β-hydroxyholost-7(8)-ene skeletonalso with six have sugaranyunits (Figure 9(11)-ene skeleton with six sugar units glycosides do not sulfate group 5), in 3β-hydroxyholost-9(11)-ene skeleton with Table six sugar units glycosides alsoK1do have any sulfate their carbohydrate chain (Figure 9 and 5) except cladolosides , Knot and L (197–199). 2 1 group in common their carbohydrate chain (Figure 9 and glycosides Table 5) except K1, presence K2 and of L1 The most structural feature of triterpene in this cladolosides category is the (197–199). The most common triterpene glycosides in thisand category is the 3-O-methylD -glucose at the bothstructural end of thefeature straightofcarbohydrate chain. Holotoxin parvimoside presence of 3-O-methylD-glucose at athe both end at of position the straight carbohydrate chain. Holotoxin and series (156–166) of compounds have keto group C-16. Double bond at C-25(26) among parvimoside series (156–166) of compounds have a keto group at C-16.the Double bond at holotoxins (156–163) is common, except 26-nor-25-oxo-holotoxin A1position (159), where double bond C-25(26) among holotoxins is common, except 26-nor-25-oxo-holotoxin A1 found (159), where is replaced by a keto group.(156–163) The α-hydroxy groups at C-12 and C-17 are commonly in the the double bond is replaced by a keto The α-hydroxy groups at C-12 and C-17 are commonly aglycone part of lessonioside series ofgroup. glycosides (175–177). The α-hydroxy group at C-12 and C-17, found in the aglycone part ofstructural lessonioside series of glycosides (175–177). (183–188). The α-hydroxy group at and 22,25-epoxy are common characteristics of holothurinosides Acetoxy group C-12 and C-17, and are common structural characteristics of holothurinosides (183–188). at C-16 and C-22 are22,25-epoxy frequently observed in cladoloside glycosides (189–199). Acetoxy group at C-16 and C-22 are frequently observed in cladoloside glycosides (189–199).

Mar. Drugs 2017, 15, 317

14 of 35

Table 5. Name and producing species of glycosides with 3β-hydroxyholost-9(11)-ene and six sugar units. Mar.Compound Drugs 2017, 15, 317 Name

of 35 Producing Species Reference Compound Name Pro. Species 14 Reference Holotoxin A (156) Holotoxin A1 (157) Stichopus japonicus [82] S. japonicus [22] 25,26-dihydroxyholotoxin A1 (158) Apostichopus japonicus Oxo-holotoxin A1 (159) [83] A. japonicus [22] Table 5. Name of glycosides with sixjaponicus sugar units. [22] Holotoxin B (160)and producing species Holotoxin B1 (161) and S. S. japonicus [22] 3β-hydroxyholost-9(11)-ene Holotoxin D (162) Holotoxin D1 (163) S. japonicus [22] A. japonicus [83] Compound Name Producing Species Reference Compound Name Pro. Species Reference Stichopus parvimensis Parvimoside A (164) Parvimoside B (165) [84] S. parvimensis [84] Holotoxin A (156) Stichopus japonicus [82] Holotoxin A1 (157) S. japonicus [22] Bivittoside C (166) Bivittoside D (167) Bohadschia bivittata [85] B. bivittata [85] 25,26-dihydroxyholotoxin A1 (158) Apostichopus japonicus [83] Oxo-holotoxin A1 (159) A. japonicus [22] 25-acetoxybivittoside D (168) Arguside Bohadschia marmorata [22][86] B. argus [22] [87] Holotoxin B (160) S. japonicus Holotoxin B1 (161)B (169) S. japonicus Holotoxin D (162) S.B. japonicus [22][87] Holotoxin D1 (163) Arguside C (170) Marmoratoside A (171)A. japonicus argus B. marmorata [83] [86] Parvimoside A (164) Stichopus parvimensis [84] Parvimoside B (165) S. parvimensis [84] Marmoratoside Impatienside B. marmorata H. impatiens [85] [86] BivittosideBC(172) (166) Bohadschia bivittata [85][86] Bivittoside D (167) A (173) B. bivittata 25-acetoxybivittoside D Bohadschia marmorata [86][86] Arguside B (169) A (175) B. argus 17α-hydroxyimpatienside A(168) (174) Lessonioside B. marmorata H. lessoni [87] [88] Arguside C (170) B. argus [87] A (171) Lessonioside B (176) Lessonioside D (177)B. marmorata Holothuria lessoni [88] Marmoratoside H. lessoni [86] [88] Marmoratoside B (172) B. marmorata [86] Impatienside A (173) H. impatiens [86] Variegatuside E (178) Lessonioside C (179) S. variegates H. lessoni [88] [88] 17α-hydroxyimpatienside A (174) B. marmorata [86][21] Lessonioside A (175) H. lessoni Lessonioside B (176) Holothuria lessoni [88][88] Lessonioside D (177) F (181) H. lessoni Lessonioside E (180) Lessonioside Holothuria lessoni H. lessoni [88] [88] Variegatuside E (178) S. variegates [21] Lessonioside C (179) H. lessoni [88] Lessonioside G (182) Holothurinoside F (183) H. lessoni [88] B. Lessonioside E (180) Holothuria lessoni [88] Lessonioside F (181) H. lessonisubrubra [88] [89] Lessonioside (182) lessoni [88][89] Holothurinoside F (183) H1 (185) B. subrubra Holothurinoside HG(184) Holothurinoside B. subrubra [89] [89] B.H.subrubra Holothurinoside H (184) B. subrubra [89][89] Holothurinoside H1 (185) I1 (187) B. subrubra Holothurinoside I (186) Holothurinoside B. subrubra B. subrubra [89] [89] Holothurinoside I (186) B. subrubra [89] Holothurinoside I1 (187) B. subrubra [89] Holothurinoside K1 K (188) Cladoloside B. subrubra C. schmeltzii [90] [90] Holothurinoside B. subrubra [89][89] Cladoloside C (189) C (189) C. schmeltzii 1 (188) Cladoloside C1 (190) Cladolabes schmeltzii [90][90] Cladoloside C2 (191) C2 (191) C. schmeltzii Cladoloside C1 (190) Cladoloside Cladolabes schmeltzii C. schmeltzii [90] [90] Cladoloside C3 (192) C. schmeltzii [91] Cladoloside D (193) C. schmeltzii [90] Cladoloside C3 (192) Cladoloside D (193) C. schmeltzii C. schmeltzii [91] C. schmeltzii [91] [90] Cladoloside G (194) C. schmeltzii [91] Cladoloside H1 (195) Cladoloside G (194) Cladoloside C. C. schmeltzii [92] [91] Cladoloside H2 (196) C. schmeltzii schmeltzii [91][91] Cladoloside K1 (197) H1 (195) C. schmeltzii Cladoloside K2 (198) C. schmeltzii schmeltzii [92][91] Cladoloside L1 (199) K1 (197) C. schmeltzii Cladoloside H2 (196) Cladoloside C. C. schmeltzii [92] [92] Cladoloside K2 (198) Cladoloside L1 (199) C. schmeltzii [92] C. schmeltzii [92]

R8

O

O

23

22

24

25

R7 R6

HO HO R5O R3

HO R4O

HO O HO O OH R2 O HO O OH

O

O OH HO R1 O O OH HO

O O O

H

O

OH

156 Holotoxin A R1=R4=R5=CH3, R2=R3=CH2OH, R6=

H, R8=H, Δ25(26)

7 O, R =

157 Holotoxin A1 R1=R4=R5=CH3, R2=H, R3=CH2OH, R6=

H, R8=H, Δ25(26)

O, R7=

158 25,26-dihydroxyholotoxin A1 R1=R4=R5=CH3, R2=R7=R8=H, R3=CH2OH, R6=

O,25-OH, 26-OH

8 159 26-nor-25-oxo-holotoxin A1 R1=R2=R4=R5=CH3, R3=CH2OH, R6= O, R = H, R =H, 25− 25(26) 8 7 160 Holotoxin B R1=R4=CH3, R2=R3=CH2OH, R5=H, R6= O, R = H, R =H, Δ 7

161 Holotoxin B1 R1=R4=CH3, R2=R5=H, R3=CH2OH, R6=

7 O, R =

H, R8=H, Δ25(26)

162 Holotoxin D R1=R3=CH2OH, R2=H, R4=R5=CH3, R6=

7 O, R =

H, R8=H, Δ25(26)

163 Holotoxin D1 R1=R3=CH2OH, R2=R5=R7=R8=H, R4=CH3, R6= O, Δ25(26) 8 7 164 Parvimoside A R1=R4=CH3, R2=R3=CH2OH, R5=H, R6= O, R = H, R =H 165 Parvimoside B R1=R4=CH3, R2=R5=H, R3=CH2OH, R6= 166 Bivittoside C R1=R4=R5=CH3, R2=R3=CH2OH, R6=H, R7= Figure Figure 9. 9. Cont. Cont.

H, R8=H

O, R7= 8

H, R =H

O

Mar. Drugs 2017, 15, 317 Mar. Drugs 2017, 15, 317

15 of 35 15 of 35

H, R8=

167 Bivittoside D R1=R4=R5=CH3, R2=R3=CH2OH, R6=H, R7=

OH

168 25-acetoxy bivittoside D R1=R4=R5=CH3, R2=R3=CH2OH, R6=H, R7= 1

4

5

2

3

6

7

169 Arguside B R =R =R =CH3, R =R =CH2OH, R =H, R = 1

2

3

4

5

6

8

OH, R =

4

5

2

3

H, R =

6

OH

8

7

OH, 25-OAc

OH

8

7

170 Arguside C R = R =R =CH2OH, R =R =CH3, R =H, R = 1

H, R8=

171 Marmoratoside A R =R =R =CH3, R =R =CH2OH, R =H, R =H, R =

OH, Δ25(26)

172 Marmoratoside B R1=R4=R5=CH3, R2=R3=CH2OH, R6=H, R7=H, R8=

OH, 25-OH, Δ23

173 Impatienside A R1=R4=R5=CH3, R2=R3=CH2OH, R6=H, R7=H, R8=

OH, Δ24 OH, R8=

174 17α-hydroxy impatienside A R1=R4=R5=CH3, R2=R3=CH2OH, R6=H, R7= 175 Lessonioside A R1=R4=R5=CH3, R2=H, R3=CH2OH, R6=OAc, R7= 7

176 Lessonioside B R1=R3=R5=CH3, R2=CH2OH, R4=H, R6=OAc, R = 1

4

5

2

3

7

6

177 Lessonioside D R =R =R =CH3, R =CH2OH, R =H, R =OAc, R = 178 Variegatuside E R1=R3=CH2OH, R2=R6=R8=H, R4=R5=Me, R7=

OH, R8=

OH

8

OH

8

OH

OH, R = OH, R = H, 23-

OH, Δ24

OH

O HO

O

O

25

OH R5 HO MeO HO HO R3O

R4

O HO O OH R2 O HO O OH

O O

O HO OH R1 O O OH HO

O

O

179 Lessonioside C R1=CH2OH, R2=R4=R5=H, R3=CH3, 25-OAc

H

180 Lessonioside E R1=CH3, R2=CH2OH, R3=R4=R5=H, 25-OAc

O

O

181 Lessonioside F R1=CH3, R2=R4=R5=CH2OH, R3=H, Δ25(26)

OH

182 Lessonioside G R1=R4=R5=CH2OH, R2=H, R3=CH3, Δ25(26)

R5

O

O

O

R4

HO R3O HO HO MeO

R2

HO

O HO O OH HO O HO O OH

O O OH HO R1 O O OH HO

O O OH

O O

H

183 Holothurinoside F R1=R2=CH3, R3=R4=H, R5=OH 184 Holothurinoside H R1=R3=CH3, R2=CH2OH, R4=H, R5=OH 185 Holothurinoside H1 R1=R2=CH2OH, R3=CH3, R4=R5=H 186 Holothurinoside I R1=R3=CH3, R2=CH2OH, R4=OH, R5=OH 187 Holothurinoside I1 R1=R2=CH2OH, R3=CH3, R4=OH, R5=H 188 Holothurinoside K1 R1=R2=CH2OH, R3=CH3, R4=OH, R5=OH

Figure Figure 9. 9. Cont. Cont.

Mar. Drugs 2017, 15, 317 Mar. Drugs 2017, 15, 317

16 of 35 16 of 35 O

O

R4 H

HO HO R 2O HO HO MeO

O HO O OH

R1

O HO O OH

R3 O

O OH HO O

O OH HO

O O

O O

H 189 Cladoloside C R1=CH2OH, R2=Me, R3=OAc, R4= 190 Cladoloside C1 R1=CH2OH, R2=Me, R3=OAc, R4=

OH

191 Cladoloside C2 R1=CH2OH, R2=Me, R3=

196 Cladoloside H2 R1=R2=Me, R3= OAc, R4=

OH

OAc

194 Cladoloside G R1=H, R2=Me, R3= OAc, R4= 195 Cladoloside H1 R1=R2=Me, R3= OAc, R4=

OAc

O, R4=

192 Cladoloside C3 R1=CH2OH, R2=Me, R3= OAc, R4= 193 Cladoloside D R1=R2=H, R3=OAc, R4=

OAc

OAc

OAc OAc

R1 O

O

26 23

H R 3O HO MeO R2 O HO MeO

HO O HO O OH O HO O OH

25 27

R O

O OH HO O

O OH HO

O O

O

H

O

197 Cladoloside K1 R=R1=OAc, R2=SO3Na, R3=H 198 Cladoloside K2 R=OAc, R1=OH, R2=SO3Na, R3=H, Δ25(26) 199 Cladoloside L1 R=O, R1=R2=H, R3=SO3Na, Δ25(26)

OH

Figure Chemical structures of holostane glycosides with 3β-hydroxyholost-9(11)-ene and six Figure 9.9.Chemical structures of holostane glycosides with 3β-hydroxyholost-9(11)-ene and six sugar units. sugar units.

Holostane Glycosides with 3β-Hydroxyholost-9(11)-ene Skeleton and Five Sugar Units Holostane Glycosides with 3β-Hydroxyholost-9(11)-ene Skeleton and Five Sugar Units The carbohydrate chains of glycosides in this group are either straight (200–218 and 223–229) The carbohydrate chains of glycosides in this group are either straight (200–218 and 223–229) or branched (219–222) (Figure 10 and Table 6). The 22,25-epoxy (200–202, 213–215) and two acetoxy or branched (219–222) (Figure 10 and Table 6). The 22,25-epoxy (200–202, 213–215) and two acetoxy groups, one at C-16 and another at C-22 (211, 212, 223–228), are common in holothurinosides and groups, one at C-16 and another at C-22 (211, 212, 223–228), are common in holothurinosides and cladolosides, respectively. Kolgaosides (204 and 205) and achlioniceosides (216–218) within their own cladolosides, respectively. Kolgaosides (204 and 205) and achlioniceosides (216–218) within their groups have the same carbohydrate chains and the only difference is in their respective aglycone own groups have the same carbohydrate chains and the only difference is in their respective side chains. aglycone side chains. Table 6. Name and producing species of glycosides with 3β-hydroxyholost-9(11)-ene and five sugar units. Table 6. Name and producing species of glycosides with 3β-hydroxyholost-9(11)-ene and five sugar Compound Name Producing Species Reference Compound Name Producing Species Reference units. Holothurinoside A (200)

Holothuria forskalii

[93]

17-dehydroxyholothurinoside A (201)

Holothuria grisea

[94]

Compound NameA1 (202)Producing Species Reference Compound Name Producing Reference Holothurinoside H.lessoni [95] Holothurinoside B (203) H. forskalii Species [93] Kolgaoside (204) Holothuria Kolgaforskalii hyalina [96] Kolgaoside B (205) hyalina Holothurinoside AA(200) 17-dehydroxyholothurinoside A (201) K. [93] Holothuria grisea [96] [94] Griseaside A (206) H. grisea [94] Impatienside B (207) H. axiloga [97] Holothurinoside AF1 (202) Holothurinoside B (203) H.lessoni [95] H. forskalii Arguside (208) Holothuria axiloga [97] Pervicoside D (209) H. axiloga [97] [93] Kolgaoside A (204) KolgaosideB1B(211) (205) KolgaA.hyalina [96] K. hyalina Cladoloside B (210) japonicus [22] Cladoloside C. schmeltzii [90] [96] Cladoloside B2 (212) schmeltzii [90] Holothurinoside H. lessoni [95] [97] Griseaside A (206) Impatienside EB(213) (207) H.C. grisea [94] H. axiloga Holothurinoside E1 (214) H. lessoni [95] Holothurinoside M (215) H. lessoni [95] Arguside F (208) Pervicoside D (209) Holothuria axiloga [97] H. axiloga [97] Achlioniceoside A1 (216) A. violaecuspidata [98] Achlioniceoside A2 (217) A. violaecuspidata [98] Cladoloside B (210) Cladoloside B 1 (211) A. japonicus [22] C. schmeltzii Achlioniceoside A3 (218) A. violaecuspidata [98] Ds-penaustroside C (219) P. australis [99] [90] Ds-penaustroside australis [99] Frondoside A2 -6 (221) C. frondosa [35] [95] Holothurinoside E (213) Cladoloside B2 (212)D (220) C. Pentacta schmeltzii [90] H. lessoni Cladoloside E1 (222) schmeltzii [91] Cladoloside E2 (223) C. schmeltzii [91] Holothurinoside M (215) Holothurinoside E1 (214) H. C. lessoni [95] H. lessoni [95] Cladoloside F1 (224) C. schmeltzii [91] Cladoloside F2 (225) C. schmeltzii [91] 1 (216) Achlioniceoside A 2 (217) Achlioniceoside A A. violaecuspidata [98] A. violaecuspidata Cercodemasoide A (226) C. anceps [100] Cladoloside I1 (227) C. schmeltzii [92] [98] Cladoloside C. schmeltzii [92] Cladoloside J1 (229) C. schmeltzii [92] [99] Ds-penaustroside C (219) Achlioniceoside A3 I(218) A. violaecuspidata [98] P. australis 2 (228) Ds-penaustroside D (220) Pentacta australis Frondoside A2-6 (221) C. frondosa [35] [99] Cladoloside E2 (223) Cladoloside E1 (222) C. schmeltzii [91] C. schmeltzii [91] Cladoloside F1 (224) Cladoloside F2 (225) C. schmeltzii [91] C. schmeltzii [91] Cercodemasoide A (226) Cladoloside I1 (227) C. schmeltzii [92] C. anceps [100] Cladoloside J1 (229) Cladoloside I2 (228) C. schmeltzii [92] C. schmeltzii [92]

Mar. Drugs 2017, 15, 317 Mar. Drugs 2017, 15, 317

17 of 35 17 of 35

R7

O

R8

O

R6

17

HO HO MeO

R3O HO R4O

R5 O 2

R O HO O OH

O

O OH HO R1 O O OH HO

O

O O

OH

200 Holothurinoside A R1=R3=R4=R5=H, R2=CH2OH, R6=R7=OH, R8=

O

201 17-dehydroxy holothurinoside A R1=R3=R5=R6=H, R2=CH2OH, R4=CH3, R7=OH, R8= 202 Holothurinoside A1 R1=R7=OH, R2=CH2OH, R3=R4=R5=R6=H, R8= 1

3

4

5

2

6

7

O

O

8

203 Holothurinoside B R =R =R =R =H, R =CH2OH, R =R =OH, R =

OAc

204 Kolgaoside A R1=R3=R4=R5=H, R2=CH2OH, R6=R7=OH, R8=

OH

205 Kolgaoside B R1=R3=R4=R5=H, R2=CH2OH, R6=R7=OH, R8=

OH

206 Griseaside A R1=R3=R4=R5=R6=H, R2=CH2OH, R7=OH, R8=

OH

207 Impatienside B R1=R3=R4=R5=R6=H, R2=CH2OH, R7=OH, R8= 208 Arguside F R1=R3=R4=R6=H, R2=CH2OH, R5=

OAc, R7=OH, R8=

209 Pervicoside D R1=R3=R4=R5=R6=H, R2=CH2OH, R7=OH, R8= 210 Cladoloside B R1=R2=R3=R4=R6=R7=H, R5=

OAc

O, R8=

211 Cladoloside B1 R1=R2=R3=R4=R6=R7=H, R5=

OAc, R8=

212 Cladoloside B2 R1=R2=R3=R4=R6=R7=H, R5=

OAc, R8=

OAc OAc

213 Holothurinoside E R1=R3=R4=R5=R6=H, R2=CH2OH, R7=OH, R8=

O

214 Holothurinoside E1 R1=OH, R3=R4=R5=R6=R7=H, R2=CH2OH, R8=

O

215 Holothurinoside M R1=R3=R5=R6=H, R2=CH2OH, R4=CH3, R7=OH, R8= 1

4

5

6

2

3

O

4

216 Achlioniceoside A1 R =R =R =R =H, R =CH2OSO3Na, R =SO3Na, R =CH3, R7=OH, R8= 217 Achlioniceoside A2 R1=R4=R5=R6=H, R2=CH2OSO3Na, R3=SO3Na, R4=CH3, R7=OH, R8= 218 Achlioniceoside A3 R1=R4=R5=R6=H, R2=CH2OSO3Na, R3=SO3Na, R4=CH3, R7=OH, R8= O

O

OH OH O

26 25

H

HO HO MeO

R2O O HO O OH

27

O 219 Ds-penaustroside C R1=R2=H, 25(26) Δ 220 Ds-penaustroside D R1=R2=H 221 Frondoside A2-6 R1=SO3Na, R2=H, Δ25(26)

O O R1O HO O O O O HO OH O O HO HO OH

222 Cercodemasoide A R1=R2=SO3Na, Δ25(26)

Figure 10. Cont. Figure 10. Cont.

Mar. Drugs 2017, 15, 317 Mar. Drugs 2017, 15, 317

18 of 35 18 of 35

OAc O

O

26

22

25

H R2 1

RO HO MeO

O

HO HO

O

O OH HO O O OH HO

O HO O OH

O

27

1 2 OAc 223 Cladoloside E1 R =R =H 224 Cladoloside E2 R1=R2=H, Δ25(26) 225 Cladoloside F1 R1=H, R2=Me

O

226 Cladoloside F2 R1=H, R2=Me, Δ25(26) 227 Cladoloside I1 R1=SO3Na, R2=CH2OH 228 Cladoloside I2 R1=SO3Na, R2=CH2OH, Δ25(26)

O

OH O

O H

NaO3SO HO MeO

HO HO O O OH HO HO

O O

O OH HO O O OH HO

O O

O

229 Cladoloside J1

O

OH

Figure 10. 10. Chemical Chemicalstructures structures of holostane glycosides with 3β-hydroxyholost-9(11)-ene andunits. five of holostane glycosides with 3β-hydroxyholost-9(11)-ene and five sugar sugar units.

Holostane Glycosides with 3β-Hydroxyholost-9(11)-ene Skeleton and Four Sugar Units Holostane Glycosides with 3β-Hydroxyholost-9(11)-ene Skeleton and Four Sugar Units The names and structures of the glycosides belonging to this group are summarized in the names and ofthe thesaponins glycosides belonging to this group summarized in the TableThe 7 and Figure 11.structures Almost all in this group contain sulfateare group at C-4 of xylose Table 7 and Figure 11. Almost all the saponins in this group contain sulfate group at C-4 of xylose sugar. The most common features of holothurins (230–233), scabrasides (235–237) and echinosides sugar. Theare most of holothurins (230–233), scabrasides (235–237) (243–249) the common presence features of hydroxy groups at C-12 and C-17 (Figure 11). Amongand the echinosides cladoloside (243–249) are the presence of hydroxy groups at C-12 and C-17 (Figure 11). Among the cladoloside series of compounds (266–271), either keto or acetoxy group is commonly found at position C-16 and series of compounds (266–271), either keto or acetoxy group is commonly found at position C-16 22. The uncommon linear sugar chain [3-O-MeGlc (1→3)-Glc (1→4)-Xyl (2→1)-Qui] is observed in and 22. The uncommon linear sugar chain [3-O-MeGlc (1→3)-Glc (1→4)-Xyl (2→1)-Qui] is observed bivittoside B (262). Another exceptional feature has been found in this category of compounds is the in bivittoside B (262). Anotherglucose exceptional has carbohydrate been found inchain this category compounds is presence of three consecutive unit infeature the linear (258 and of 259). the presence of three consecutive glucose unit in the linear carbohydrate chain (258 and 259). Table 7. Name and producing species of glycosides with 3β-hydroxyholost-9(11)-ene and four sugar units. Table 7. Name and producing species of glycosides with 3β-hydroxyholost-9(11)-ene and four sugar units. Compound Name

Producing Species Producing

Reference

Compound Name

Producing

Reference

Compound Name

Species ProducingSpecies

Holothurin A (230) Holothurin A (230) Holothurin A3 (232) Holothurinoside C (234) Holothurin A3 (232) Scabraside B Holothurinoside C (236) (234) Fuscocineroside A (238) Scabraside B (236) 17-hydroxy fuscocineroside B (240) Fuscocineroside A (238) Fuscocineroside C (242) Ds-echinoside A (244) P. graeffei 17-hydroxy fuscocineroside B. marmorata 22-hydroxy-24-dehydroechinoside A (246) Actinopyga flammea B (240) 25-hydroxydehydroechinoside A (248) A. flammea Fuscocineroside C (242) H. fuscocinerea Desholothurin A (250) P. graeffei Ds-echinoside AB(244) P.H.graeffei Pervicoside (252) pervicax Arguside A (254) Bohadschia argus 22-hydroxy-24-dehydroechinoside A Actinopyga flammea Hemoiedemoside A (256) H. spectabilis (246) Arguside D (258) B. argus 25-hydroxydehydroechinoside A (248) A. flammea Psolusoside A (260) Psolus fabricii Desholothurin P. graeffeibivitta BivittosideAB(250) (262) Bohadschia Holothurinoside Y (264) H.lessoni Pervicoside B (252) H. pervicax Cladoloside A1 (266) Cladolabes chmeltzii Arguside A (254) Bohadschia argus Cladoloside A (268) C. chmeltzii Hemoiedemoside A3 (256) H. C. spectabilis Cladoloside A5 (270) chmeltzii Arguside D (258) B. Colochiroside C (272) C. argus chmeltzii Mollisoside B1 (274) A. fabricii mollis Psolusoside A (260) Psolus

[101] [101] [103] [93] [103] [104] [93] [106] 104] [107] [106] [106] [109] [107] [110] [110] [106] [93] [109] [111] [112] [110] [113] [114] [110] [115] [93] [85] [116] [111] [117] [112] [117] [113] [117] [114] [64] [55] [115]

Holothurin A1 (231) Holothurin (231) Holothurin AA4 1(233) Scabraside AA(235) Holothurin 4 (233) Scabraside D Scabraside A(237) (235) Fuscocineroside B (239) Scabraside D (237) 25-hydroxy-fuscocineroside B (241) Fuscocineroside B (239) Echinoside A (243) 24-dehydroechinoside A (245) 25-hydroxy-fuscocineroside 24-hydroxy-25-dehydroechinoside A (247) B (241) 22-acetoxyechinoside A (249) Echinoside A (243) Pervicoside A (251) 24-dehydroechinoside Pervicoside C (253)A (245) Holothurinoside J1 (255) 24-hydroxy-25-dehydroechinoside A Hemoiedemoside (247) B (257) Arguside E (259) 22-acetoxyechinoside A (249) Liouvilloside A4 (261) Pervicoside AX(251) Holothurinoside (263) Holothurinoside (265) Pervicoside C Z(253) Cladoloside A2 (267) Holothurinoside J1 (255) Cladoloside A4 (269) Hemoiedemoside B (257) Cladoloside A6 (271) Arguside ED(259) Colochiroside (273) Neothyonidioside Liouvilloside A4 (275) (261)

H. grisea H.scabra grisea H. H. H. scabra scabra H. H. scabra scabra H. fuscocinerea H. scabra B. marmorata H.A.fuscocinerea echinites H. scabra B.A.marmorata flammea A. flammea A. echinites H. pervicax H.pervicax scabra H. P. graeffei A. flammea H. spectabilis B. argus A. flammea S. liouvillei H. H. pervicax lessoni H. pervicax lessoni H. C.P.chmeltzii graeffei C. chmeltzii H. spectabilis C. chmeltzii argus C.B. robustus mollis S.A.liouvillei

Bohadschia bivitta H.lessoni Cladolabes chmeltzii C.chmeltzii C.chmeltzii C.chmeltzii A. mollis

[85] [116] [117] [117] [117] [64] [55]

Holothurinoside X (263) Holothurinoside Z (265) Cladoloside A2 (267) Cladoloside A4 (269) Cladoloside A6 (271) Colochiroside D (273) Neothyonidioside (275)

H. lessoni H. lessoni C. chmeltzii C. chmeltzii C. chmeltzii C. robustus A. mollis

Compound Name

Bivittoside B (262) Holothurinoside Y (264) Cladoloside A1 (266) Cladoloside A3 (268) Cladoloside A5 (270) Colochiroside C (272) Mollisoside B1 (274)

Species Actinopyga agassizi Actinopyga agassizi Holothuria scabra H. forskalii Holothuria scabra scabra H. H. forskalii H. fuscocinerea H. scabra B. marmorata H.H. fuscocinerea fuscocinerea

Reference

Reference [102] [102] [103] [104] [103] [105] [104] [106] [105] [107] [106] [108] [105] [107] [110] [110] [108] [111] [105] [111] [95] [110] [113] [114] [110] [46] [111] [116] [116] [111] [117] [95] [117] [113] [117] [114] [63] [118] [46]

[116] [116] [117] [117] [117] [63] [118]

Mar. Drugs 2017, 15, 317 Mar. Drugs 2017, 15, 317

19 of 35 19 of 35

O

HO

R3

O 17

HO O HO O OH

HO HO MeO

O

R1O HO O O OH HO

O

242 Fuscocineroside C R1=SO3Na, R2=H, R3=

O

O

R2

O

243 Echinoside A R1=SO3Na, R2=OH, R3= 244 Ds-echinoside A R1=H, R2=OH, R3=

OH

24

1

2

3

230 Holothurin A R =SO3Na, R =OH, R = 1

2

O

246 22-hydroxy-24-dehydroechinoside A R1=H, R2=OH,

3

231 Holothurin A1 R =SO3Na, R =OH, R = 1

245 24-dehydroechinoside A R1=H, R2=OH, R3=

2

OH

R3=

3

232 Holothurin A3 R =SO3Na, R =OH, R =

OH

O

OH 247 24-hydroxy-25-dehydroechinoside A R1=SO3Na, OH

OH

233 Holothurin A4 R1=SO3Na, R2=OH, R3= 234 Holothurinoside C R1=R2=H, R3=

R2=OH, R3= 248 25-hydroxydehydroechinoside A R1=SO3Na,

O

R2=OH, R3=

235 Scabraside A R1=SO3Na, R2=OH, R3= 236 Scabraside B R1=SO3Na, R2=OH, R3=

249 22-acetoxy-echinoside A R1=H, R2=OH, 3 R=

O

237 Scabraside D R1=SO3Na, R2=OH, R3= 1

2

OH

250 Desholothurin A R1=H, R2=OH, R3=

3

238 Fuscocineroside A R =SO3Na, R =H, R =

O 240 17-hydroxy fuscocineroside B R1=SO3Na, R2=OH,

252 Pervicoside B R1=SO3Na, R2=H, R3=

R3= O 241 25-hydroxy fuscocineroside B R =SO3Na,

253 Pervicoside C R1=SO3Na, R2=H, R3=

1

4

6

7

8

R =R =R =R =OH, R =

R4 HO MeO

R3O O HO O OH

254 Arguside A R1=H, R2=

25

O

R7

O

R8

O

R

3

OAc

OAc, R3=

O

R2=R6=R7=H, R4=OH, R8=

1 3 4 R5 257 Hemoiedemoside B R =R =SO3Na, R = OSO3Na

R2=R6=R7=H, R5= O, R8= H O 258 Arguside D R1=R3=R6=H, R2=R4=R7=OH, R5=H, R8= O O 1 3 6 2 4 7 5 8 259 Arguside E R =R =R =H, R =R =R =OH, R =H, R = OH O O O

260 Psolusoside A R1=R2=R6=R7=H, R3=SO3Na, R4=OSO3Na, R5= 1

O

256 Hemoiedemoside A R1=R3=SO3Na, R5=

6

O

R1O HO R2 O O OH HO

OAc

OH

255 Holothurinoside J1 R1=R3=H, R5=H, 2

OH

251 Pervicoside A R1=SO3Na, R2=H, R3=

O

239 Fuscocineroside B R1=SO3Na, R2=H, R3=

R2=H, R3=

24

2

4

6

7

5

261 Liouvilloside A4 R =R =SO3Na, R =R =R =R =H, R =

O, R8= 8

O, R =

Figure Figure 11. 11. Cont. Cont.

OAc

Mar. Drugs 2017, 15, 317 Mar. Drugs 2017, 15, 317

20 of 35 20 of 35 HO

O

O

25

HO

HO O HO O OH

O O OH HO HO HO

O

O

H

262 Bivittoside B

HO MeO

HO

O

O

O HO O HO MeO OH

H

1

R

O HO O OH

O

OH

HO HO HO O O OH HO O

R3

22

O

O

1 O O 263 Holothurinoside X R =H, 22- O 1 264 Holothurinoside Y R =Me OH 265 Holothurinoside Z R1=Me, 22-OH

266 Cladoloside A1 R1=H, R2=OAc, R3=

H 267 Cladoloside A R1=H, R2=OAc, R3= 2

OAc

R2 268 Cladoloside A3 R1=H, R2=OAc, R3= HO HO MeO

R1

O HO O OH

HO HO O O OH HO

O

O

269 Cladoloside A4 R1=H, R2=

O O

270 Cladoloside A5 R1=H, R2=

O, R3=

O

OH

O, R3=

271 Cladoloside A6 R1=CH2OH, R2=OAc, R3=

OH

OAc

OAc

O H O

4

RO HO MeO

O HO O OH

R3

R1O HO R2 O O OH HO

O O

272 Colochiroside C R1=R4=SO3Na, R2=R3=H

O

273 Colochiroside D R1=R4=H, R2=OH, R3=CH2OSO3Na

O

274 Mollisoside B1 R1=SO3Na, R2=OH, R3=R4=H 275 Neothyonidioside R1=SO3Na, R2=R3=R4=H

OH

Figure 11. Chemical Chemicalstructures structures of holostane glycosides with 3β-hydroxyholost-9(11)-ene Figure 11. of holostane glycosides with 3β-hydroxyholost-9(11)-ene and fours and ugarfours units. ugar units.

Holostane Glycosides with 3β-Hydroxyholost-9(11)-ene Skeleton and 1–3 Sugar Units Holostane Glycosides with 3β-Hydroxyholost-9(11)-ene Skeleton and 1–3 Sugar Units Only one type of carbohydrate chain, D-xylose-D-quinovose, is found in all glycosides in this group -xyloseis foundchain in allis glycosides in this Only type of carbohydrate chain, D having twoone monosaccharide units (278–290), except 291D-quinovose, where carbohydrate D-xylose- D-xylose group having two monosaccharide units (278–290), except 291 where carbohydrate chain is (Figure 12 and Table 8); sulfate groups at C-4 of xylose units are also commonly found as well, except D-xylose-D-xylose (Figure 12 and Table 8); sulfate groups at C-4 of xylose units are also commonly 285, 288 and 291. Hydroxy groups at either C-12 or C-17, or both positions, are observed in all the found as well, except 285, 288 and 291. Hydroxy groups at either C-12 or C-17, or both positions, are compounds in this category (Figure 12), except cercodemasoides (276–279). observed in all the compounds in this category (Figure 12), except cercodemasoides (276–279). Table 8. Name and producing species of glycosides with 3β-hydroxyholost-9(11)-ene and 1–3sugar units. Table 8. Name and producing species of glycosides with 3β-hydroxyholost-9(11)-ene and 1–3sugar units. Compound Name Producing Species Reference Compound Name Producing Species Reference Cercodemasoide B (276)

Cercodemas anceps

[100]

Cercodemasoide C (277)

C. anceps

[100]

Compound Name Producing Species Reference Compound Name Producing Species[100] Reference Cercodemasoide D (278) C. anceps [100] Cercodemasoide E (279) C. anceps Cercodemasoide (276) Cercodemasoide C (277) H. lessoni Cercodemas anceps [100] C. anceps Holothurin B (280) Holothuria lessoni [119] Holothurin B1 (281) [120] [100] Holothurin B (282) polii [121] Holothurin B3 (283) H. polii [121] [100] Cercodemasoide D2 (278) Cercodemasoide E (279) C.H.anceps [100] C. anceps Holothurin B4 (284) H. polii [121] Holothurinoside D (285) H. forskalii [93] Holothurin B (280) Holothurin B 1 (281) Holothuria lessoni [119] H. lessoni [120] Leucospilotaside A (286) H. leucospilota [122] Leucospilotaside B (287) H. leucospilota [122] Holothurin B2 (282) Holothurin B3 (283) H. polii [121] H. polii Bivittoside A (288) Bohadschia bivittata [85] Echinoside B (289) A. echinites [108] [121] mauritiana [123] Hillaside C (291)D (285) Holothuria hilla [124] [93] 24-dehydroechinoside Holothurin B4 (284) B (290) Actinopyga Holothurinoside H. polii [121] H. forskalii Hillaside B (292) H. hilla [81] Leucospilotaside A (286) Leucospilotaside B (287) H. leucospilota [122] H. leucospilota [122] Bivittoside A (288) Echinoside B (289) Bohadschia bivittata [85] A. echinites [108] 24-dehydroechinoside B (290) Actinopyga mauritiana Hillaside C (291) [123] Holothuria hilla [124] Hillaside B (292) H. hilla [81]

Mar. Drugs 2017, 15, 317

21 of 35

Mar. Drugs 2017, 15, 317

21 of 35

O

O H

O NaO3SO HO RO HO NaO3SO HO RO HO R1O HO HO 1 RHO O HO

O

26 NaO3SO O 21 of 35 276 Cercodemasoide B R= HO HO 27 OH NaO3SO O 26 HO R= 3SO 277 Cercodemasoide CNaO HO 25 OOH , Δ25(26) HO 276 Cercodemasoide B R=HHO 278 Cercodemasoide DR= 27 OH Δ25(26) 279 Cercodemasoide E NaO R=H, 3SO O HO 1 2 3 4 277 Cercodemasoide 280 Holothurin B R =SO3Na,CRR= =R =OH, HO R = OH O , Δ25(26) 278 Cercodemasoide 2 281 Holothurin B1 R1=SO3Na,DRR=H =R3=OH, R4= 279 Cercodemasoide E R=H, Δ25(26) 2 282 Holothurin B R1=SO3Na, R =R3=OH, R4= 280 Holothurin B 2R1=SO3Na, R2=R3=OH, R4= OH O 281 R4=R4= 283 Holothurin Holothurin B B13 R R11=SO =SO33Na, Na, R R22=R =H,3=OH, R3=OH, O 25

Mar. Drugs 2017, 15, 317

O

O H

O 3O

O O

R4 O

O

R

R2

O O OH O O OOHO O O O OH O

R3

O

R4

O

R2

H

284 Holothurin Holothurin B24 R R11=SO33Na, Na, R22=R =R33=OH, =OH, R R44== 282

OH

OH

283 B3 R1=SO Na,2=H, R2=H, R3=OH, 285Holothurin Holothurinoside D R13=R R3=OH, R4=R4= O O 1 2 3 4 O 284 Holothurin B4 R =SO R =R =OH, = 3Na, R2=R3=OH, 3Na, 289 Echinoside B R1R=SO O OH 286 Leucospilotaside A R1=SO3Na, R2=R3=OH, R4= HO O OH 4 HO R 4= 1 2 3 OH O 287 Leucospilotaside B R1=SO3Na, R2=R3=OH, R4=285 Holothurinoside D R =R =H, R =OH, R = OH OH 290 24-dehydroechinoside B R12=SO33Na, 1 1 21 3 43 289 Echinoside B R =SO Na, R =R =OH, 2 3 2 4 3 4 288Leucospilotaside Bivittoside A R =R R3Na, =OH, R =R =OH, R = 286 A R=H, =SO RR =R= =OH, R = O OH R4= 4 O O O 2 3 287 Leucospilotaside B R1=SOHO HO 3Na, R =RO=OH, R = OH OH 290 24-dehydroechinoside B R1=SO OH3Na, OH 1 2 3 4 4 288 Bivittoside A R =R =H, R =OH, R = OH R2=R3=OH, ROH = H

HO

O

O

HO

O

O

OAc

OH OH O O OH HO HO H H 292 Hillaside B 291 Hillaside C HO HO OH OAc O O HO HO O O OH O O HO HO H H 292 Hillaside B 291 Hillaside C HO HO OH O Figure 12. Chemical structure of holostane glycosides with 3β-hydroxyholost-9(11)-ene and 1–3 O Figure 12.HO Chemical structure of holostane glycosides with 3β-hydroxyholost-9(11)-ene and 1–3 sugar units. HO units. sugar OH OH

O O

12. Chemical structure of holostane glycosides with Skeleton 3β-hydroxyholost-9(11)-ene 4.1.3.Figure Holostane Glycosides with 3β-Hydroxyholost-8(9)-ene 4.1.3. Holostane Glycosides with 3β-Hydroxyholost-8(9)-ene Skeleton

and 1–3

sugar units.

Only three glycosides belong to this group with carbohydrate chain consisting of 4–5

Only three glycosides belong to this group with carbohydrate chain consisting of 4–5 monosaccharide units (Table 9 and Figure 13). Among holostane sea cucumber glycosides, only one 4.1.3. Holostane Glycosides with 3β-Hydroxyholost-8(9)-ene Skeleton monosaccharide (TableA19(293 and Figureketo 13). Among glycoside,units synaptoside ), contains group at C-7. holostane sea cucumber glycosides, only three glycosides belong to thisketo group with at carbohydrate chain consisting of 4–5 one glycoside,Only synaptoside A1 (293), contains group C-7. monosaccharide (Table 9 and Figure 13). Among holostane sea cucumber glycosides, only one Table 9. Nameunits and producing species of holostane glycosides with 3β-hydroxyholost-8(9)-ene skeleton. glycoside, synaptoside A1 (293), contains keto group at C-7.

Name and producing species of holostane with 3β-hydroxyholost-8(9)-ene skeleton. Table 9.Compound Name Producing Species Referenceglycosides Compound Name Producing Species Reference Synaptoside A1 (293) Variegatuside B (294) Stichopus variegates Synapta maculata [41] [73] Table 9. Name and producing species of holostane glycosides with 3β-hydroxyholost-8(9)-ene skeleton. Variegatuside Stichopus variegatesReference [21] Compound Name D (295) Producing Species Compound Name Producing Species Reference Compound Name Producing Species Reference Compound Name Producing Species Reference Synaptoside A1 (293) Synapta maculata [41] Variegatuside B (294) Stichopus variegates [73] Synaptoside A1 (293) Variegatuside B (294) Stichopus variegates Synapta maculata [41] [73] O O Variegatuside D (295) Stichopus variegates [21] Variegatuside D (295) Stichopus variegates [21]

HO O NaO3SO HO HO HO NaOOC NaO SO O 3HO HO HO O MeO OHHO HO NaOOC O HO HO 2017, 15, 317 Mar. Drugs O MeO OH

O

O OH HO O O O O OH HO HO OH O

O OH HO O

O

O

O

H

O O

HO O

O

O O O H OH O O Figure 13. Cont.

O

293 Synaptoside A1 293 Synaptoside A1

O

22 of 35

OH Figure 13. Cont. H OH

R3O HO HO R2O R1O

O O

O

H

O

HO O HO 294 Variegatuside B R1= HO O MeO OH HO O O HO 295 Variegatuside D R1=H, R2= HO O MeO OH OH

O OH

, R2=R3=H

HO , R3= HO HO

O OH

OH

Figure 13. Chemical structures of holostane glycosides with 3β-hydroxyholost-8(9)-ene skeleton.

Figure 13. Chemical structures of holostane glycosides with 3β-hydroxyholost-8(9)-ene skeleton. 4.2. Nonholostane Glycosides As mention earlier, like holostane glycosides, nonholostane glycosides do not have γ(18,20)-lactone structural unit (Figures 14 and 15, Table 10). There are six different structural units (Figure 14) present in D- and E rings of aglycone in nonholostane glycosides. The aglycone side chain can be long or short, and may contain keto, methylene, hydroxy and acetoxy functional groups (Figure 15). Instead of γ(18,20)-lactone, some glycosides in this group contain γ(16,18)-lactone

MeO R3O HO HO R2O R1O

O O

O

HO 295 Variegatuside D R1=H, R2= HO MeO

H

O

OH

OH O

O HO O OH

OH

HO , R3= HO HO

O OH

OH

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22 of 35

Figure 13. Chemical structures of holostane glycosides with 3β-hydroxyholost-8(9)-ene skeleton.

4.2. Nonholostane Glycosides As mention earlier, like holostane glycosides, nonholostane nonholostane glycosides glycosides do not have γ(18,20)-lactone structural γ(18,20)-lactone structural unit unit (Figures (Figures 14 14 and 15, Table 10). There are six different structural units (Figure 14) present in in DD- and and EE rings rings of of aglycone aglycone in in nonholostane nonholostane glycosides. glycosides. The aglycone side chain can be long or short, and may contain keto, methylene, hydroxy and acetoxy functional groups (Figure 15). 15).Instead Instead γ(18,20)-lactone, glycosides this contain group γ(16,18)-lactone contain γ(16,18)-lactone (Figure of of γ(18,20)-lactone, somesome glycosides in thisin group (296–300, (296–300, 314, 322, and 341). Cucumariosides (305) contain and A9uncommon (306) contain uncommon 314, 322, 332–340 and332–340 341). Cucumariosides A8 (305) and A98 (306) hydroxy group hydroxy group at C-18. 1 (322) and D 3 (327) are novel glycosides with unprecedented at C-18. Fallaxosides B1Fallaxosides (322) and DB (327) are novel glycosides with unprecedented skeletons of 3 skeletons ofPsolusoside aglycones.BPsolusoside B (314) and Kuriloside (316) have four members which sugar aglycones. (314) and Kuriloside C (316) have fourCmembers sugar architecture architecture which areholostane uncommon both holostane and nonholostane glycosides. Another are uncommon in both and in nonholostane glycosides. Another uncommon feature of this uncommon feature ofisthis of compounds is the presence of keto at group C-11 (323 and 325). group of compounds thegroup presence of keto group at C-11 (323 and 325).group Sulfate is commonly Sulfateatgroup commonly found at C-4 first of xylose unit (Figure 15). Most ofhave the branched nonholostane found C-4 ofisfirst xylose unit (Figure 15).ofMost the nonholostane glycosides five glycosidescarbohydrate have branched five(Figure members members chain 15).carbohydrate chain (Figure 15). O

O O

H

I

H

II

H III

O

O

HO

O AcO

HO

H

IV

V

VI

Figure 14. DD- and E-ring structural architectures present in nonholotane glycosides. Table 10. Name and producing species of nonholostane glycosides. Table 10. Name and producing species of nonholostane glycosides. Compound Name Producing Species Reference Compound Name Producing Species Reference Cucumarioside G2 (296) Cucumarioside A10 (297) E. fraudatrix [125] E. fraudatrix [67] Compound Name Producing Species Reference Compound Name Producing Species Reference Calcigeroside B (298) Calcigeroside C1 (299) P. calcigera [37] P. calcigera [37] Cucumarioside G2 (296) E. fraudatrix [125] Cucumarioside A10 (297) E. fraudatrix [67] Cucumarioside 3-2 (301) Cucumarioside H3 B(300) E. fraudatrix [30] C.P. conicospermium Calcigeroside (298) P. calcigera [37] Calcigeroside C1A(299) calcigera [37] [26] 3 -3 (302) Koreoside A (303) Cucumarioside A C. conicospermium [26] C. koraiensis Cucumarioside H3 (300) E. fraudatrix [30] Cucumarioside A3 -2 (301) C. conicospermium [26] [126] Cucumarioside A3 -3 (302) C. conicospermium C. conicospermium [26] Koreoside A (303) C. koraiensis [126] [67] Isokoreoside A (304) Cucumarioside A8 (305) E. fraudatrix [26] Isokoreoside A (304) C. conicospermium [26] Cucumarioside A8 (305) E. fraudatrix [67] Holotoxin F (307) Cucumarioside A9 (306) E. fraudatrix [67] A. japonicus [22] Cucumarioside A9 (306) E. fraudatrix [67] Holotoxin F (307) A. japonicus [22] Holotoxin G (308) Holotoxin (309) A. A. japonicus [22] S. japonicus Holotoxin G (308) japonicus [22] Holotoxin HH (309) S. japonicus [127] [127] Holotoxin I (310) S. japonicus [127] Ds-penaustroside A (311) P. australis [99] [99] Holotoxin I (310) Ds-penaustroside A (311) S. japonicus [127] P. australis Ds-penaustroside B (312) P. australis [99] Frondoside C (313) C. frondosa [128] Ds-penaustroside B (312) Frondoside C (313) P. australis [99] C. frondosa [128] Psolusoside B (314) Psolus fabricii [129] Kuriloside A (315) D. kurilensi [130] Psolusoside B (314) Kuriloside (315) Psolus fabricii [129] D. kurilensi Kuriloside C (316) D. kurilensi [130] Frondoside A2 A -7 (317) C. frondosa [36] [130] Frondoside A2 -8 (318) frondosa [36] Frondoside AA (319) C. frondosa [43] [36] (317) Kuriloside C (316) Frondoside C. frondosa D. C. kurilensi [130] 7 -32-7 Frondoside frondosa [43] IsofrondosideAC7-3 (321) C. frondosa [43] [43] 7 -4 (320) Frondoside (319) Frondoside A2-8A(318) C. C. frondosa [36] C. frondosa Fallaxoside B1 (322) C. fallax [131] Fallaxoside C1 (323) C. fallax [132] Isofrondoside C (321) Frondoside A7-4C(320) C. frondosa [43] frondosa Fallaxoside C. fallax [132] Fallaxoside D1 (325) C.C. fallax [132] [43] 2 (324) Fallaxoside 1 (323) Fallaxoside B1 (322) C. C. fallax [131] C. fallax Fallaxoside D2 (326) fallax [132] Fallaxoside D3C(327) C. fallax [131] [132] Fallaxoside D4 (328) fallax [133] Fallaxoside D5D(329) C. fallax [133] [132] Fallaxoside 1 (325) Fallaxoside C2 (324) C. C. fallax [132] C. fallax Fallaxoside D6 (330) C. fallax [133] Fallaxoside D7 (331) C. fallax [133] Fallaxoside D3 (327) Fallaxoside D2 (326) C. fallax [132] C. fallax [131] Magnumoside A1 (332) Massinium magnum [134] Magnumoside A2 (333) M. magnum [134] Fallaxoside AD45(335) (329) Fallaxoside D4 (328) C. [133] C. fallax Magnumoside A3 (334) M.fallax magnum [134] Magnumoside M. magnum [134] [133] Magnumoside B1 (336) M.fallax magnum [134] Magnumoside M. magnum [134] [133] Fallaxoside BD27(337) (331) Fallaxoside D6 (330) C. [133] C. fallax Magnumoside C1 (338) M. magnum [134] Magnumoside C2 (339) M. magnum [134] Magnumoside A2 (333) Magnumoside A1 (332) Massinium magnum [134] M. magnum [134] Magnumoside C4 (340)

M. magnum

[134]

Colochiroside E (341)

C. robustus

[135]

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Magnumoside A3 (334) Magnumoside B1 (336) 1 (338) Magnumoside Mar. Drugs 2017, C 15, 317 Magnumoside C4 (340)

M. magnum M. magnum M. magnum M. magnum

Magnumoside A4 (335) Magnumoside B2 (337) Magnumoside C2 (339) Colochiroside E (341)

[134] [134] [134] [134]

M. magnum M. magnum M. magnum C. robustus

[134] [134] [134] 23 of 35 [135]

O 296 Cucumarioside G2 R1=SO3Na, R2=H 297 Cucumarioside A10 R1=R2=H O

1

HO MeO

RO HO

HO O HO O OH

H 298 Calcigeroside B R1=SO3Na, R2= HO HO HO HO 299 Calcigeroside C R1=SO3Na, R2= HO

O

O

H

300 Cucumarioside H3 R1=SO3Na, R2= HO HO

O O

O

O OH HO

O OH O OH O

OH O 301 Cucumarioside A3-2 R1=R2=SO3Na, R3=H, Δ7(8)

OR2

1 2 3 9(11) H 302 Cucumarioside A3-3 R =R =SO3Na, R =H, Δ 303 Koreoside A R1=R2=R3=SO3Na, Δ7(8)

R3O HO MeO

R2O O HO O OH

O OH HO

R

O HO O OH

R

H 21

R7 HO 18

O O

HO HO

2

304 Isokoreoside A R1=R2=R3=SO3Na, Δ9(11) O

O O

O

3

HO R4O

O

R1O HO

O

R1O HO O OH HO

25 20

H

OH

O

R8

R6 305 Cucumarioside A8 R1=R3=R5=R8=H, R2=CH2OH,

O

R4=Me, R6=OAc, R7=OH, Δ7(8),24 306 Cucumarioside A9, R1=R3=R5=R8=H, R2=CH2OH, R4=Me, R6=OAc, R7=OH, 24-OH, Δ7(8),25(26)

H

O O OR5

HO O 307 Holotoxin F R1= HO , R2=R5=R7=R8=H, R3=CH2OH, R4=Me, R6= O, Δ9(11),25(26) HO OH HO O 308 Holotoxin G R1= HO , R2=R4=R5=R7=R8=H, R3=CH2OH, R6= O, Δ9(11),25(26) HO OH HO O , R2=R4=R5=R7=R8=H, R3=CH2OH, R6= O, Δ9(11),25(26), de-Me at C-20 309 Holotoxin H R1= HO HO OH HO O , R2=R5=R7=R8=H, R3=CH OH, R4=Me, R6= O, Δ9(11),25(26), de-Me at C-20 310 Holotoxin I R1= HO 2 HO O OH HO 311 Ds-penaustroside A R1=R6=R7=R8=H, R2=R3=CH2OH, R4=Me, R5= HO , Δ9(11) OH O HO 312 Ds-penaustroside B R1=R6=R7=R8=H, R2=R3=CH2OH, R4=Me, R5= HO , Δ9(11),25(26) OH O HO 313 Frondoside C R1=SO3Na, R2=R3=CH2OSO3Na, R4=Me, R5= HO , R6=R7=H, R8=OAc, Δ9(11),24(25) OH O AcO O

314 Psolusoside B NaO3SO HO HO HO HO HO

O

O OH HO O HO O OH HO

O O HO O HO O MeO OH

O

H

H OAc

H

NaO3SO O HO O OH

O OH

O

O HO

RO HO

Figure 15. Figure 15. Cont. Cont.

O OH

O

O

H HO 315 Kuriloside A R= HO HO 316 Kuriloside C R=H

O OH

Mar. Drugs 2017, 15, 317 Mar. Drugs 2017, 15, 317

24 of 35 24 of 35

R3 HO 317 Frondoside A2-7 R1=R2=H, R3=OAc, Δ9(11) 318 Frondoside A2-8 R1=R2=H, R3=OAc, Δ7(8) NaO3SO HO O O OH HO

R1O O HO O OH

R2O HO MeO

HO HO 21

319 Frondoside A7-3 R1=R2=SO3Na, R3=OH, Δ9(11)

O

320 Frondoside A7-4 R1=R2=SO3Na, R3=OH, Δ7(8)

O O

321 Isofrondoside C R1=R2=SO3Na, R3=OAc, Δ7(8)

O O OH

O

18

O

O

O

20

11

H

17

H

13

O

H

Sugars

O

NaO3SO HO O O OH HO

R1O O HO O OH

R2O HO MeO

H B

Sugars

A

O

HO HO

O

17

O

16

H

Sugars

C

324 Fallaxoside C2 Aglycone=B, R1=SO3Na, R2=H 325 Fallaxoside D1 Aglycone=A, R1=SO3Na, R2=SO3Na; 326 Fallaxoside D2 Aglycone=B, R1=SO3Na, R2=SO3Na

O O

327 Fallaxoside D3 Aglycone=D, R1=SO3Na, R2=SO3Na O

O

O

HO

H

HO

Sugars

O

OH

H

O

H

Sugars

H

O Sugars

ii

i

iii

O

H

HO HO

O O O

O

Sugars

H

OH

H iv

328 Fallaxoside D4 Aglycone + i 329 Fallaxoside D5 Aglycone + ii 330 Fallaxoside D6 Aglycone + iii 331 Fallaxoside D7 Aglycone + iv

332 Magnumoside A1 R=

R O

H

OH

O

H

O Algycone NaO3SO HO NaO3SO NaO3SO O O O HO O O HO O HO MeO OH OH O O HO HO OH

NaO3SO HO

O

333 Magnumoside A2 R= HO 334 Magnumoside A3 R= HO

H

O

D

H

O

OH

323 Fallaxoside C1 Aglycone=A, R1=SO3Na, R2=H

O O

O HO

H

O Algycone 322 Fallaxoside B1 Aglycone=C, R1=H, R2=SO3Na

OH

H

O

O

H

Sugars

O

H

H

7

O

H

HO O 18

335 Magnumoside A4 R= HO

OH Figure 15. Cont. Figure 15. Cont.

H

OH OH

Mar. Drugs 2017, 15, 317 Mar. Drugs 2017, 15, 317

25 of 35 25 of 35

R2 O

HO

22

H

O

1

RO HO MeO

O OH

O HO

O

NaO3SO HO O O OH HO

26 25 27

336 Magnumoside B1 R1=R2=H, 25-OH, Δ23 O

336 Magnumoside B2 R1=H, R2=OH, Δ25(26) 338 Magnumoside C1 R1=SO3Na, R2=H, 25-OH, Δ23

H

O O

339 Magnumoside C2 R1=SO3Na, R2=OH, Δ25(26)

OH

340 Magnumoside C4 R1=SO3Na, R2=H, Δ24 O AcO O

HO HO HO

O

O HO OSO3Na HO HO HO

O

O

O

H

341 Colochiroside E

H

O

OH

Figure 15. Chemical structures of nonholostane glycosides. Figure 15. Chemical structures of nonholostane glycosides.

5. The Important Biological Properties of Sea Cucumber Glycosides 5. The Important Biological Properties of Sea Cucumber Glycosides Triterpene glycosides are the prime bioactive metabolites of sea cucumbers, and are commonly Triterpene glycosides are the prime bioactive metabolites sea cucumbers, are commonly known as toxins of sea cucumbers to eukaryotic cells. These of glycosides showed and a wide range of known as toxins of seaincluding cucumbers to eukaryotic cells. antiviral, These glycosides a wide and range biological activities cytotoxic, antifungal, hemolytic,showed antiprotozoal of immunomodulatory biological activitiesactivities. including cytotoxic, antifungal, antiviral, hemolytic, antiprotozoal and Sea cucumbers produce some major glycosides in sufficient amount immunomodulatory activities. Sea cucumbers produce some major glycosides in sufficient amount to carry out a wide range of biological activity tests [37,94]. Besides major glycosides, they also to produce carry out a wide range of biologicaltoactivity testsof[37,94]. Besides major glycosides, they also minor glycosides insufficient test a range biological activities [66,67]. The point to be produce minor insufficient to testare a range of exhibit biological activities [66,67]. to be noted here is glycosides that sea cucumber glycosides able to biological activities in The bothpoint in vitro and here in vivo models [5]. The remarkable biological showed byactivities some triterpene noted is that sea cucumber glycosides are able properties to exhibit biological in bothglycosides in vitro and Table 11. Triterpene glycosides do not exhibit antibacterial activity, indicating thatare in are vivosummarized models [5].inThe remarkable biological properties showed by some triterpene glycosides these glycosides are probably produced by sea cucumbers for defence against eukaryotic predators. that summarized in Table 11. Triterpene glycosides do not exhibit antibacterial activity, indicating these glycosides are probably produced by sea cucumbers for defence against eukaryotic predators. Table 11. Remarkable biological activities exhibited by some sea cucumber glycosides.

Table 11. Remarkable biological activities exhibited by some sea cucumber glycosides. Compound Activity Against/For Activity Result Reference Hillaside C (285) Cytotoxic Human tumor cell lines IC50: 0.15–3.20 µg/mL [124] Compound Activity Against/For Activity Result 23 mm zone Reference [113] Hemoiedemoside A (251) Antifungal C. cucumerinum 20 µg/disc: Fuscocineroside C (237) Cytotoxic Human tumor cell lines IC50: 0.88µg/mL and 0.58 µg/mL[124] [106] Hillaside C (285) Cytotoxic Human tumor cell lines IC50 : 0.15–3.20 Hemoiedemoside Antifungal C. cucumerinum zone µg/mL [113] Intercedenside A (66) A (251) Cytotoxic Human tumor cell lines 20 µg/disc: ED23 50: mm 0.96–4.0 [49] Fuscocineroside Cytotoxic Human tumor cell lines and500.58 µg/mLµg/mL [106] Intercedenside B (67)C (237) : 0.61–2.0 [49] Cytotoxic Human tumor cell lines IC50 : 0.88 ED Intercedenside A (66) Cytotoxic Human tumor cell lines ED50 : 0.96–4.0 µg/mL [49] Intercedenside C (68) 50: 0.96–4.0 µg/mL [49] Cytotoxic Human tumor cell lines ED Intercedenside B (67) Cytotoxic Human tumor cell lines ED50 : 0.61–2.0 µg/mL [49] Holothurinoside A (195) [93] Cytotoxic Human tumor cell lines IC50: 0.33–0.71 Intercedenside C (68) Cytotoxic Human tumor cell lines ED50 : 0.96–4.0 µg/mL µg /mL [49] Holothurinoside A (195) Cytotoxic Human tumor cell lines IC50 : 0.33–0.71 µg/mL µg /mL [93] Holothurinoside C (229) [93] Cytotoxic Human tumor cell lines IC50: 0.16–0.93 Holothurinoside Cytotoxic Human tumor cell lines IC50 : 0.16–0.93