Sea Cucumber Glycosides: Chemical Structures, Producing Species and Important Biological Properties

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Review 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 School of Science and Technology, Bangladesh Open University, Board Bazar, Gazipur 1705, Bangladesh; [email protected] 2 Marine Natural Products Laboratory, Korea Institute of Ocean Science and Technology, 787 Haeanro, Ansan 427-744, Korea 3 World Fisheries University Pilot Programme, Pukyong National University (PKNU), 45 Yongso-ro, Nam-gu, Busan 48513, Korea; [email protected] 4 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 www.mdpi.com/journal/marinedrugs Mar. Drugs 2017, 15, 317 2 of 35 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 H2O. Desalting will be carried out by passing this fraction through a Polychrom column (Teflon), eluting first the inorganic salts and crude polar impurities with H2O 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-H2O). 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 13C and 1H NMR spectra, respectively. The sequence Mar. Drugs 2017, 15, 317 3 of 35 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 (1H NMR, 13C 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-lanostano- γ(18,20)-lactone] (Figure1). 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) (Figure2) 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 (Figure3). 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 (Figure3). 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. Mar. Drugs 2017, 15, 317 3 of 35

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 (1H NMR, 13C 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-lanostano- γ(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 Mar. Drugs 2017“Ds”, 15 stands, 317 for desulfated. Sea cucumber triterpene glycosides are chemotaxonomic markers 4 of 35 specific for groups of genera within each family.

21 22 21 21 20 26 26 18 25 O O O 18 O 26 H 20 25 18 23 20 23 25 11 27 E 19 13 17 11 17 27 11 17 19 13 19 C13 27 1 9 H 14 1 H 9 16 1 9 H D 16 10 8 H 10 8 10 8 32 3 H A H 4 32 3 B 32 4 4 6 H H 6 HO 6 30 31 30 H 31 30 31 5α-lanostane 20S-hydroxy-5α-lanostano-γ(18,20)-lactone 3β,20S-dihydroxy-5α-lanostano-γ(18,20)-lactone (Holostane) (Holostanol) Figure 1. Structures of lanostane, holostane and holostanol. Mar. Drugs 2017, 15, 317Figure 1. Structures of lanostane, holostane and holostanol. 4 of 35

Mar. Drugs 2017, 15, 317 4 of 35 HO HO O O O O O HOHO OH HOHO OH HO OH HO OH HO OH HOHO O OH MeO O OH HO O MeO O OH HO O OH OH HO HO OH HO OH HO HO MeO OH HO OH MeO HO OH D-glucose 3-O-methyl-D-glucose D-xylose Mar. Drugs 2017, 15OH, 317 OH OH 3-O-methyl-D-xyloseOH D-quinovoseOH 4 of 35 D-glucose 3-O-methyl-D-glucose D-xylose 3-O-methyl-D-xylose D-quinovose Figure 2. Common sugar units present in sea cucumber glycosides. HO Figure 2. HOCommon sugar units present in sea cucumber glycosides. O Figure 2. CommonO sugar units presentO in sea cucumber Oglycosides. O HO OH HO OH HO OH HO OH HO OH MeGlcHO Glc Xyl MeO HO 6 HO 5 MeO1 HOHO 5 HO 1 MeGlc O O O O 1 O HO HOOHGlc O Xyl OH HO OH O OH HO OH HO 6 HOO 5 1 O HO 5 O HO 1 O MeOD-glucoseO 3-O O-HOmethyl-D-glucoseO HOD-xyloseO HO 1 O 4 HO 3 O HO OHHO OH O HO OH 3-O O-methyl-D-xyloseHO OD-quinovoseHO 2 O O O O O O O HO HO O O MeO 4 HO 3 HO HO 4 HOHO 3 HO 2 O HO 4 HOO O HO OH OOH 2 O OOH O MeOHO 3 O HO 2 O O HO O OHO HO O OHO HO OH O HO 4 HOO 3 FigureO 2. CommonHO sugar4 unitsHOO 3present in sea cucumberO HO glycosides. O 5 O MeOHO O HO 2 MeO O O HO 2 O MeO O HO O OHO HO OH OOH HO OHHO OH O OH OH HOOH HO O Glc O Qui O HO 5 O MeOMeGlc HO MeO HO OOH OH OH OH1 O OHHO 3 OH OH 1 O HO MeGlc GlcGlc HOQui O 1 O HO HO MeGlc6 HO 5 Xyl O HO O O OH1 HO O HO1 1 O HOHO HO3 5 1 O HO 1 O O O HO 4O HO 3 HO 2O OHO HOO 1 O O HO HO HO HO OHO O O O O HO HO O 2O 2 O HO O O MeOHO HOO HOOHO O O HO O O O O HO O O HO O HO 4OH HOO 3OH 2 HO OHHO HOOH HO HO HO 4 HO HO3 OH2 MeO O O HO O O HO 2 HO 2 O OO HOO OO O HO 4 OHHO 3 OH O OHO 3 OHO O O HO OH HO O HO HO O 2 HO 4 HO HOO 2 HO O OH MeO O O HO O O HO O HOMeO OH OH HO HO HOOH OHO OHHO HO O OH O O MeO O HO OH 5 O MeO OHFigure 3.OH SomeHO commonOH carbohydrateOH architecturesOH foundOH in sea cucumber glycosides.HO MeGlc Glc Qui HO 1 HO 3 1 OH Figure 3. Some commonO carbohydrate architecturesO 1 O found in sea cucumberO glycosides. Figure 3. Some commonHO carbohydrateHO architecturesO foundHO in sea cucumber glycosides. HO O O HO O O TriterpeneHO 4 HO glycosides3 can2 be classifiedHO asOH HOholostane type having 3β-hydroxy-5HO α-lanostano- O O O O 2 2 O O HO O HO HO O O O HO γ(18,20)-lactoneMeOTriterpene O glycosidesstructuralHO featurecan be andclassified nonholostane asHO holostane type dotype not having have a 3γβ(18,20)-lactone-hydroxy-5αOH-lanostano- but have OH OH OH HO HO OH Triterpeneotherγ(18,20)-lactone structural glycosides featuresstructural can like feature be holostane classiﬁed and typenonholostane glycosides. as holostane typeOH do typenot have having a γ(18,20)-lactone 3β-hydroxy-5 but haveα -lanostano- γ(18,20)-lactoneother structural structuralFigure features 3. Some feature likecommon holostane and carbohydrate nonholostane type glycosides. architectures type dofound not in sea have cucumber a γ(18,20)-lactone glycosides. but have other 4.1. Holostane Type Triterpene Glycosides structural4.1. features Holostane like Type holostane Triterpene typeGlycosides glycosides. TriterpeneDepending glycosideson the position can be of classifieddouble bond as holostane in the B andtype Chaving ring of 3 βthe-hydroxy-5 aglyconeα -lanostano-(Figure 1), γ(18,20)-lactoneDepending structuralon the position feature of and double nonholostane bond in thetype B doand not C havering aof γ the(18,20)-lactone aglycone (Figure but have 1), 4.1. Holostaneholostane Type Triterpenetype glycosides Glycosides can be further subdivided into three groups: glycosides with other3holostaneβ-hydroxyholost-7(8)-ene, structural type featuresglycosides like 3holostaneβcan-hydroxyholost-9(11)-ene, be typefurther glycosides. subdivided and into 3β -hydroxyholost-8(9)-enethree groups: glycosides aglycone with Dependingskeletons.3β-hydroxyholost-7(8)-ene, on There the are position eight pentacyclic3β of-hydroxyholost-9(11)-ene, double triterpene bond and in the30 andalkane B and3β -hydroxyholost-8(9)-eneside C chain ring aglycone of the aglyconearchitectures aglycone (Figure 1), 4.1.skeletons. Holostane There Type are Triterpene eight pentacyclic Glycosides triterpene and 30 alkane side chain aglycone architectures holostanecommonly type glycosides found in holostane can betype furtherglycosides subdivided (Figure 4). In these into architectures, three groups: certain functional glycosides with groupscommonlyDepending are foundgenerally on in theholostane attached position typeto of the doubleglycosides specific bond (Figurecarbons: in the 4). Bketo Inand theseand C ring βarchitectures,-acetoxy of the groupsaglycone certain at (FigureC-16,functional and 1), 3β-hydroxyholost-7(8)-ene,holostaneαgroups-hydroxy are group typegenerally glycosidesat C-12 attached 3β and-hydroxyholost-9(11)-ene, canC-17. to be the furtherspecific subdividedcarbons: keto andinto and 3three ββ-acetoxy-hydroxyholost-8(9)-ene groups: groups glycosides at C-16, withand aglycone skeletons.3αβ-hydroxy There-hydroxyholost-7(8)-ene, are group eight at C-12 pentacyclic and 3 βC-17.-hydroxyholost-9(11)-ene, triterpene and 30and alkane 3β-hydroxyholost-8(9)-ene side chain aglycone aglycone architectures skeletons. There are eight21 pentacyclic triterpene and 30 alkane side chain aglycone architectures commonly found in holostaneO O 21 type glycosidesO O (Figure4). InO theseO architectures,O O certain functional commonly found in18 holostane20 type glycosides (Figure 4). In these architectures, certain functional groups are generally attachedO O to the speciﬁcO carbons:O keto and βO-acetoxyO groupsO at C-16,O and α-hydroxy groups are 11generally13 18 attached1720 to the specific carbons: keto and β-acetoxy groups at C-16, and 1 16 group at C-12α-hydroxy and C-17.group119 13 at C-1217 and C-17. 110 9 8 16 O OAc O 3 10 8 32 O OAc 46 21 O O O 3 32 O O 4631 O O II O IIIO O IVO O 30 I Sugar O O OSugar OSugar O Sugar 31 18 20 30 I Sugar II III IV 11 O O 17 O Sugar O O Sugar O Sugar HO 13 HO O HO HO O 1 O O HO9 O16 O O HO O O O HO OH OH HO OH 10 8 O OAc O 3 32 OH OH OH 46 O O O O OAc 31 III IV 30 I Sugar II Sugar O OAc SugarO O O SugarO O O O O O O O OSugar HOV OSugar HOVIOSugar HO VII OSugar HOVIII O Sugar V VISugar VII VIII Sugar OH(a) OHSugar OH (a) O OAc O O O O Sugar V Sugar VISugar VII Sugar VIII (a)

Figure 4. Cont.

Mar. Drugs 2017, 15, 317 5 of 35

22 24 26 25 O O 27 O OH O O OH OH O OH

OH OH OH OH OAc OAc

OH OEt OnBu O OAc OAc OAc

OAc OAc O OAc (b)

Figure 4. Pentacyclic triterpene and alkane side chain skeletons are commonly found in holostane Figure 4. typePentacyclic glycosides. triterpene (a) Pentacylic and triterpene alkane skeletons. side chain Substitution skeletons by selective are commonly functional groups found and in holostane type glycosides.unsaturation (a) Pentacylicgenerally take triterpene place in the skeletons.alkane side chain Substitution (2-methylpentane) by selective attached functional to C-20 of the groups and unsaturationE-ring generally of aglycone. take (b) Alkane place inside the chain alkane architectures. 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

4.1.1. 3β-Hydroxyholost-7(8)-eneSubstantial number of triterpene Skeleton glycosides Containing in this Holostanecategory is produced Glycosides by sea cucumbers. The species Eupentacta fraudatrix, Holothuria lessoni, Bohadschia marmorata, Stichopus chloronotus and SubstantialStaurocucumis number liouvillei of produce triterpene most glycosides of the compounds in this in categorythis group. isFor produced convenience, by the sea large cucumbers. number of compounds in this category can be further subdivided into four groups depending on The species Eupentacta fraudatrix, Holothuria lessoni, Bohadschia marmorata, Stichopus chloronotus and the number of sugar units. Staurocucumis liouvillei produce most of the compounds in this group. For convenience, the large number ofHolostane compounds Glycosides in this with category 3β-Hydroxyholost-7(8)-ene can be further subdividedSkeleton and Six into Sugar four Units groups depending on the number of sugarThe 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 Holostanecategory Glycosides are the with presence 3β-Hydroxyholost-7(8)-ene of α-acetoxy group at C-23,Skeleton double bond and at Six C-25(C-26) Sugar Unitsand terminal 3-O-methyl-D-glucose in carbohydrate chain. An interesting point to be noted in here is that the The namesulfate group of the is compoundstotally absent in in this this group group, of compounds. their producing species, chemical structures and references are summarized in Table1 and Figure5. 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 are the presence of α-acetoxy group at C-23, double bond at C-25(C-26) and terminal units. 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 totallyStichoposide absent C (1 in) thisThelenota group anax of compounds.[17] Stichoposide D (2) Thelenota anax [18] Stichoposide E (3) Stichopus chloronotus [19] Stichloroside A1 (4) S. chloronotus [20] TableStichloroside 1. Name and A2 producing(5) S. chloronotus species of glycosides[20] withStichloroside 3β-hydroxyholost-7(8)-ene B1 (6) S. chloronotus and sixs[20] ugar units. Stichloroside B2 (7) S. chloronotus [20] Stichloroside C1 (8) S. chloronotus [20] Stichloroside C2 (9) S. chloronotus [20] Synallactoside A2 (10) Synallactes nozawai [16] Compound Name Producing Species Reference Compound Name Producing Species Reference Synallactoside B1 (11) S. nozawai [16] Variegatuside F (12) S. variegates [21] StichoposideHolotoxin C (1) E (13) ThelenotaS. japonicus anax [17[22]] Stichoposide D (2) Thelenota anax [18] Stichoposide E (3) Stichopus chloronotus [19] Stichloroside A1 (4) S. chloronotus [20] Stichloroside A2 (5) S. chloronotus [20] Stichloroside B1 (6) S. chloronotus [20] Stichloroside B2 (7) S. chloronotus [20] Stichloroside C1 (8) S. chloronotus [20] Stichloroside C2 (9) S. chloronotus [20] Synallactoside A2 (10) Synallactes nozawai [16] Synallactoside B1 (11) S. nozawai [16] Variegatuside F (12) S. variegates [21] Holotoxin E (13) S. japonicus [22]

Mar. Drugs 2017, 15, 317 6 of 35 Mar. Drugs 2017, 15, 317 6 of 35

1 2 3 O O 23 25 1 Stichoposide C R = CH3, R = H, R = CH2OH 1 3 2 Stichoposide D R = R =CH2OH, R2 = H H OAc 1 2 3 3 Stichoposide E R = H, R = R = CH2OH 16 1 2 3 R3 7 4 Stichloroside A1 R = H, R = CH2OH, R = CH2OH 6 HO 5 O O 1 O O 5 Stichloroside A R1 = H, R2 = CH OH, R3 = CH OH, Δ25(26) HO HOO O H 2 2 2 MeO OH HO 6 Stichloroside B R1 = CH OH, R2 = H, R3 = CH OH OH 2 1 2 2 R 1 O ) 3 R 1 2 3 Δ25(26 HO 4 O 2 O 7 Stichloroside B2 R = CH2OH, R = H, R = CH2OH, O HO O HO O 8 Stichloroside C R1 = CH , R2 = H, R3 = CH OH MeO OHHO OH 1 3 2 OH 1 2 3 Δ25(26) 9 Stichloroside C2 R = CH3, R = H, R = CH2OH, 1 2 3 Δ25(26) 10 Synallactoside A2 R = CH3, R = H, R = H, 1 2 3 Δ25(26) 11 Synallactoside B1 R = CH3, R = CH3OH, R = H, 1 3 2 12 Variegatuside F R =R =CH2OH, R =H, 23- OH instead of OAc 1 2 3 13 Holotoxin E R =CH3, R =H, R =CH2OH, 16- O, 23-H instead of OAc, Δ25(26) sugar unit 6=Glc, Figure 5. ChemicalChemical structures structures of of holostane glycosides with 3 β-hydroxyholost-7(8)-ene-hydroxyholost-7(8)-ene and six sugar units.

Holostane Glycosides with 3β-Hydroxyholost-7(8)-ene Skeleton andand FiveFive SugarSugar UnitsUnits The name of the compoundscompounds in this group,group, theirtheir producingproducing species,species, chemical structures and references areare summarized summarized in in Table Table2 and 2 and Figure Figure6. The 6. mostThe most common common structural structural features features in this groupin this aregroup the are sulfate the groupssulfate atgroups C-4 of at xylose C-4 of and xylose C-6 ofan glucosed C-6 of and glucose methylglucose and methylglucose with either withβ-acetoxy either orβ-acetoxy keto group or keto at C-16group and at C-16 C-25(26) and C-25(26) double bond.double A bond. quite A number quite number of compounds of compounds contain contain a keto a groupketo group at C-23.The at C-23.The rare structural rare structural features features of triterpene of triterpene glycoside areglycoside the presence are the of presence 16,22-epoxy of 16,22-epoxy group (33), ethoxy group (29) and methylglucuronic acid (51). Cucumarioside A1-2 (17) group (33), ethoxy group (29) and methylglucuronic acid (51). Cucumarioside A1-2 (17) is the onlyis the example only example of triterpene of triterpene glycosides glycosides containing contai anning acetate an acetate group group at C-6 at of C-6 the of terminal the terminal sugar sugar unit. Carbohydrateunit. Carbohydrate chain can chain be one can branched be one (14 –48branchedand 52– 54(14) or–48 straight and52 (49–54–51) ).or 3- Ostraight-methyl- D(-xylose49–51). as3-O a-methyl- terminalD monosaccharide-xylose as a terminal unit thatmonosaccharide is a characteristic unit featurethat is ofa characteristic all the glycosides feature isolated of all from the Eupentactaglycosides fraudatrixisolated from. Eupentacta fraudatrix.

Table 2. Name and producing species of glycosides with 3 3ββ-hydroxyholost-7(8)-ene-hydroxyholost-7(8)-ene and and five five sugar sugar units. 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 [23] Cucumarioside A0-2 (15) C. japonica [23] Cucumarioside A0-1 (14) Cucumaria japonica [23] Cucumarioside A0-2 (15) C. japonica [23] Cucumarioside A0-3 (16) C. japonica [23] Cucumarioside A1-2 (17) C. japonica [24] Cucumarioside A0-3 (16) C. japonica [23] Cucumarioside A1-2 (17) C. japonica [24] 2 2 CucumariosideCucumarioside A A-22-2 (18 (18)) C.C. japonica japonica [[25]25] CucumariosideCucumarioside A 2A-3 (-319 )(19) C. japonicaC. japonica [24] [24] CucumariosideCucumarioside A A2-42-4 (20 (20)) C.C. japonica japonica [[24]24] CucumariosideCucumarioside A 2A-52 (-521 )(21)C.C. conicospermium conicospermium [26] [26] Cucumarioside A -2 (22) C. japonica [24] Cucumarioside A -2 (23) C. japonica [27] Cucumarioside A4-24 (22) C. japonica [24] Cucumarioside 6A6-2 (23) C. japonica [27] Cucumarioside A7-1 (24) C. japonica [28] Cucumarioside A7-2 (25) C. japonica [28] Cucumarioside A7-1 (24) C. japonica [28] Cucumarioside A7-2 (25) C. japonica [28] Cucumarioside A7-3 (26) C. japonica [28] Cucumarioside H (27) E. fraudatrix [29] CucumariosideCucumarioside A7 H-32 ((2628)) C.E. fraudatrixjaponica [[28]30] Cucumarioside H4 H(29 ()27) E. fraudatrixE. fraudatrix [30] [29] CucumariosideCucumarioside H H2 5(28(30)) E.E. fraudatrix fraudatrix [[30]29] Cucumarioside Cucumarioside H 6H(314 ()29) E. fraudatrixE. fraudatrix [29] [30] Cucumarioside H7 (32) E. fraudatrix [29] Cucumarioside H8 (33) E. fraudatrix [29] Cucumarioside H5 (30) E. fraudatrix [29] Cucumarioside H6 (31) E. fraudatrix [29] Cucumarioside I1 (34) E. fraudatrix [31] Cucumarioside I2 (35) E. fraudatrix [32] CucumariosideCucumarioside H I73 ((3236)) E.E. fraudatrix fraudatrix [[29]31] Cucumarioside Frondoside A (37 H)8 (33) C.E. frondosa fraudatrix [33] [29] CucumariosideFrondoside BI1 ((3834) ) E.C. fraudatrix frondosa [[31]34] Cucumarioside Frondoside A2-1 (39I2 )(35) C.E. frondosa fraudatrix [35] [32] Frondoside A -2 (40) C. frondosa [35] Frondoside A -3 (41) C. frondosa [35] Cucumarioside 2I3 (36) E. fraudatrix [31] Frondoside2 A (37) C. frondosa [33] Frondoside A2-4 (42) C. frondosa [36] Calcigeroside C2 (43) P. calcigera [37] Frondoside B (38) Frondoside A2-1 (39) Calcigeroside D2 (44) C.P. frondosa calcigera [[34]38] Calcigeroside E (45) P. calcigeraC. frondosa [38] [35] FrondosideColochiroside A2-2A (40 (46)) C.C. frondosa anceps [[35]39] CucumariosideFrondoside A C21-3(47 (41) ) E. fraudatrixC. frondosa [40] [35] Cucumarioside C (48) E. fraudatrix [40] Synallactoside B (49) S. nozawai [16] Frondoside A2-4 (422 ) C. frondosa [36] Calcigeroside 2C2 (43) P. calcigera [37] Synallactoside C (50) S. nozawai [16] Synaptoside A (51) Synapta maculata [41] Calcigeroside D2 (44) P. calcigera [38] Calcigeroside E (45) P. calcigera [38] Okhotoside A2-1 (52) C. okhotensis [42] Frondoside A7-1 (53) C. frondosa [43] ColochirosideFrondoside AA7-2 (46 (54) ) C. frondosaanceps [[39]43] Cucumarioside C1(47) E. fraudatrix [40] Cucumarioside C2 (48) E. fraudatrix [40] Synallactoside B2 (49) S. nozawai [16] Synallactoside C (50) S. nozawai [16] Synaptoside A (51) Synapta maculata [41] Okhotoside A2-1 (52) C. okhotensis [42] Frondoside A7-1 (53) C. frondosa [43] Frondoside A7-2 (54) C. frondosa [43]

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O O R7

R6 O R1O O R3 R2 HO O O HO OHO O O 4 O R O OH OHHO R5 O O HO HO OH 1 2 3 4 5 6 7 14 Cucumarioside A0-1 R =SO3Na, R =H, R =CH2OH, R =CH3, R =H, R = OAc, R =

1 2 3 4 5 6 7 O 15 Cucumarioside A0-2 R =SO3Na, R =H, R =CH2OH, R =CH3, R =H, R = OAc, R = 1 2 3 4 5 6 7 16 Cucumarioside A0-3 R =SO3Na, R =H, R =CH2OH, R =CH3, R =H, R = O, R = 1 2 3 4 5 6 7 17 Cucumarioside A1-2 R =SO3Na, R =CH2OH, R =CH2OAc, R =H, R =H, R = O, R = 1 2 3 4 5 6 7 18 Cucumarioside A2-2 R =SO3Na, R =CH2OH, R =CH2OH, R =CH3, R =H, R = O, R = 1 2 3 4 5 6 7 19 Cucumarioside A2-3 R =SO3Na, R =CH2OH, R =CH2OH, R =CH3, R =H, R = O, R =

1 2 3 4 5 6 7 20 Cucumarioside A2-4 R =SO3Na, R =CH2OH, R =CH2OH, R =CH3, R =H, R = H, R = 1 2 3 4 5 6 7 21 Cucumarioside A2-5 R =SO3Na, R =CH2OH, R =CH2OH, R =CH3, R =H, R = OAc, R = O 1 2 3 4 5 6 7 22 Cucumarioside A4-2 R =SO3Na, R =CH2OH, R =CH2OH, R =CH3, R =H, R = O, R =

1 2 3 4 5 6 7 23 Cucumarioside A6-2 R =SO3Na, R =CH2OH, R =CH2OSO3Na, R =CH3, R =H, R = O, R =

1 2 3 4 5 6 7 24 Cucumarioside A7-1 R =SO3Na, R =CH2OSO3Na, R =CH2OSO3Na, R =CH3, R =H, R = O, R = 1 2 3 4 5 6 7 25 Cucumarioside A7-2 R =SO3Na, R =CH2OSO3Na, R =CH2OSO3Na, R =CH3, R =H, R = O, R = 1 2 3 4 5 6 7 26 Cucumarioside A7-3 R =SO3Na, R =CH2OSO3Na, R =CH2OSO3Na, R =CH3, R =H, R =H, R = 1 5 2 3 4 6 7 27 Cucumarioside H R =R =H, R =R =CH2OH, R =Me, R = OAc, R = 1 2 3 5 4 6 7 OH 28 Cucumarioside H2 R =SO3Na, R =CH2OH, R =R =H, R =Me, R = OAc, R = 29 Cucumarioside H R1=SO Na, R2=CH OH, R3=R5=H, R4=Me, R6= OAc, R7= 4 3 2 OEt 1 2 3 4 5 6 7 30 Cucumarioside H5 R =SO3Na, R =CH2OH, R =H, R =CH3, R =H, R = OAc, R =

1 2 3 4 5 6 7 31 Cucumarioside H6 R =SO3Na, R =CH2OH, R =H, R =CH3, R =H, R = OAc, R =

1 2 3 4 5 6 7 32 Cucumarioside H7 R =SO3Na, R =CH2OH, R =H, R =CH3, R =H, R = OAc, R = 33 Cucumarioside H R1=SO Na, R2=CH OH, R3=H, R4=CH R5=H, R6= OAc, R7= 8 3 2 3, OH , 16,22-epoxy 1 2 3 4 5 6 7 34 Cucumarioside I1 R =SO3Na, R =CH2OSO3Na, R =H, R =CH3, R =H, R = OAc, R = 1 2 3 4 5 6 7 35 Cucumarioside I2 R =SO3Na, R =CH2OSO3Na, R =H, R =CH3, R =H, R = OAc, R = 1 2 3 4 5 6 7 36 Cucumarioside I3 R =SO3Na, R =CH2OSO3Na, R =H, R =CH3, R =H, R = OAc, R = OH 1 2 5 3 4 6 7 37 Frondoside A R =SO3Na, R =R =H, R =CH2OH, R =CH3, R = OAc, R =

1 2 3 4 5 6 7 38 Frondoside B R =SO3Na, R =CH2OSO3Na, R =CH2OH, R =CH3, R =R =H, R = 1 2 3 4 5 6 R7= 39 Frondoside A2-1 R =SO3Na, R =R =CH2OH, R =CH3, R =H, R = O, O

1 2 3 4 5 6 7 40 Frondoside A2-2 R =SO3Na, R =R =CH2OH, R =CH3, R =R =H, R = 1 2 3 4 5 6 7 41 Frondoside A2-3 R =SO3Na, R =R =CH2OH, R =CH3, R =R =H, R = OH 1 2 3 4 5 6 7 42 Frondoside A2-4 R =SO3Na, R =R =CH2OH, R =CH3, R =R =H, R =

Figure 6. Cont.

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1 2 3 4 5 6 7 43 Calcigeroside C2 R =SO3Na, R =CH2OH, R =H, R =CH3, R =CH2OH, R =H, R = O 1 2 3 4 5 6 7 44 Calcigeroside D2 R =SO3Na, R =CH2OSO3Na, R =H, R =CH3, R =CH2OH, R =H, R = O 45 Calcigeroside E R1=SO Na, R2=R5=CH OH, R3=CH OSO Na, R4=CH R6= OAc, R7= 3 2 2 3 3, OH 1 2 3 4 5 6 7 46 Colochiroside A R =SO3Na, R =CH2OSO3Na, R =CH2OH, R =CH3, R =H, R = O, R = 1 5 2 3 4 6 7 47 Cucumarioside C1 R =R =H, R =R =CH2OH, R =CH3, R = OAc, R = 1 5 2 3 4 6 7 48 Cucumarioside C2 R =R =H, R =R =CH2OH, R =CH3, R = OAc, R =

22 O O 26 25 R4

R1O O O HO O O 1 2 3 4 Δ25(26) HO 49 Synallactoside B2 R =R =R =H, R = OAc, OH HO R2 O 50 Synallactoside C R1=R2=H, R3=CH OH, R4= OAc,Δ25(26) R3 O O 2 HO O 1 2 3 4 HO O O HO 51 Synaptoside A R =SO3Na, R =CH2OH, R =COONa, R =O MeO OH OH OH 22 O O 26 25

R3 O 52 Okhotoside A -1 R1=OH, R2=H, R3= OAc, Δ25(26) NaO SO O 2 3 HO 2 R2O 1 1 2 3 Δ24 R O R O 53 Frondoside A7-1 R =H, R =SO3Na, R = O, O HO O O HO O 1 2 2 Δ24 MeO O HO 54 Frondoside A7-2 R =R =H, R =SO3Na, OH OH O HO O HO OH

Figure 6. 6. ChemicalChemical structures structures of holostane of holostane glycosides glycosides with 3 withβ-hydroxyholost-7(8)-ene 3β-hydroxyholost-7(8)-ene and five and sugar ﬁve sugarunits. 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 (Table3). 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 (Figure7). 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 79 n 113 114 (sugarand units), in artifact carbohydrate-butoxy chain ( ()72 and) are ethoxy rare structural ( ) groups features at C-25, in this and category. three consecutive Cucumariosides xylose sugar units in carbohydrate chain (72) are rare structural features in this category. Cucumariosides A A1 (111), A5 (115) and A11 (118) are the desulfated derivatives of cucumariosides G1 (123), G3 (124) 1 (111), A (115) and A (118) are the desulfated derivatives of cucumariosides G (123), G (124) and and G4 (5125), respectively.11 1 3 G4 (125), respectively. Table 3. Name and producing species of glycosides with 3β-hydroxyholost-7(8)-ene and four sugar β Tableunits. 3. Name and producing species of glycosides with 3 -hydroxyholost-7(8)-ene and four sugar units.

CompoundCompound Name Name Producing Producing Species Species Reference Reference Compound Name Name Producing Producing Species Species Reference Reference Liouvilloside A (55) Staurocucumis liouvillei [44] Liouvilloside A1 (56) S. liouviellei [45] Liouvilloside A (55) Staurocucumis liouvillei [44] Liouvilloside A1 (56) S. liouviellei [45] LiouvillosideLiouvilloside A2 (57 A2) (57) S. S.liouvillei liouvillei [45][45] Liouvilloside A A3 (358(58) ) S. liouvilleiS. liouvillei [45] [45] LiouvillosideLiouvilloside A5 (59 A5) (59) S. S.liouvillei liouvillei [46][46] Liouvilloside B B (60 (60) ) S. liouvilleiS. liouvillei [44] [44] LiouvillosideLiouvilloside B1 (61 B1) (61) S. S.liouvillei liouvillei [45][45] Liouvilloside B 2B(262(62) ) S. liouvilleiS. liouvillei [45] [45] Violaceuside A (63) P. violeceus [47] Violaceuside B (64) P. violeceus [47] Violaceuside A (63) P. violeceus [47] Violaceuside B (64) P. violeceus [47] Violaceuside I (65) P. violeceus [48] Violaceuside II (66) P. violeceus [48] Violaceuside I (65) P. violeceus [48] Violaceuside II (66) P. violeceus [48] Violaceuside III (67) P. violeceus [48] Intercedenside A (68) M. intercedens [49] Intercedenside B (67) Mensamria intercedens [49] Intercedenside C (70) M. intercedens [49]

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Intercedenside D (71) M. intercedens Table[50] 3. Cont.Intercedenside E (72) M. intercedens [50] Intercedenside F (73) M. intercedens [50] Intercedenside G (74) M. intercedens [50] Intercedenside H (75) M. intercedens [50] Intercedenside I (76) M. intercedens [50] Compound Name Producing Species Reference Compound Name Producing Species Reference Patagonicoside A (77) Psolus patagonicus [51] Patagonicoside B (78) P. patagonicus [52] Violaceuside III (67) P. violeceus [48] Intercedenside A (68) M. intercedens [49] Patagonicoside C (79) P. patagonicus [52] Philinopside A (80) P. quadrangularis [53] Intercedenside B (67) Mensamria intercedens [49] Intercedenside C (70) M. intercedens [49] PhilinopsideIntercedenside B (81) D (71) PentactaM. quadrangularis intercedens [[53]50] IntercedensidePhilinopside E E (72 (82) ) M.P. intercedens quadrangularis [50] [54] PhilinopsideIntercedenside F (83) F (73) P. quadrangularisM. intercedens [[54]50] IntercedensideMollisoside G A (74 (84) ) M. intercedensA. mollis [50] [55] MollisosideIntercedenside B2 (85) H (75) AustralostichopusM. intercedens mollis [[55]50] IntercedensideEximisoside I A (76 ()86) M. intercedensP. eximius [50] [56] Patagonicoside A (77) Psolus patagonicus [51] Patagonicoside B (78) P. patagonicus [52] Pseudostichoposide A (87) Pseudostichopus trachus [57] Cucumarioside F1 (88) E. fraudatrix [58] Patagonicoside C (79) P. patagonicus [52] Philinopside A (80) P. quadrangularis [53] CucumariosidePhilinopside F2 (89 B ()81 ) PentactaE. fraudatrix quadrangularis [[58]53] Pseudocnoside Philinopside E (82 A) (90) P. quadrangularisP. leoninus [54] [59] TypicosidePhilinopside A1 (91 F) (83) ActinocucumisP. quadrangularis typica [[60]54] MollisosideTypicoside A A (842 ()92) A. mollisA. typica [55] [60] TypicosideMollisoside B1 (93 B)2 (85) AustralostichopusA. typica mollis [[60]55] EximisosideTypicoside A C (861 ()94) P. eximiusA. typica [56] [60] 87 Pseudostichopus trachus 88 E. fraudatrix TypicosidePseudostichoposide C2 (95) A ( ) A. typica [[60]57] CucumariosideFrondoside FA1 1( (96) ) C. okhotensis [58] [61] Cucumarioside F2 (89) E. fraudatrix [58] Pseudocnoside A (90) P. leoninus [59] Okhotoside A1-1 (97) Cucumaria okhotensis [61] Okhotoside B1 (98) C. okhotensis [62] Typicoside A1 (91) Actinocucumis typica [60] Typicoside A2 (92) A. typica [60] Okhotoside B2 (99) C. okhotensis [62] Okhotoside B3 (100) C. okhotensis [62] Typicoside B1 (93) A. typica [60] Typicoside C1 (94) A. typica [60] ColochirosideTypicoside A1 ( C1012 (95) ) ColochirusA. typica robustus [[63]60] Colochiroside Frondoside A1 (A962)(102) C. okhotensisC. robustus [61] [63] ColochirosideOkhotoside A3 A(1031-1) ( 97) CucumariaC. robustus okhotensis [[63]61] Colochiroside Okhotoside B1 (B981 )(104) C. okhotensisC. robustus [62] [64] Okhotoside B (99) C. okhotensis [62] Okhotoside B (100) C. okhotensis [62] Colochiroside B2 (1052 ) C. robustus [64] Colochiroside3 B3 (106) C. robustus [64] Colochiroside A (101) Colochirus robustus [63] Colochiroside A (102) C. robustus [63] Violaceusosides C (1071 ) P. violaceus [65] Violaceusosides2 D (108) P. violaceus [65] Colochiroside A3 (103) C. robustus [63] Colochiroside B1 (104) C. robustus [64] ViolaceusosidesColochiroside E (109 B2 ()105 ) P. C.violaceus robustus [[65]64] ColochirosideViolaceusosides B3 ( 106G ()110) C. robustusP. violaceus [64] [65] CucumariosideViolaceusosides A1 (111 C ()107 ) E. fraudatrixP. violaceus [[66]65] ViolaceusosidesCucumarioside D A (1082 (112) ) P. violaceusE. fraudatrix [65] [67] Violaceusosides E (109) P. violaceus [65] Violaceusosides G (110) P. violaceus [65] Cucumarioside A3 (113) E. fraudatrix [66] Cucumarioside A4 (114) E. fraudatrix [66] Cucumarioside A1 (111) E. fraudatrix [66] Cucumarioside A2 (112) E. fraudatrix [67] Cucumarioside A5 (115) E. fraudatrix [66] Cucumarioside A6 (116) E. fraudatrix [66] Cucumarioside A3 (113) E. fraudatrix [66] Cucumarioside A4 (114) E. fraudatrix [66] 7 11 CucumariosideCucumarioside A (117 A5 )( 115) E. E.fraudatrix fraudatrix [[67]66] CucumariosideCucumarioside A6 A(116(118) ) E. fraudatrixE. fraudatrix [66] [67] CucumariosideCucumarioside A12 (119 A7 ()117 ) E. E.fraudatrix fraudatrix [[66]67] CucumariosideCucumarioside A11 A(11813 (120) ) E. fraudatrixE. fraudatrix [67] [67] CucumariosideCucumarioside A14 ( A12112 )( 119) E. E.fraudatrix fraudatrix [[67]66] CucumariosideCucumarioside A13 A(12015 (122) ) E. fraudatrixE. fraudatrix [67] [66] Cucumarioside A14 (121) E. fraudatrix [67] Cucumarioside A15 (122) E. fraudatrix [66] Cucumarioside G1 (123) C. fraudatrix [68] Cucumarioside G3 (124) E. fraudatrix [69] Cucumarioside G1 (123) C. fraudatrix [68] Cucumarioside G3 (124) E. fraudatrix [69] Cucumarioside G4 (125) E. fraudatrix [70] Pentactaside B (126) P. quadrangularis [71] Cucumarioside G4 (125) E. fraudatrix [70] Pentactaside B (126) P. quadrangularis [71] PentactasidePentactaside C (127 C) ( 127) P. quadrangularisP. quadrangularis [[71]71] PseudostichoposidePseudostichoposide B ( 128B ()128) P. trachusP. trachus [72] [72] VariegatusideVariegatuside A (129 A ()129 ) S. S.variegates variegates [[73]73] VariegatusideVariegatuside C (C130 (130) ) S. variegatesS. variegates [21] [21] Synallactoside A (131) S. nozawai [16] Thelenotoside A (132) Thelenota ananas [74] Synallactoside A1(1311) S. nozawai [16] Thelenotoside A (132) Thelenota ananas [74] Thelenotoside B (133) T. ananas [74] Cucumechinoside A (134) C. echinata [75] ThelenotosideCucumechinoside B (133) B (135) T.C. ananas echinata [[74]75] CucumechinosideCucumechinoside C (A136 ()134) C. echinataC. echinata [75] [75] CucumechinosideCucumechinoside B (135 D) (137 ) C. C.echinata echinata [[75]75] CucumechinosideCucumechinoside E (138C ()136) C. echinataC. echinata [75] [75] CucumechinosideCucumechinoside D (137 F ()139 ) C. C.echinata echinata [[75]75] Cucumechinoside Lefevreoside A1 (140 E) (138) C. lefevreiC. echinata [76] [75] CucumechinosideLefevreoside F A(1392 (141) ) C. C.echinata lefevrei [[75]76] LefevreosideLefevreoside C (A1421 ()140) C. lefevreiC. lefevrei [76] [76] Lefevreoside D (143) C. lefevrei [76] Lefevreoside A2 (141) C. lefevrei [76] Lefevreoside C (142) C. lefevrei [76] Lefevreoside D (143) C. lefevrei [76]

O O R7 R8 R6

R5 O R1O O HO R4 R3 R2 O OHO O O O HO O MeO OHHO OH OH 1 2 3 4 5 6 7 8 55 Liouvilloside A R =SO3Na, R =CH3, R =R =CH2OSO3Na, R = OAc, R =H, R = , R =H 1 2 3 4 5 6 7 8 56 Liouvilloside A1 R =SO3Na, R =CH3, R =CH2OSO3Na, R =CH2OH, R = O , R =H, R = , R =H

1 2 3 4 5 6 7 8 57 Liouvilloside A2 R =SO3Na, R =CH3, R =CH2OSO3Na, R =CH3, R = O, R =H,R = , R =H 1 2 3 4 5 6 7 8 58 Liouvilloside A3 R =SO3Na, R =CH3, R =CH2OSO3Na, R =CH3, R = OAc, R =H, R = , R =H

Figure 7. Cont.

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1 2 3 4 5 6 7 8 59 Liouvilloside A5 R =SO3Na, R =CH3, R =CH2OSO3Na, R =CH3, R = OAc, R =H, R = , R =H OH 1 2 3 4 5 6 7 8 60 Liouvilloside B R =H, R =CH3, R =CH2OSO3Na, R =CH2OSO3Na, R = OAc, R =H, R = , R =H

1 2 3 4 5 6 7 8 61 Liouvilloside B1 R =SO3Na, R =CH3, R =CH2OSO3Na, R =CH2OSO3Na, R = O, R =H, R = , R =H 1 2 3 4 5 6 7 , R8=H 62 Liouvilloside B2 R =SO3Na, R =CH3, R =CH2OSO3Na, R =CH2OSO3Na, R = OAc, R =H, R =

1 2 3 4 5 6 7 , R8=H 63 Violaceuside A R =SO3Na, R =CH3, R =H, R =CH2OH, R = OAc, R =H, R = 1 2 3 4 5 6 7 8 64 Violaceuside B R =SO3Na, R =CH2OH, R =H, R =CH2OH, R = OAc, R =H, R = , R =H

1 2 3 4 5 6 7 8 65 Violaceuside I R =SO3Na, R =CH2OH, R =H, R =CH2OH, R = O , R =H, R = , R = OH 1 2 3 4 5 6 7 8 66 Violaceuside II R =SO3Na, R =CH3, R =H, R =CH2OSO3Na, R = O , R =H, R = , R = OH 1 2 3 4 5 6 7 8 67 Violaceuside III R =SO3Na, R =CH3, R =H, R =CH2OSO3Na, R = O, R =H, R = , R = OH

1 2 3 4 8 6 7 5 68 Intercedenside A R =SO3Na, R =CH3, R =H, R =CH2OH, R =H, R = H, R = , R = OAc

1 2 3 4 8 6 7 5 69 Intercedenside B R =SO3Na, R =CH3, R =H, R =CH2OSO3Na, R =H, R = H, R = , R = OAc

1 2 3 4 8 6 7 5 70 Intercedenside C R =SO3Na, R =CH2OH, R =H, R =CH2OH, R =H, R = OH, R = , R = OAc 1 2 4 3 8 6 7 5 71 Intercedenside D R =SO3Na, R =R =CH2OH, R =H, R =H, R = OH, R = , R = OAc 1 2 3 4 8 6 7 5 72 Intercedenside E R =SO3Na, R =R = H, R =CH2OH, R =H, R = OH, R = , R = OAc 1 2 4 3 8 6 7 5 73 Intercedenside F R =SO3Na, R =R = CH2OH, R =H, R =H, R = OH, R = , R = OAc 1 2 4 3 8 6 7 5 74 Intercedenside G R =SO3Na, R =R =CH2OH, R =H, R =H, R =H, R = , R = OAc

1 2 3 4 8 6 7 5 75 Intercedenside H R =SO3Na, R =CH3, R =H, R =CH2OH, R =H, R = OH, R = , R = OAc

1 2 3 4 8 6 7 5 76 Intercedenside I R =SO3Na, R =CH3, R =H, R =CH2OH, R =H, R = OH, R = , R = OAc

1 2 3 4 5 6 7 8 77 Patagonicoside A R =SO3Na, R =CH3, R =CH2OSO3Na, R =CH2OH, R = H, R = OH, R = , R =H

1 2 3 4 5 6 7 8 78 Patagonicoside B R =SO3Na, R =CH3, R =H, R =CH2OH, R = H, R = OH, R = , R = OH 1 2 3 4 5 6 7 8 79 Patagonicoside C R =SO3Na, R =CH3, R =CH2OH, R =CH2OH, R = H, R = OH, R = , R = OH

1 2 3 4 5 6 7 8 80 Philinopside A R =SO3Na, R =CH3, R =H, R =CH2OH, R = OAc, R = H, R = , R =H

1 2 3 4 5 6 7 8 81 Philinopside B R =SO3Na, R =CH3, R =H, R =CH2OH, R = OAc, R = H, R = , R =H, additional OSO3Na at C-2 of Xyl 1 2 3 4 5 6 7 8 82 Philinopside E R =SO3Na, R =CH3, R =H, R =CH2OH, R = O, R = H, R = , R =H

1 2 3 4 5 6 7 8 83 Philinopside F R =SO3Na, R =CH2OH, R =H, R =CH2OH, R = OAc, R = H, R = , R =H

1 2 3 4 5 6 7 8 84 Mollisoside A R =SO3Na, R =CH3, R =CH2OH, R =CH2OH, R =H, R =H, R = , R =H O 1 2 3 4 5 6 7 8 85 Mollisoside B2 R =SO3Na, R =CH2OH, R =H, R =CH2OH, R = O, R =H, R = , R =H 1 2 3 4 5 6 7 86 Eximisoside A R =H, R =CH2OH, R =H, R =CH2OH, R =OAc, R =H, R = , R8=H OH 8 87 Pseudostichoposide A R1=SO Na, R2=CH , R3=H, R4=CH OH, R5=H, R6=H, R7= , R =H 3 3 2 O 1 2 3 4 5 6 7 8 88 Cucumarioside F1 R =SO3Na, R =CH3, R =CH2OSO3Na, H, R =H, R = OAc, R =H, R = , R =H 1 2 3 4 5 6 7 8 89 Cucumarioside F2 R =SO3Na, R =CH3, R =CH2OSO3Na, H, R =H, R = OAc, R =H, R = , R =H

1 2 3 4 5 6 7 8 90 Pseudocnoside A R =SO3Na, R =CH3, R =CH2OSO3Na, R =CH2OH, R = O, R = H, R = , R =H 1 2 3 4 5 6 7 8 91 Typicoside A1 R =SO3Na, R =CH3, R =H, R =CH2OH, R = OAc, R = H, R = , R =H 92 Typicoside A R1=SO Na, R2=CH , R3=H, R4=CH OH, R5=H, R6= H, R7= , R8=H 2 3 3 2 OAc OAc 93 Typicoside B R1=SO Na, R2=CH , R3=CH OH, R4=CH OH, R5=H, R6= H, R7= , R8=H 1 3 3 2 2 OH

1 2 3 4 5 6 7 , R8=H 94 Typicoside C1 R =SO3Na, R =CH3, R =CH2OSO3Na, R =CH2OH, R =H, R = H, R = OAc

95 Typicoside C R1=SO Na, R2=CH , R3=CH OSO Na, R4=CH OH, R5=H, R6= H, R7= , R8=H 2 3 3 2 3 2

FigureFigure 7. 7. Cont.Cont.

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1 2 3 6 4 5 7 8 96 Frondoside A1 R =SO3Na, R =CH3, R =R =H, R =CH2OH, R = OAc, R = , R =H

1 2 3 6 4 5 7 8 97 Okhotoside A1-1 R =SO3Na, R =CH3, R =R =H, R =CH2OH, R = OAc, R = , R =H O 1 2 3 4 6 5 7 8 98 Okhotoside B1 R =SO3Na, R =R =R =CH2OH, R =H, R = OAc, R = , R =H

1 2 4 3 6 5 7 , R8=H 99 Okhotoside B2 R =SO3Na, R =R =CH2OH, R =CH2OSO3Na, R =H, R = OAc, R =

1 2 3 4 6 5 7 8 100 Okhotoside B3 R =OH, R =CH2OH, R =R =CH2OSO3Na, R =H, R = OAc, R = , R =H

1 2 4 3 5 6 7 , R8=H 101 Colochiroside A1 R =SO3Na, R =R =CH2OH, R =H, R = OAc, R = H, R = 1 2 4 3 5 6 7 , R8=H 102 Colochiroside A2 R =SO3Na, R =R =CH2OH, R = R =H, R = H, R =

1 2 4 3 5 6 R7= , R8=H 103 Colochiroside A3 R =SO3Na, R =R =CH2OH, R = R =H, R = H, OH

1 2 3 4 5 6 7 8 104 Colochiroside B1 R =SO3Na, R =CH3, R =H, R =CH2OH, R = OAc, R = H, R = , R =H

8 105 Colochiroside B R1=SO Na, R2=CH , R3=H, R4=CH OH, R5= OAc, R6= H, R7= , R =H 2 3 3 2 O OH

1 2 3 4 5 6 7 , R8=H 106 Cloochiroside B3 R =SO3Na, R =CH3, R =H, R =CH2OH, R = OAc, R = H, R =

1 2 3 4 5 6 7 , R8=H 107 Violaceusoside C R =SO3Na, R =CH3, R =H, R =CH2OH, R = O, R = H, R =

1 2 3 4 5 6 7 , R8=H 108 Violaceusoside D R =SO3Na, R =CH3, R =CH2OSO3Na, R =CH2OH, R = OAc, R = H, R = 8 1 2 3 4 5 6 7 , R =H 109 Violaceusoside E R =SO3Na, R =CH3, R =H, R =CH2OH, R = O, R = H, R = (additional OSO3Na at C-3 of Qui) 1 2 3 4 5 6 7 , R8=H 110 Violaceusoside G R =SO3Na, R =CH3, R =H, R =CH2OSO3Na, R = OAc, R = H, R = (additional OSO Na at C-3 of Qui) 3 O O R 111 Cucumarioside A R= 1 OAc H 112 Cucumarioside A2 R= OAc 113 Cucumarioside A3 R= OnBu O HO O 114 Cucumarioside A4 R= HO OEt HO O 115 Cucumarioside A OHO O O 5 R= HO O O MeO OH HO OH OH 116 Cucumarioside A6 R= HO

117 Cucumarioside A7 R= 118 Cucumarioside A R= O O 11 OH OH 119 Cucumarioside A12 R=

120 Cucumarioside A13 R= 121 Cucumarioside A14 R= 122 Cucumarioside A R= OH 15 O O R

123 Cucumarioside G1 R= H 124 Cucumarioside G R= OAc 3

O 125 Cucumarioside G4 R= NaO SO O OH 3 HO HO O O O R2 OHO O O HO O O MeO HO OH OH OH H 126 Pentactaside B R1= OAc, R2= 1 R 127 Pentactaside C R1= OAc, R2= O O O NaO3SO 1 2 HO HO 128 Pseudostichoposide B R =H, R = OHO O O O HO O O MeO OH OHHO OSO3Na

Figure 7. Cont.Cont.

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O O R2 129 Variegatuside A R1=OH, R2= H OH 130 Variegatuside C R1=OH, R2= OH 1 2 O O 131 Synallactoside A1 R =H, R = HO H HO OAc R1 O 1 2 O 132 Thelenotoside A R =H, R = HO HO O OAc O HO O OH 1 2 HO O 133 Thelenotoside B R =OH, R = MeO OH OH OAc O O

1 O O R O H 1 2 4 3 HO 134 Cucumechinoside A R=O, R =SO3Na, R =R =H, R =CH2OSO3Na 3 4 R O 1 2 4 3 R O 135 Cucumechinoside B R=H2, R =SO3Na, R =R =H, R =CH2OSO3Na O O O 1 2 4 3 HO HO O 136 Cucumechinoside C R=O, R =R =R =SO Na, R =H O HO 3 MeO OH 2 OH 1 2 3 4 OR 137 Cucumechinoside D R=O, R =R =SO3Na, R = R =H 1 4 2 3 138 Cucumechinoside E R=O, R =R =SO3Na, R =H, R =CH2OSO3Na 1 4 2 3 139 Cucumechinoside F R=H2, R =R =SO3Na, R =H, R =CH2OSO3Na

O O 26 24 25 H 1 140 Lefevreoside A1 R =H OAc 1 141 Lefevreoside A2 R =SO3Na 1 Δ24(25) 1 O O 142 Lefevreoside C R =SO3Na, R O H 1 Δ25(26) HO 143 Lefevreoside D R =SO3Na, HO O O O O HO O HO O MeO HO OH OH OH Figure 7.7.Chemical Chemical structures structures of holostane of holostane glycosides glycosides with 3β with-hydroxyholost-7(8)-ene 3β-hydroxyholost-7(8)-ene and four sugar and units.four 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 referencesThe name are summarized of the compounds in Table 4in and this Figure group,8. Thethei mostr producing common species, feature chemical of triterpene structures glycosides and 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 B1(146) is the geometric cucumarioside B2 (142) and pentactaside III (148) is the positional isomer of stichoposide A (153). isomer of cucumarioside B2 (142) and pentactaside III (148) is the positional isomer of stichoposide A (153Table). 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 Compoundunits. Name Producing Species Reference Compound Name Producing Species Reference Pentactaside I (144) Pentacta quadrangularis [77] Pentactaside II (145) P. quadrangularis [77] CompoundCucumarioside Name B1 (146) ProducingE. fraudatrix Species Reference[78] Cucumarioside Compound B2 (Name147) E. Producing fraudatrix Species[ 78 Reference] PentactasidePentactaside I (144 III (148) ) PentactaP. quadrangularis quadrangularis [77[77]] StichoposidePentactaside A (149 II )(145) S.P. cloronotus quadrangularis [79] [77] Stichoposide B (150) Stichopus cloronotus [79] Stichorrenoside A (151) Stichopus horrens [80] CucumariosideStichorrenoside B1 ( B146 (152) ) E. fraudatrixS. horrens [80[78]] StichorrenosideCucumarioside C (153 B2) (147) S. horrensE. fraudatrix [80] [78] PentactasideStichorrenoside III (148 D ()154 ) P. quadrangularisS. horrens [80[77]] Stichoposide Hillaside A (155 A) (149) H.S. hilla cloronotus [81] [79] Stichoposide B (150) Stichopus cloronotus [79] Stichorrenoside A (151) Stichopus horrens [80] Stichorrenoside B (152) S. horrens [80] Stichorrenoside C (153) S. horrens [80] Stichorrenoside D (154) S. horrens [80] Hillaside A (155) H. hilla [81]

Mar. Drugs 2017, 15, 317 13 of 35 Mar. Drugs 2017, 15, 317 13 of 35

24 22 144 Pentactaside I R =SO3Na, Δ O O 25 25(26) O O 145 Pentactaside II R =SO3Na, Δ H Δ22Z,25(26) 4 146 Cucumarioside B1 R =H, H R Δ22E,25(26) OAc 147 Cucumarioside B2 R =H, R3 O O RO O HO R1O O O HO O O R2 1 2 4 3 Δ24 HO O O 148 Pentactaside III R =SO3Na, R =R =H, R =OAc, HO HO HO O OH 1 2 3 4 Δ25(26) OH HO 149 Stichoposide A R =SO3Na, R =R =H, R =OAc, OH 150 Stichoposide B R1=R3=H, R2=OH, R4=OAc, Δ25(26) R3 O O 26 25 H R4 27 1 2 4 3 151 Stichorrenoside A R =CH2OH, R =R =H, R =OH 1 2 3 4 152 Stichorrenoside B R =CH2OH, R =SO3Na, R =OH, R =H O HO O 153 Stichorrenoside C R1=CH OH, R2=R3=H, R4=OAc, Δ25(26) HO 2 1 1 2 3 4 25(26) R O 154 Stichorrenoside D R =R =R =H, R =OAc, Δ R2O O HO OH O O OH

O O HO H HO 155 Hillaside A OH Figure 8.8. ChemicalChemical structures structures of of holostane holostane glycosides glycosides with with 3β-hydroxyholost-7(8)-ene 3β-hydroxyholost-7(8)-ene and 1–3 and sugar 1–3 sugar 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 compoundsThe species in this Holothuria group. For lessoni, convenience, Bohadschia the marmorata large number and Bohadschia of compounds bivittata in this produce category most can of also the becompounds further subdivided in this group. into fourFor groupsconvenience, depending the la onrge the number number of of compounds sugar units in this category can 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 (Figure5), 3 β-hydroxyholost- 9(11)-eneSimilar skeleton to 3β with-hydroxyholost-7(8)-ene six sugar units glycosides skeleton alsowith do notsix havesugar any units sulfate (Figure group 5), in their3β-hydroxyholost-9(11)-ene carbohydrate chain (Figure skeleton9 and with Table six sugar5) except units cladolosides glycosides also K 1do,K not2 and have L 1any(197 sulfate–199). Thegroup most in commontheir carbohydrate structural featurechain (Figur of triterpenee 9 and glycosidesTable 5) except in this cladolosides category is theK1, presenceK2 and ofL1 3-(197O-methyl-–199). TheD-glucose most common at the both structural end of the feature straight of carbohydrate triterpene glycosides chain. Holotoxin in this and category parvimoside is the seriespresence (156 of–166 3-O)-methyl- of compoundsD-glucose have at athe keto both group end atof positionthe straight C-16. carbohydrate Double bond chain. at C-25(26) Holotoxin among and holotoxinsparvimoside (156 series–163 )(156 is common,–166) of compounds except 26-nor-25-oxo-holotoxin have a keto group at A 1position(159), where C-16. theDouble double bond bond at isC-25(26) replaced among by a ketoholotoxins group. (156 The–163α-hydroxy) is common, groups except at C-12 26-nor-25-oxo-holotoxin and C-17 are commonly A1 found(159), where in the aglyconethe double part bond of lessoniosideis replaced by series a keto of group. glycosides The α (175-hydroxy–177). Thegroupsα-hydroxy at C-12 and group C-17 at C-12are commonly and C-17, andfound 22,25-epoxy in the aglycone are common part of structural lessonioside characteristics series of glycosides of holothurinosides (175–177). (The183– α188-hydroxy). Acetoxy group group at atC-12 C-16 and and C-17, C-22 and are 22,25-epoxy frequently observedare common in cladoloside structural characteristics glycosides (189 of–199 holothurinosides). (183–188). 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, 15Name, 317 Producing Species Reference Compound Name Pro. Species 14 Reference of 35 Holotoxin A (156) Stichopus japonicus [82] Holotoxin A1 (157) S. japonicus [22] 25,26-dihydroxyholotoxin A1 (158) Apostichopus japonicus [83] Oxo-holotoxin A1 (159) A. japonicus [22] Table 5. Name and producing species of glycosides with 3β-hydroxyholost-9(11)-ene and six sugar units. Holotoxin B (160) S. japonicus [22] Holotoxin B1 (161) S. japonicus [22] Holotoxin D (162) S. japonicus [22] Holotoxin D1 (163) A. japonicus [83] Compound Name Producing Species Reference Compound Name Pro. Species Reference Parvimoside A (164) Stichopus parvimensis [84] Parvimoside B (165) S. parvimensis [84] BivittosideHolotoxin C (166 A (156) ) BohadschiaStichopus japonicus bivittata [82][85] HolotoxinBivittoside A1 (157) D (167) S. japonicusB. bivittata [22] [85] 25,26-dihydroxyholotoxin A1 (158) Apostichopus japonicus [83] Oxo-holotoxin A1 (159) A. japonicus [22] 25-acetoxybivittosideHolotoxin B (D160 ()168) BohadschiaS. japonicus marmorata [22][86] HolotoxinArguside B1 (161) B (169) S. japonicus B. argus [22] [87] ArgusideHolotoxin C (170 D (162) ) S.B. japonicus argus [22][87] HolotoxinMarmoratoside D1 (163) A (171A.) japonicusB. marmorata [83] [86] Parvimoside A (164) Stichopus parvimensis [84] Parvimoside B (165) S. parvimensis [84] MarmoratosideBivittoside B C ( (172166) BohadschiaB. marmorata bivittata [85][86] BivittosideImpatienside D (167) A (173) B. bivittataH. impatiens [85] [86] 17α-hydroxyimpatienside25-acetoxybivittoside DA ((168174) ) BohadschiaB. marmorata marmorata [86][86] ArgusideLessonioside B (169) A (175) B. argusH. lessoni [87] [88] LessoniosideArguside B C(176 (170)) HolothuriaB. argus lessoni [87][88] MarmoratosideLessonioside A (171 )D (177) B. marmorataH. lessoni [86] [88] Marmoratoside B (172) B. marmorata [86] Impatienside A (173) H. impatiens [86] Variegatuside17α-hydroxyimpatienside E (178) A (174) S.B. marmoratavariegates [86][21] LessoniosideLessonioside A (175) C (179) H. lessoniH. lessoni [88] [88] LessoniosideLessonioside E (180 B (176) ) HolothuriaHolothuria lessoni lessoni [88][88] LessoniosideLessonioside D (177) F (181) H. lessoniH. lessoni [88] [88] Variegatuside E (178) S. variegates [21] Lessonioside C (179) H. lessoni [88] LessoniosideLessonioside G (182 E (180) ) HolothuriaH. lessoni lessoni [88][88] LessoniosideHolothurinoside F (181) F (183)H. lessoniB. subrubra [88] [89] HolothurinosideLessonioside H G (184 (182) B.H. subrubra lessoni [88][89] HolothurinosideHolothurinoside F (183) H1 (185B.) subrubraB. subrubra [89] [89] Holothurinoside H (184) B. subrubra [89] Holothurinoside H (185) B. subrubra [89] Holothurinoside I (186) B. subrubra [89] Holothurinoside1 I1 (187) B. subrubra [89] Holothurinoside I (186) B. subrubra [89] Holothurinoside I1 (187) B. subrubra [89] 1 HolothurinosideHolothurinoside K K(1881 (188) ) B.B. subrubra [89][89] CladolosideCladoloside C (189) C (189) C. schmeltziiC. schmeltzii [90] [90] CladolosideCladoloside C1 ( C1901 (190) ) CladolabesCladolabes schmeltziischmeltzii [90][90] CladolosideCladoloside C2 (191) C2 (191) C. schmeltziiC. schmeltzii [90] [90] Cladoloside C3 (192) C. schmeltzii [91] Cladoloside D (193) C. schmeltzii [90] Cladoloside C3 (192) C. schmeltzii [91] Cladoloside D (193) C. schmeltzii [90] Cladoloside G (194) C. schmeltzii [91] Cladoloside H1 (195) C. schmeltzii [91] CladolosideCladoloside G ( H1942 (196) ) C.C. schmeltzii [91][91] CladolosideCladoloside K1 (197) H1 (195) C. schmeltziiC. schmeltzii [92] [91] Cladoloside K (198) C. schmeltzii [92] Cladoloside L (199) C. schmeltzii [92] Cladoloside H2 (1962 ) C. schmeltzii [91] Cladoloside1 K1 (197) C. schmeltzii [92] Cladoloside K2 (198) C. schmeltzii [92] Cladoloside L1 (199) C. schmeltzii [92]

O O 23 25 R8 22 24 R7

R6 HO HO O O O O HO HOO O H R5O OH OH HO 2 1 O R3 R R O O O HO HO O O HO R4O OH OH OH 25(26) 1 4 5 2 3 6 7 8 Δ 156 Holotoxin A R =R =R =CH3, R =R =CH2OH, R = O, R = H, R =H, 1 4 5 2 3 6 7 8 Δ25(26) 157 Holotoxin A1 R =R =R =CH3, R =H, R =CH2OH, R = O, R = H, R =H, 1 4 5 2 7 8 3 6 158 25,26-dihydroxyholotoxin A1 R =R =R =CH3, R =R =R =H, R =CH2OH, R = O,25-OH, 26-OH 1 2 4 5 3 6 7 8 25− 159 26-nor-25-oxo-holotoxin A1 R =R =R =R =CH3, R =CH2OH, R = O, R = H, R =H, O 1 4 2 3 5 6 7 8 Δ25(26) 160 Holotoxin B R =R =CH3, R =R =CH2OH, R =H, R = O, R = H, R =H, 1 4 2 5 3 6 7 8 Δ25(26) 161 Holotoxin B1 R =R =CH3, R =R =H, R =CH2OH, R = O, R = H, R =H, 1 3 2 4 5 6 7 8 Δ25(26) 162 Holotoxin D R =R =CH2OH, R =H, R =R =CH3, R = O, R = H, R =H, 1 3 2 5 7 8 4 6 Δ25(26) 163 Holotoxin D1 R =R =CH2OH, R =R =R =R =H, R =CH3, R = O, 1 4 2 3 5 6 7 8 164 Parvimoside A R =R =CH3, R =R =CH2OH, R =H, R = O, R = H, R =H 1 4 2 5 3 6 7 8 165 Parvimoside B R =R =CH3, R =R =H, R =CH2OH, R = O, R = H, R =H 1 4 5 2 3 6 R7= R8=H 166 Bivittoside C R =R =R =CH3, R =R =CH2OH, R =H, H,

FigureFigure 9. 9. Cont.Cont.

Mar. Drugs 2017, 15, 317 15 of 35 Mar. Drugs 2017, 15, 317 15 of 35

1 4 5 2 3 6 7 8 167 Bivittoside D R =R =R =CH3, R =R =CH2OH, R =H, R = H, R = OH 1 4 5 2 3 6 7 8 168 25-acetoxy bivittoside D R =R =R =CH3, R =R =CH2OH, R =H, R = H, R = OH, 25-OAc 1 4 5 2 3 6 7 8 169 Arguside B R =R =R =CH3, R =R =CH2OH, R =H,R = OH, R = OH 1 2 3 4 5 6 7 8 170 Arguside C R = R =R =CH2OH, R =R =CH3, R =H, R = H, R = OH 1 4 5 2 3 6 7 8 Δ25(26) 171 Marmoratoside A R =R =R =CH3, R =R =CH2OH, R =H, R =H, R = OH, 1 4 5 2 3 6 7 8 Δ23 172 Marmoratoside B R =R =R =CH3, R =R =CH2OH, R =H,R =H, R = OH,25-OH, 1 4 5 2 3 6 7 8 Δ24 173 Impatienside A R =R =R =CH3, R =R =CH2OH, R =H, R =H, R = OH, α 1 4 5 2 3 6 7 8 Δ24 174 17 -hydroxy impatienside A R =R =R =CH3, R =R =CH2OH, R =H, R = OH,R = OH, 1 4 5 2 3 6 7 8 175 Lessonioside A R =R =R =CH3, R =H, R =CH2OH, R =OAc, R = OH,R = OH 1 3 5 2 4 6 7 8 176 Lessonioside B R =R =R =CH3, R =CH2OH, R =H, R =OAc, R = OH,R = OH 1 4 5 2 3 6 7 8 177 Lessonioside D R =R =R =CH3, R =CH2OH, R =H, R =OAc, R = OH,R = OH 1 3 2 6 8 4 5 7 178 Variegatuside E R =R =CH2OH, R =R =R =H, R =R =Me, R = H, 23- OH O O O 25 HO OH

O R5 R4 O O O HO HO O O 179 Lessonioside C R1=CH OH, R2=R4=R5=H, R3=CH , 25-OAc MeO O HO H 2 3 OH OH 1 2 3 4 5 R2 1 O 180 Lessonioside E R =CH , R =CH OH, R =R =R =H, 25-OAc HO R 3 2 O HO O O HO O 181 Lessonioside F R1=CH , R2=R4=R5=CH OH, R3=H, Δ25(26) 3 O HO 3 2 R O OH OH OH 1 4 5 2 3 25(26) 182 Lessonioside G R =R =R =CH2OH, R =H, R =CH3,Δ

O O R5 O R4

R2 HO O O O 1 2 3 4 5 HO HO O O 183 Holothurinoside F R =R =CH3, R =R =H, R =OH 3 O HO H R O OH OH 1 3 2 4 5 O 184 Holothurinoside H R =R =CH3, R =CH2OH, R =H, R =OH HO R1 HO O O O 1 2 3 4 5 HO HO O 185 Holothurinoside H1 R =R =CH2OH, R =CH3, R =R =H O HO MeO OH 1 3 2 4 5 OH OH 186 Holothurinoside I R =R =CH3, R =CH2OH, R =OH, R =OH 1 2 3 4 5 187 Holothurinoside I1 R =R =CH2OH, R =CH3, R =OH, R =H 1 2 3 4 5 188 Holothurinoside K1 R =R =CH2OH, R =CH3, R =OH, R =OH

FigureFigure 9. Cont.Cont.

Mar. Drugs 2017, 15, 317 16 of 35 Mar. Drugs 2017, 15, 317 16 of 35

O O R4

3 1 R HO R O O O HO HO O O 2 O HO H R O OH OH O 189 Cladoloside C R1=CH OH, R2=Me, R3=OAc, R4= HO 2 OAc O O O HO HO O 1 2 3 4 MeO O HO 190 Cladoloside C1 R =CH2OH, R =Me, R =OAc, R = OH OH OH OAc 1 2 3 4 191 Cladoloside C2 R =CH2OH, R =Me, R = O, R = 192 Cladoloside C R1=CH OH, R2=Me, R3= OAc, R4= 3 2 OH 193 Cladoloside D R1=R2=H, R3=OAc, R4= OAc 194 Cladoloside G R1=H, R2=Me, R3= OAc, R4= OAc 195 Cladoloside H R1=R2=Me, R3= OAc, R4= 1 OAc 196 Cladoloside H R1=R2=Me, R3= OAc, R4= 2 OAc R1 O O 26 23 25

H 27

R R3O HO O O O HO HO O O 1 2 3 O HO H 197 Cladoloside K1 R=R =OAc, R =SO3Na, R =H MeO OH OH O 1 2 3 Δ25(26) R2O 198 Cladoloside K2 R=OAc, R =OH, R =SO3Na, R =H, O HO O O HO O 1 2 3 Δ25(26) MeO O HO 199 Cladoloside L1 R=O, R =R =H, R =SO3Na, OH OH OH

Figure 9.9.Chemical Chemical structures structures of holostane of holostane glycosides glycosides with 3β with-hydroxyholost-9(11)-ene 3β-hydroxyholost-9(11)-ene and six sugar and units. six 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 Table6). 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 units.Compound Name Producing Species Reference Compound Name Producing Species Reference Holothurinoside A (200) Holothuria forskalii [93] 17-dehydroxyholothurinoside A (201) Holothuria grisea [94] CompoundHolothurinoside Name A 1 (202 Producing) H.lessoni Species Reference[95] Holothurinoside Compound Name B (203) ProducingH. forskalii Species [93 Reference] HolothurinosideKolgaoside A A(200 (204)) HolothuriaKolga forskalii hyalina [93][96 ]17-dehydroxyholothurinoside Kolgaoside B (205) A (201) K.Holothuria hyalina grisea [96] [94] Griseaside A (206) H. grisea [94] Impatienside B (207) H. axiloga [97] HolothurinosideArguside A F1 ( 202208)) H.lessoniHolothuria axiloga [95][97 ]Holothurinoside Pervicoside D (209 B) (203) H. axilogaH. forskalii [97] [93] KolgaosideCladoloside A (204 B) (210 ) KolgaA. hyalina japonicus [96][22 ] CladolosideKolgaoside B 1B( 211(205) ) C. schmeltziiK. hyalina [90] [96] GriseasideCladoloside A (206 B2) (212) H. C.grisea schmeltzii [94][90 ] HolothurinosideImpatienside EB ((213207) ) H. lessoniH. axiloga [95] [97] Holothurinoside E (214) H. lessoni [95] Holothurinoside M (215) H. lessoni [95] Arguside F (208) 1 Holothuria axiloga [97] Pervicoside D (209) H. axiloga [97] Achlioniceoside A1 (216) A. violaecuspidata [98] Achlioniceoside A2 (217) A. violaecuspidata [98] 1 CladolosideAchlioniceoside B (210 A) 3 (218) A.A. japonicus violaecuspidata [22][98 ] Ds-penaustrosideCladoloside B C( (211219)) P. australisC. schmeltzii [99] [90] CladolosideDs-penaustroside B2 (212) D (220) C. Pentactaschmeltzii australis [90][99 ]Holothurinoside Frondoside A2-6 ( 221E ()213) C. frondosaH. lessoni [35] [95] Cladoloside E (222) C. schmeltzii [91] Cladoloside E (223) C. schmeltzii [91] Holothurinoside E1 (1214) H. lessoni [95] Holothurinoside2 M (215) H. lessoni [95] Cladoloside F1 (224) C. schmeltzii [91] Cladoloside F2 (225) C. schmeltzii [91] 1 2 AchlioniceosideCercodemasoide A (216 A ()226 ) A. violaecuspidataC. anceps [98][100 ]Achlioniceoside Cladoloside I1 (227 A )(217) C.A. schmeltzii violaecuspidata [92] [98] AchlioniceosideCladoloside A3 I(2218(228) ) A. violaecuspidataC. schmeltzii [98][92 ]Ds-penaustroside Cladoloside J1 (229 C) (219) C. schmeltziiP. australis [92] [99] Ds-penaustroside D (220) Pentacta australis [99] Frondoside A2-6 (221) C. frondosa [35] Cladoloside E1 (222) C. schmeltzii [91] Cladoloside E2 (223) C. schmeltzii [91] Cladoloside F1 (224) C. schmeltzii [91] Cladoloside F2 (225) C. schmeltzii [91] Cercodemasoide A (226) C. anceps [100] Cladoloside I1 (227) C. schmeltzii [92] Cladoloside I2 (228) C. schmeltzii [92] Cladoloside J1 (229) C. schmeltzii [92]

Mar. Drugs 2017, 15, 317 17 of 35 Mar. Drugs 2017, 15, 317 17 of 35

O O R8 R7 6 17 R R5 R3O O O HO O O R4O HO 2 OH HO R R1 O OHO O O O HO O MeO OHHO OH OH

1 3 4 5 2 6 7 8 200 Holothurinoside A R =R =R =R =H, R =CH2OH, R =R =OH, R = O 1 3 5 6 2 4 7 8 201 17-dehydroxy holothurinoside A R =R =R =R =H, R =CH2OH, R =CH3, R =OH, R = O

1 7 2 3 4 5 6 8 202 Holothurinoside A1 R =R =OH, R =CH2OH, R =R =R =R =H, R = O 203 Holothurinoside B R1=R3=R4=R5=H, R2=CH OH, R6=R7=OH, R8= 2 OAc 204 Kolgaoside A R1=R3=R4=R5=H, R2=CH OH, R6=R7=OH, R8= 2 OH 205 Kolgaoside B R1=R3=R4=R5=H, R2=CH OH, R6=R7=OH, R8= 2 OH 206 Griseaside A R1=R3=R4=R5=R6=H, R2=CH OH, R7=OH, R8= 2 OH 1 3 4 5 6 2 7 8 207 Impatienside B R =R =R =R =R =H, R =CH2OH, R =OH, R =

1 3 4 6 2 5 7 8 208 Arguside F R =R =R =R =H, R =CH2OH, R = OAc, R =OH, R = 209 Pervicoside D R1=R3=R4=R5=R6=H, R2=CH OH, R7=OH, R8= 2 OAc 210 Cladoloside B R1=R2=R3=R4=R6=R7=H, R5= O, R8=

1 2 3 4 6 7 5 8 211 Cladoloside B1 R =R =R =R =R =R =H, R = OAc, R = OAc 1 2 3 4 6 7 5 8 212 Cladoloside B2 R =R =R =R =R =R =H, R = OAc, R = OAc

1 3 4 5 6 2 7 8 213 Holothurinoside E R =R =R =R =R =H, R =CH2OH, R =OH, R = O

1 3 4 5 6 7 2 8 214 Holothurinoside E1 R =OH, R =R =R =R =R =H, R =CH2OH, R = O

1 3 5 6 2 4 7 8 215 Holothurinoside M R =R =R =R =H, R =CH2OH, R =CH3, R =OH, R = O 1 4 5 6 2 3 4 7 8 216 Achlioniceoside A1 R =R =R =R =H, R =CH2OSO3Na, R =SO3Na, R =CH3, R =OH, R = OH 1 4 5 6 2 3 4 7 8 217 Achlioniceoside A2 R =R =R =R =H, R =CH2OSO3Na, R =SO3Na, R =CH3, R =OH, R = OH 1 4 5 6 2 3 4 7 8 218 Achlioniceoside A3 R =R =R =R =H, R =CH2OSO3Na, R =SO3Na, R =CH3, R =OH, R = O

O O 26 25

H 27

O 219 Ds-penaustroside C R1=R2=H, Δ25(26) O 1 2 R1O O 220 Ds-penaustroside D R =R =H HO R2O HO 221 Frondoside A -6 R1=SO Na, R2=H, Δ25(26) O 2 3 HO OHO O O O O 222 Cercodemasoide A R1=R2=SO Na, Δ25(26) MeO OH OHHO 3 O O HO HO OH

Figure 10. Cont.

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OAc O O 26 22 25

H 27 1 2 223 Cladoloside E1 R =R =H 2 OAc R 224 Cladoloside E R1=R2=H, Δ25(26) O 2 HO O O 1 2 O 225 Cladoloside F1 R =H, R =Me HO OH HO R1O O 226 Cladoloside F R1=H, R2=Me, Δ25(26) O 2 HO OHO O O 1 3 2 O 227 Cladoloside I1 R =SO Na, R =CH2OH MeO OHHO 1 3 2 Δ25(26) OH OH 228 Cladoloside I2 R =SO Na, R =CH2OH, O O

O HO O O NaO3SO HO O O O O 229 Cladoloside J1 HO OH HO MeO OH O HO O O O HO OH HO OH Figure 10.10. ChemicalChemical structures structures of holostaneof holostane glycosides glycosides with 3β with-hydroxyholost-9(11)-ene 3β-hydroxyholost-9(11)-ene and five sugar and units five. 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 TableThe7 and names Figure and 11 .structures Almost all of the the saponins glycosides in thisbelonging group containto this sulfategroup are group summarized at C-4 of xylose in the sugar.Table 7 The and most Figure common 11. Almost features all the of holothurinssaponins in (this230 –group233), scabrasidescontain sulfate (235 group–237) andat C-4 echinosides of xylose (sugar.243–249 The) are most the common presence features of hydroxy of holothurins groups at C-12 (230 and–233 C-17), scabrasides (Figure 11 ().235 Among–237) and the echinosides cladoloside series(243–249 of) compounds are the presence (266–271 of ),hydroxy either keto groups or acetoxy at C-12 group and C-17 is commonly (Figure 11). found Among at position the cladoloside C-16 and 22.series The of uncommon compounds linear (266– sugar271), either chain [3-ketoO-MeGlc or acetoxy (1→ 3)-Glcgroup (1is →commonly4)-Xyl (2→ found1)-Qui] at isposition observed C-16 in bivittosideand 22. The B uncommon (262). Another linear exceptional sugar chain feature [3-O has-MeGlc been (1 found→3)-Glc in this(1→4)-Xyl category (2→ of1)-Qui] compounds is observed is the presencein bivittoside of three B (262 consecutive). Another glucose exceptional unit in feature the linear has carbohydratebeen found in chain this category (258 and of259 compounds). is 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. Producing Compound Name ProducingProducing Species Reference Compound Name Reference Compound Name Reference Compound Name ProducingSpeciesSpecies Reference Species Holothurin A (230) Actinopyga agassizi [101] Holothurin A1 (231) H. grisea [102] HolothurinHolothurin A ( A2303 (232) ) ActinopygaHolothuria agassizi scabra [101][103] Holothurin Holothurin AA41(233(231) ) H. scabragrisea [103[102]] HolothurinHolothurinoside A3 (232 C) ( 234) HolothuriaH. forskalii scabra [103][93] Holothurin Scabraside AA (4235 (233) ) H. scabrascabra [104[103]] HolothurinosideScabraside BC ((236234) ) H. H.forskalii scabra [[93]104] Scabraside Scabraside DA (237(235) ) H. scabrascabra [105[104]] Fuscocineroside A (238) H. fuscocinerea [106] Fuscocineroside B (239) H. fuscocinerea [106] 17-hydroxyScabraside fuscocineroside B (236) B (240) H.B. marmoratascabra [104]107] 25-hydroxy-fuscocinerosideScabraside D (237) B (241) B.H. marmorata scabra [107[105]] FuscocinerosideFuscocineroside A ( C238 (242) ) H. H.fuscocinerea fuscocinerea [106][106] Fuscocineroside Echinoside A ( 243B ()239) H.A. fuscocinerea echinites [108[106]] 17-hydroxyDs-echinoside fuscocineroside A (244) P. graeffei [109]25-hydroxy-fuscocineroside 24-dehydroechinoside A (245) H. scabra [105] B. marmorata [107] B. marmorata [107] 22-hydroxy-24-dehydroechinosideB (240) A (246) Actinopyga flammea [110] 24-hydroxy-25-dehydroechinosideB (241) A (247) A. flammea [110] 25-hydroxydehydroechinoside A (248) A. flammea [110] 22-acetoxyechinoside A (249) A. flammea [110] FuscocinerosideDesholothurin C A(242 (250) ) H. fuscocinereaP. graeffei [106][93] Echinoside Pervicoside A ((251243) ) A.H. pervicaxechinites [111[108]] Ds-echinosidePervicoside A B(244 (252)) P.H. graeffei pervicax [109][111] 24-dehydroechinoside Pervicoside C (253 )A (245) H.H. pervicax scabra [111[105]] 22-hydroxy-24-dehydroechinosideArguside A (254) A Bohadschia argus [112]24-hydroxy-25-dehydroechinoside Holothurinoside J1 (255) A P. graeffei [95] Actinopyga flammea [110] A. flammea [110] Hemoiedemoside(246) A (256) H. spectabilis [113] Hemoiedemoside(247) B (257) H. spectabilis [113] Arguside D (258) B. argus [114] Arguside E (259) B. argus [114] 25-hydroxydehydroechinoside A (248) A. flammea [110] 22-acetoxyechinoside A (249) A. flammea [110] Psolusoside A (260) Psolus fabricii [115] Liouvilloside A4 (261) S. liouvillei [46] DesholothurinBivittoside A B ( (250262) BohadschiaP. graeffei bivitta [93][85] HolothurinosidePervicoside A X(251 (263)) H.H. pervicax lessoni [116[111]] PervicosideHolothurinoside B (252 Y) (264) H. pervicaxH.lessoni [111][116] HolothurinosidePervicoside C Z(253 (265)) H.H. pervicax lessoni [116[111]] Cladoloside A (266) Cladolabes chmeltzii [117] Cladoloside A (267) C. chmeltzii [117] Arguside A (2541 ) Bohadschia argus [112] Holothurinoside2 J1 (255) P. graeffei [95] Cladoloside A (268) C. chmeltzii [117] Cladoloside A (269) C. chmeltzii [117] Hemoiedemoside A3 (256) H. spectabilis [113] Hemoiedemoside4 B (257) H. spectabilis [113] Cladoloside A5 (270) C. chmeltzii [117] Cladoloside A6 (271) C. chmeltzii [117] ArgusideColochiroside D (258 C) ( 272) B.C. argus chmeltzii [114][64] ColochirosideArguside E D(259 (273)) C.B. robustus argus [63[114]] PsolusosideMollisoside A ( B2601 (274) ) PsolusA. fabricii mollis [115][55] Liouvilloside Neothyonidioside A4 (275261)) S.A. liouvillei mollis [118[46]] Bivittoside B (262) Bohadschia bivitta [85] Holothurinoside X (263) H. lessoni [116] Holothurinoside Y (264) H.lessoni [116] Holothurinoside Z (265) H. lessoni [116] Cladoloside A1 (266) Cladolabes chmeltzii [117] Cladoloside A2 (267) C. chmeltzii [117] Cladoloside A3 (268) C.chmeltzii [117] Cladoloside A4 (269) C. chmeltzii [117] Cladoloside A5 (270) C.chmeltzii [117] Cladoloside A6 (271) C. chmeltzii [117] Colochiroside C (272) C.chmeltzii [64] Colochiroside D (273) C. robustus [63] Mollisoside B1 (274) A. mollis [55] Neothyonidioside (275) A. mollis [118]

Mar. Drugs 2017, 15, 317 19 of 35 Mar. Drugs 2017, 15, 317 19 of 35

O O R3 HO 17 R2

O R1O O 1 2 3 HO 242 Fuscocineroside C R =SO3Na, R =H, R = O HO HO O O 1 2 3 OHO O O 243 Echinoside A R =SO3Na, R =OH, R = HO O MeO OHHO OH OH 244 Ds-echinoside A R1=H, R2=OH, R3= 24 1 2 3 1 2 3 245 24-dehydroechinoside A R =H, R =OH, R = 230 Holothurin A R =SO3Na, R =OH, R = O 1 2 1 2 3 246 22-hydroxy-24-dehydroechinoside A R =H, R =OH, 231 Holothurin A1 R =SO3Na, R =OH, R = 24 OH R3= 1 2 3 OH 232 Holothurin A3 R =SO3Na, R =OH, R = OH O OH 1 247 24-hydroxy-25-dehydroechinoside A R =SO3Na, OH 1 2 3 233 Holothurin A4 R =SO3Na, R =OH, R = R2=OH, R3= 1 2 3 248 25-hydroxydehydroechinoside A R1=SO Na, 234 Holothurinoside C R =R =H, R = O 3 2 3 235 Scabraside A R1=SO Na, R2=OH, R3= R =OH, R = 3 OH 249 22-acetoxy-echinoside A R1=H, R2=OH, 1 2 3 3 236 Scabraside B R =SO3Na, R =OH, R = R = O OAc 1 2 3 237 Scabraside D R =SO3Na, R =OH, R = OH 1 2 3 250 Desholothurin A R =H, R =OH, R = O 238 Fuscocineroside A R1=SO Na, R2=H, R3= 3 1 2 3 O 251 Pervicoside A R =SO3Na, R =H, R = 1 2 3 OAc 239 Fuscocineroside B R =SO3Na, R =H, R = O 252 Pervicoside B R1=SO Na, R2=H, R3= 1 2 3 240 17-hydroxy fuscocineroside B R =SO3Na, R =OH, 3 1 2 3 R = 253 Pervicoside C R =SO3Na, R =H, R = O 241 25-hydroxy fuscocineroside B R1=SO Na, 3 254 Arguside A R1=H, R2= OAc, R3= R2=H, R3= 25 O OH O 8 1 3 5 7 O R 256 Hemoiedemoside A R =R =SO3Na, R = O 1 3 5 R 255 Holothurinoside J1 R =R =H, R =H, R6 R2=R6=R7=H, R4=OH, R8=

2 4 6 7 8 5 1 3 4 R =R =R =R =OH, R = O R 257 Hemoiedemoside B R =R =SO3Na, R = OSO3Na R2=R6=R7=H, R5= R8= R1O O O O, HO H 3 1 3 6 2 4 7 5 8 4 R O 2 O 258 Arguside D R =R =R =H, R =R =R =OH, R =H, R = R R O OAc O O O HO HO O O HO 1 3 6 2 4 7 5 8 MeO OH OH OH 259 Arguside E R =R =R =H, R =R =R =OH, R =H, R = O

1 2 6 7 3 4 5 8 260 Psolusoside A R =R =R =R =H, R =SO3Na, R =OSO3Na, R = O, R = 1 3 2 4 6 7 5 8 261 Liouvilloside A4 R =R =SO3Na, R =R =R =R =H, R = O, R =

Figure 11. Cont.Cont.

Mar. Drugs 2017, 15, 317 20 of 35 Mar. Drugs 2017, 15, 317 20 of 35

O 22 HO O 25 O O HO H OH 262 Bivittoside B

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

O O R3 266 Cladoloside A R1=H, R2=OAc, R3= 1 OAc H 267 Cladoloside A R1=H, R2=OAc, R3= 2 OAc 2 1 2 3 R 268 Cladoloside A3 R =H, R =OAc, R = O O 1 2 3 HO 269 Cladoloside A4 R =H, R = O, R = 1 HO HO R O OH O O O 1 2 3 HO HO O 270 Cladoloside A5 R =H, R = O, R = MeO O HO OH OH 1 2 3 OH 271 Cladoloside A6 R =CH2OH, R =OAc, R = OAc O O

O 1 4 2 3 O 272 Colochiroside C R =R =SO3Na, R =R =H R1O O 1 4 2 3 3 HO 273 Colochiroside D R =R =H, R =OH, R =CH OSO Na R4O R 2 O 2 3 O R 1 2 3 4 OHO O 274 Mollisoside B1 R =SO3Na, R =OH, R =R =H HO O O MeO OH OHHO 275 Neothyonidioside R1=SO Na, R2=R3=R4=H OH 3

FigureFigure 11. ChemicalChemical structures structures of holostaneof holostane glycosides glycosides with 3withβ-hydroxyholost-9(11)-ene 3β-hydroxyholost-9(11)-ene and fours and ugar fours 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 Only one type of carbohydrate chain, D-xylose-D-quinovose, is found in all glycosides in this having two monosaccharide units (278–290), except 291 where carbohydrate chain is D-xylose-D-xylose group having two monosaccharide units (278–290), except 291 where carbohydrate chain is (Figure 12 and Table8); 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] CompoundCercodemasoide Name D (278) ProducingC. anceps Species Reference[100] Cercodemasoide Compound EName (279) ProducingC. anceps Species[ 100 Reference] CercodemasoideHolothurin B (280276)) CercodemasHolothuria lessonianceps [[100]119] Cercodemasoide Holothurin B1 (281 C) (277) H. lessoniC. anceps [120] [100] CercodemasoideHolothurin BD2 (278282)) C.H. anceps polii [[100]121] Cercodemasoide Holothurin B3 (283 E) (279) H. poliiC. anceps [121] [100] Holothurin B4 (284) H. polii [121] Holothurinoside D (285) H. forskalii [93] HolothurinLeucospilotaside B (280 A) (286) HolothuriaH. leucospilota lessoni [[119]122] LeucospilotasideHolothurin B B1 ((287281) ) H. leucospilotaH. lessoni [122] [120] HolothurinBivittoside B2 ( A282 (288) ) BohadschiaH. polii bivittata [121][85] Holothurin Echinoside B (B2893 ()283) A. echinitesH. polii [108] [121] Holothurin24-dehydroechinoside B4 (284) B (290) ActinopygaH. polii mauritiana [[121]123] Holothurinoside Hillaside C (291 )D (285) HolothuriaH. forskalii hilla [124] [93] LeucospilotasideHillaside BA (292 (286) ) H. leucospilotaH. hilla [122][81] Leucospilotaside B (287) H. leucospilota [122] Bivittoside A (288) Bohadschia bivittata [85] Echinoside B (289) A. echinites [108] 24-dehydroechinoside B (290) Actinopyga mauritiana [123] Hillaside C (291) Holothuria hilla [124] Hillaside B (292) H. hilla [81]

Mar. Drugs 2017, 15, 317 21 of 35

O O 26 NaO3SO Mar. Drugs 2017, 15, 317 25 HO O 21 of 35 H 276 Cercodemasoide B R= HO 27 NaO SO OH 3 O O O O 26 HO 277 Cercodemasoide CNaOR= 3SO Δ25(26) 25 HO OOH , 276 Cercodemasoide B R= HO NaO SO O O H 278 Cercodemasoide D R=HHO 3 27 25(26) OH HO 279 Cercodemasoide ENaO R=H,3SOΔ O 4 O O O R3 O R O HO RO 277 Cercodemasoide1 C R=2 3 4 Δ25(26) HO 280 Holothurin B R =SO3Na, R =R =OH,HO R = OH O, O R2 NaO SO OH O 281 Holothurin278 Cercodemasoide B R1=SO Na, D RR=H2=R3=OH, R4= 3 HO 1 3 Δ25(26) 4 279 Cercodemasoide E R=H, O 3 O O R 1 2 3 4 RO O R 282 Holothurin B2 R1 =SO3Na, R2 =R3 =OH, R4 = 280 Holothurin B R =SO3Na, R =R =OH, R = OHO HO 2 1 OOHO R 11 22 3 3 4 4 R O H 281283 HolothurinHolothurin BB1 RR =SO=SO3Na,Na, RR =R=H,=OH, R =OH, R = R = HO 3 3 O 11 22 33 44 O 282284 Holothurin B24 R =SO33Na, R =R =OH, R = HO O OH OH HO1 O O R O OH H 283285 HolothurinHolothurinoside B R1 =SOD R1=RNa,2 =H,R2=H, R3 =OH,R3=OH, R4 =R4= HO 3 3 O O O 284 Holothurin B R1=SO Na, R2=R3=OH, 1R4= 2 3 O 1 2 3 4 4 2893 Echinoside B R =SO3Na, R =R =OH, HO286 Leucospilotaside A R =SO3Na, R =R =OH, R = OH O OH 4 HO 1 2 3 R4= OH 1 2 3 4 285 Holothurinoside D R =R =H, R =OH, R = O 287 Leucospilotaside B R =SO3Na, R =R =OH, R = 1 OH OH 290 24-dehydroechinoside B R =SO3Na, 1 2 3 4 289 Echinoside B R1=SO Na, R2=R3=OH, 286288 Leucospilotaside Bivittoside A R =RA R=H,1=SO R Na,=OH, R2 R=R=3=OH, R4= R2=R3=OH, R4= 3 3 O OH R4= 1 O 2 O3 4 O O 287 Leucospilotaside B R =SOHO3Na, R =R =OH, R = HO 1 OH OH 290 24-dehydroechinoside B R =SO3Na, 1 2 3 4 OH OH 288 Bivittoside A R =R =H, R =OH, R = OH R2=R3=OH, ROH4= O O O HO O HO OAc OH OH O O OH O O OH HO H HO H HO 291 Hillaside C HO 292 Hillaside B O OH OAc HO O HO OHO O O O HO H HO H HO 291 Hillaside C HO 292 Hillaside B O O OH Figure 12.HOFigureChemical 12. Chemical structure structure of holostane of holostane glycosides glycosides with 3withβ-hydroxyholost-9(11)-ene 3β-hydroxyholost-9(11)-ene and and 1–3 1–3 sugar units. sugarHO units. OH 4.1.3. Holostane4.1.3.Figure Holostane Glycosides 12. Chemical Glycosides with structure with 3β-Hydroxyholost-8(9)-ene 3ofβ -Hydroxyholost-8(9)-eneholostane glycosides with Skeleton3β Skeleton-hydroxyholost-9(11)-ene and 1–3 sugar units. Only threeOnly glycosidesthree glycosides belong belong to to this this groupgroup with with carbohydrate carbohydrate chain chainconsisting consisting of 4–5 of 4–5 4.1.3.monosaccharide Holostane Glycosides units (Table with 9 and 3β -Hydroxyholost-8(9)-eneFigure 13). Among holostane Skeleton sea cucumber glycosides, only one monosaccharideglycoside, units synaptoside (Table A91 (and293), contains Figure keto13). group Among at C-7. holostane sea cucumber glycosides, only Only three glycosides belong to this group with carbohydrate chain consisting of 4–5 one glycoside, synaptoside A1 (293), contains keto group at C-7. monosaccharideTable 9. Name units and producing (Table 9 andspecies Figure of holostane 13). Among glycosides holostane with 3 seaβ-hydroxyholost-8(9)-ene cucumber glycosides, skeleton. only one glycoside, synaptoside A1 (293), contains keto group at C-7. Table 9.CompoundName and Name producing Producing species Species of holostane Reference glycosides Compound with Name 3β-hydroxyholost-8(9)-ene Producing Species Reference skeleton. Synaptoside A1 (293) Synapta maculata [41] Variegatuside B (294) Stichopus variegates [73] Table 9. Name and producing species of holostane glycosides with 3β-hydroxyholost-8(9)-ene skeleton. CompoundVariegatuside Name D (295 Producing) Stichopus Species variegates Reference[21] 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) Synapta maculata [41] Variegatuside B (294) Stichopus variegates [73] Variegatuside D (295) Stichopus variegates [21] O O Variegatuside D (295) Stichopus variegates [21] H O O O O 293 Synaptoside A NaO SO 1 3 O O H O HO O O O HO H OH HO O NaOOC HO O 293 Synaptoside A1 NaO SO O O O3HO O O O HO HOO O O O MeO HO H OHHO OH HO OH NaOOC HO O O O O HO HO O Figure 13. Cont. Mar. Drugs 2017, 15, 317 O HO 22 of 35 MeO OH OH OH O O Figure 13. Cont. H OH HO O HO O 294 Variegatuside B R1= HO O , R2=R3=H MeO OH OH 3 O O HO HO R O H O O HO 295 Variegatuside D R1=H, R2= O HO , 3 HO HO O R = O HO HO O MeO OH OH OH R2O 1 R O 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 (296–300, 314, 322, 332–340 and 341). Cucumariosides A8 (305) and A9 (306) contain uncommon hydroxy group at C-18. Fallaxosides B1 (322) and D3 (327) are novel glycosides with unprecedented skeletons of aglycones. Psolusoside B (314) and Kuriloside C (316) have four members sugar architecture which are uncommon in both holostane and nonholostane glycosides. Another uncommon feature of this group of compounds is the presence of keto group at C-11 (323 and 325). Sulfate group is commonly found at C-4 of first xylose unit (Figure 15). Most of the nonholostane glycosides have branched five members carbohydrate chain (Figure 15).

O O HO O HO O AcO H H H O H O

I II III IV V VI Figure 14. D- and E-ring structural architectures present in nonholotane glycosides.

Table 10. Name and producing species of nonholostane glycosides.

Compound Name Producing Species Reference Compound Name Producing Species Reference Cucumarioside G2 (296) E. fraudatrix [125] Cucumarioside A10 (297) E. fraudatrix [67] Calcigeroside B (298) P. calcigera [37] Calcigeroside C1 (299) P. calcigera [37] Cucumarioside H3 (300) E. fraudatrix [30] Cucumarioside A3-2 (301) C. conicospermium [26] Cucumarioside A3-3 (302) C. conicospermium [26] Koreoside A (303) C. koraiensis [126] Isokoreoside A (304) C. conicospermium [26] Cucumarioside A8 (305) E. fraudatrix [67] Cucumarioside A9 (306) E. fraudatrix [67] Holotoxin F (307) A. japonicus [22] Holotoxin G (308) A. japonicus [22] Holotoxin H (309) S. japonicus [127] Holotoxin I (310) S. japonicus [127] Ds-penaustroside A (311) P. australis [99] Ds-penaustroside B (312) P. australis [99] Frondoside C (313) C. frondosa [128] Psolusoside B (314) Psolus fabricii [129] Kuriloside A (315) D. kurilensi [130] Kuriloside C (316) D. kurilensi [130] Frondoside A2-7 (317) C. frondosa [36] Frondoside A2-8 (318) C. frondosa [36] Frondoside A7-3 (319) C. frondosa [43] Frondoside A7-4 (320) C. frondosa [43] Isofrondoside C (321) C. frondosa [43] Fallaxoside B1 (322) C. fallax [131] Fallaxoside C1 (323) C. fallax [132] Fallaxoside C2 (324) C. fallax [132] Fallaxoside D1 (325) C. fallax [132] Fallaxoside D2 (326) C. fallax [132] Fallaxoside D3 (327) C. fallax [131] Fallaxoside D4 (328) C. fallax [133] Fallaxoside D5 (329) C. fallax [133] Fallaxoside D6 (330) C. fallax [133] Fallaxoside D7 (331) C. fallax [133] Magnumoside A1 (332) Massinium magnum [134] Magnumoside A2 (333) M. magnum [134]

Mar. Drugs 2017, 15, 317 22 of 35

O O

H OH HO O HO O 294 Variegatuside B R1= HO O , R2=R3=H MeO OH OH 3 O O HO HO R O H O O HO 295 Variegatuside D R1=H, R2= O HO , 3 HO HO O R = O HO HO O MeO OH OH OH R2O 1 R O OH Mar. Drugs 2017, 15, 317 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,glycosides, nonholostane glycosides do not have γ(18,20)-lactone structural unit unit (Figures (Figures 1414 andand 15,15, Table 1010).). There are six different structuralstructural units (Figure 1414)) presentpresent inin D-D- andand EE ringsrings ofof aglyconeaglycone inin nonholostanenonholostane glycosides.glycosides. The aglycone side chain can be long or short, and may contain keto, methylene, hydroxy and acetoxy functional groups (Figure 1515).). Instead Instead of ofγ(18,20)-lactone, γ(18,20)-lactone, some some glycosides glycosides in this in group this containgroup γcontain(16,18)-lactone γ(16,18)-lactone (296–300, 314(296,–322300,,332 314–340, 322and, 332341–340). Cucumariosides and 341). Cucumariosides A8 (305) and A 98 (306305)) containand A9 uncommon(306) contain hydroxy uncommon group athydroxy C-18. Fallaxosidesgroup at C-18. B1 Fallaxosides(322) and D B3 1( (327322)) areand novel D3 (327 glycosides) are novel with glycosides unprecedented with unprecedented skeletons of aglycones.skeletons of Psolusoside aglycones. BPsolusoside (314) and Kuriloside B (314) and C (316 Kuriloside) have four C members (316) have sugar four architecture members whichsugar arearchitecture uncommon which in both are holostane uncommon and in nonholostane both holostane glycosides. and nonholostane Another uncommon glycosides. feature Another of this groupuncommon of compounds feature of isthis the group presence of compounds of keto group is the at C-11 presence (323 and of keto325 ).group Sulfate at groupC-11 (323 is commonly and 325). foundSulfate at group C-4 of is ﬁrst commonly xylose unit found (Figure at C-4 15 ).of Most first ofxylose the nonholostane unit (Figure 15). glycosides Most of have the branchednonholostane ﬁve membersglycosides carbohydrate have branched chain five (Figure members 15). carbohydrate chain (Figure 15).

O O HO O HO O AcO H H H O H O

I II III IV V VI Figure 14. D- and E-ring structural architecture architecturess 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) E. fraudatrix [125] Cucumarioside A10 (297) E. fraudatrix [67] Compound Name Producing Species Reference Compound Name Producing Species Reference Calcigeroside B (298) P. calcigera [37] Calcigeroside C1 (299) P. calcigera [37] Cucumarioside G2 (296) E. fraudatrix [125] Cucumarioside A10 (297) E. fraudatrix [67] Cucumarioside H3 (300) E. fraudatrix [30] Cucumarioside A3-2 (301) C. conicospermium [26] Calcigeroside B (298) P. calcigera [37] Calcigeroside C1 (299) P. calcigera [37] CucumariosideCucumarioside A3-3 H (3302(300) ) C. conicospermiumE. fraudatrix [26][30] CucumariosideKoreoside AA3 -2(303 (301) ) C. conicospermiumC. koraiensis [26] [126] IsokoreosideCucumarioside A (304 A3-3) (302) C. conicospermiumC. conicospermium [26][26] Cucumarioside Koreoside A (303 A8) (305) C. koraiensisE. fraudatrix [126] [67] Isokoreoside A (304) C. conicospermium [26] Cucumarioside A8 (305) E. fraudatrix [67] Cucumarioside A9 (306) E. fraudatrix [67] Holotoxin F (307) A. japonicus [22] Cucumarioside A9 (306) E. fraudatrix [67] Holotoxin F (307) A. japonicus [22] HolotoxinHolotoxin G (308 G (308) ) A. A.japonicus japonicus [22][22] Holotoxin H H (309 (309) ) S. japonicusS. japonicus [127][127] HolotoxinHolotoxin I (310 I (310) ) S. japonicusS. japonicus [127][127] Ds-penaustroside Ds-penaustroside A (311A (311) ) P. australisP. australis [99] [99] Ds-penaustrosideDs-penaustroside B (312 B (312) ) P. australisP. australis [99][99] Frondoside Frondoside C C (313 (313) ) C. frondosaC. frondosa [128][128] Psolusoside B (314) Psolus fabricii [129] Kuriloside A (315) D. kurilensi [130] Psolusoside B (314) Psolus fabricii [129] Kuriloside A (315) D. kurilensi [130] Kuriloside C (316) D. kurilensi [130] Frondoside A2-7 (317) C. frondosa [36] KurilosideFrondoside C ( A3162-8) (318) D. C.kurilensi frondosa [130][36] Frondoside Frondoside A A7-32-7 (319 (317) ) C. frondosaC. frondosa [43] [36] Frondoside A -4 (320) C. frondosa [43] Isofrondoside C (321) C. frondosa [43] Frondoside A2-8 (7318) C. frondosa [36] Frondoside A7-3 (319) C. frondosa [43] Fallaxoside B1 (322) C. fallax [131] Fallaxoside C1 (323) C. fallax [132] Frondoside A7-4 (320) C. frondosa [43] Isofrondoside C (321) C. frondosa [43] Fallaxoside C2 (324) C. fallax [132] Fallaxoside D1 (325) C. fallax [132] FallaxosideFallaxoside B1 ( D3222 (326) ) C. C.fallax fallax [131][132] Fallaxoside D 3C(1327 (323) ) C. fallaxC. fallax [131][132] FallaxosideFallaxoside C2 ( D3244 (328) ) C. C.fallax fallax [132][133] Fallaxoside D 5D(3291 (325) ) C. fallaxC. fallax [133][132] Fallaxoside D6 (330) C. fallax [133] Fallaxoside D7 (331) C. fallax [133] Fallaxoside D2 (326) C. fallax [132] Fallaxoside D3 (327) C. fallax [131] Magnumoside A1 (332) Massinium magnum [134] Magnumoside A2 (333) M. magnum [134] 4 5 FallaxosideMagnumoside D (328 A3)( 334) C.M. fallax magnum [133][134] MagnumosideFallaxoside AD4 ((335329) ) M. magnumC. fallax [134][133] FallaxosideMagnumoside D6 (330 B1 )( 336) C.M. fallax magnum [133][134] MagnumosideFallaxoside BD27( (337331) ) M. magnumC. fallax [134][133] Magnumoside C (338) M. magnum [134] Magnumoside C (339) M. magnum [134] Magnumoside A1 (3321 ) Massinium magnum [134] Magnumoside 2A2 (333) M. magnum [134] Magnumoside C4 (340) M. magnum [134] Colochiroside E (341) C. robustus [135]

Mar. Drugs 2017, 15, 317 23 of 35

Magnumoside A3 (334) M. magnum [134] Magnumoside A4 (335) M. magnum [134] Magnumoside B1 (336) M. magnum [134] Magnumoside B2 (337) M. magnum [134] Mar.Magnumoside Drugs 2017, C151 ,( 317338) M. magnum [134] Magnumoside C2 (339) M. magnum 23[134] of 35 Magnumoside C4 (340) M. magnum [134] Colochiroside E (341) C. robustus [135]

O 296 Cucumarioside G R1=SO Na, R2=H 2 3 H 297 Cucumarioside A R1=R2=H 1 2 O 10 O 298 Calcigeroside B R =SO3Na, R = HO HO HO OH O 1 O O 1 2 HO R O 299 Calcigeroside C R =SO3Na, R = HO HO H OH HO 1 2 HO O O O O O 300 Cucumarioside H3 R =SO3Na, R = HO HO O HO O HO OH MeO OH 2 OH OR 1 2 3 Δ7(8) O 301 Cucumarioside A3-2 R =R =SO3Na, R =H, 1 2 3 Δ9(11) H 302 Cucumarioside A3-3 R =R =SO3Na, R =H, 1 2 3 Δ7(8) 303 Koreoside A R =R =R =SO3Na, 1 2 3 Δ9(11) 304 Isokoreoside A R =R =R =SO3Na, R1O O O HO H 2 8 R3O R O 21 R O O O O 7 HO HO O R HO 25 O HO 18 20 MeO OH OH O HO O H HO OH R6 1 3 5 8 2 305 Cucumarioside A8 R =R =R =R =H, R =CH2OH, 1 O R O O 4 6 7 Δ7(8),24 HO H R =Me, R =OAc, R =OH, 2 R3 R 306 Cucumarioside A , R1=R3=R5=R8=H, R2=CH OH, O O O O 9 2 HO HO O R4=Me, R6=OAc, R7=OH, 24-OH, Δ7(8),25(26) 4 O HO R O OH OH OR5 HO 1 O 2 5 7 8 3 4 6 Δ9(11),25(26) 307 Holotoxin F R = HO , R =R =R =R =H, R =CH2OH, R =Me, R = O, HO OH HO 1 O 2 4 5 7 8 3 6 Δ9(11),25(26) 308 Holotoxin G R = HO , R =R =R =R =R =H, R =CH2OH, R = O, HO OH HO 1 O 2 4 5 7 8 3 6 Δ9(11),25(26) 309 Holotoxin H R = HO , R =R =R =R =R =H, R =CH2OH, R = O, , de-Me at C-20 HO OH HO 1 O 2 5 7 8 3 4 6 Δ9(11),25(26) 310 Holotoxin I R = HO , R =R =R =R =H, R =CH2OH, R =Me, R = O, , de-Me at C-20 HO OH O 1 6 7 8 2 3 4 5 HO Δ9(11) 311 Ds-penaustroside A R =R =R =R =H, R =R =CH2OH, R =Me, R = HO , OH O 1 6 7 8 2 3 4 5 HO Δ9(11),25(26) 312 Ds-penaustroside B R =R =R =R =H, R =R =CH2OH, R =Me, R = HO , OH O 1 2 3 4 5 HO 6 7 8 Δ9(11),24(25) 313 Frondoside C R =SO3Na, R =R =CH2OSO3Na, R =Me, R = HO , R =R =H, R =OAc, OH

O AcO O H 314 Psolusoside B O H

NaO SO OAc 3 O HO O O O H HO HO NaO3SO OH HO O O H HO O HO O O HO HO O HO O HO O HO O O OH 315 Kuriloside A R= HO O MeO HO HO HO OH O OH OH O OH RO 316 Kuriloside C R=H HO OH

FigureFigure 15. Cont.Cont.

Mar. Drugs 2017, 15, 317 24 of 35 Mar. Drugs 2017, 15, 317 24 of 35

R3 HO

1 2 3 Δ9(11) 317 Frondoside A2-7 R =R =H, R =OAc, 1 2 3 Δ7(8) 318 Frondoside A2-8 R =R =H, R =OAc, O 1 2 3 9(11) NaO SO O 319 Frondoside A7-3 R =R =SO3Na, R =OH, Δ 3 HO R2O R1O O O 320 Frondoside A -4 R1=R2=SO Na, R3=OH, Δ7(8) HO OHO O O 7 3 MeO O HO OH OH 321 Isofrondoside C R1=R2=SO Na, R3=OAc, Δ7(8) O O 3 HO HO OH O H 21 HO O 18 O O H O 18 H O 20 17 11 17 H H 16 13 O

7 H O O O O O O O H OH H H H Sugars Sugars Sugars A B Sugars C D Algycone 1 2 O 322 Fallaxoside B1 Aglycone=C, R =H, R =SO3Na NaO3SO 2 1 HO 1 2 R O R O 323 Fallaxoside C1 Aglycone=A, R =SO3Na, R =H O O O O HO HO O 324 Fallaxoside C Aglycone=B, R1=SO Na, R2=H MeO O HO 2 3 OH OH 1 2 O O 325 Fallaxoside D1 Aglycone=A, R =SO3Na, R =SO3Na; HO HO 326 Fallaxoside D Aglycone=B, R1=SO Na, R2=SO Na OH 2 3 3 1 2 327 Fallaxoside D3 Aglycone=D, R =SO3Na, R =SO3Na O O O HO O H H HO H HO H OH H H

O OH O O O O OH H H H H Sugars Sugars Sugars Sugars i ii iii iv

OAlgycone NaO SO 328 Fallaxoside D4 Aglycone + i 3 HO NaO SO NaO SO 3 3 O 329 Fallaxoside D5 Aglycone + ii OHO O O O HO O MeO OH OHHO 330 Fallaxoside D6 Aglycone + iii O O HO 331 Fallaxoside D Aglycone + iv HO 7 OH

O OH R 332 Magnumoside A1 R= O OH H H O 333 Magnumoside A2 R= HO

HO O 334 Magnumoside A3 R= NaO3SO O HO H HO O 335 Magnumoside A4 R= HO O HO OH

FigureFigure 15. Cont.Cont.

Mar. Drugs 2017, 15, 317 25 of 35 Mar. Drugs 2017, 15, 317 25 of 35

R2 O HO 26 22 25

H 27 O 1 2 23 336 Magnumoside B1 R =R =H, 25-OH, Δ O 1 2 25(26) NaO3SO O 336 Magnumoside B2 R =H, R =OH, Δ HO H 1 1 2 Δ23 R O 338 Magnumoside C1 R =SO3Na, R =H, 25-OH, O O O O HO O 339 Magnumoside C 1 2 Δ25(26) O HO HO 2 R =SO3Na, R =OH, MeO OH OH 1 2 Δ24 OH 340 Magnumoside C4 R =SO3Na, R =H,

O AcO

H O 341 Colochiroside E

HO O O O HO O H HO HO OSO3Na HO O HO O HO 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 knownTriterpene as toxins glycosides of sea cucumbers are the prime to eukaryotic bioactive metabolitescells. These ofglycosides sea cucumbers, showed anda wide are commonlyrange of knownbiological as toxins activities of sea including cucumbers cytotoxic, to eukaryotic antifungal, cells. antiviral, These glycosides hemolytic, showed antiprotozoal a wide and range ofimmunomodulatory biological activities activities. including Sea cytotoxic,cucumbers antifungal,produce some antiviral, major glycosides hemolytic, in sufficient antiprotozoal amount and immunomodulatoryto carry out a wide activities. range of Seabiological cucumbers activity produce tests [37,94]. some majorBesides glycosides major glycosides, in sufﬁcient they amount also toproduce carry out minor a wide glycosides range ofinsufficient biological to activitytest a range tests of [37 biological,94]. Besides activities major [66,67]. glycosides, The point they to be also producenoted here minor is glycosidesthat sea cucumber insufﬁcient glycosides to test are a range able to of exhibit biological biological activities activities [66,67 ].in Theboth point in vitro to be notedand herein vivo is that models sea cucumber[5]. The remarkable glycosides biological are able properties to exhibit biologicalshowed by activitiessome triterpene in both glycosidesin vitro and inare vivo summarizedmodels [5]. in The Table remarkable 11. Triterpene biological glycosides properties do not exhibit showed antibacterial by sometriterpene activity, indicating glycosides that are summarizedthese glycosides in Table are probably 11. Triterpene produced glycosides by sea cu documbers not exhibit for defence antibacterial against eukaryotic activity, indicatingpredators. that these glycosides are probably produced by sea cucumbers for defence against eukaryotic predators. Table 11. Remarkable biological activities exhibited by some sea cucumber glycosides.

CompoundTable 11. RemarkableActivity biological activities exhibited Against/For by some sea cucumber Activity glycosides. Result Reference Hillaside C (285) Cytotoxic Human tumor cell lines IC50: 0.15–3.20 µg/mL [124] HemoiedemosideCompound A (251) Antifungal Activity Against/ForC. cucumerinum Activity 20 µg/disc: Result 23 mm zone Reference [113]

FuscocinerosideHillaside C ( C237 (285) )Cytotoxic Cytotoxic Human Human tumor tumor cell linescell lines IC50: 0.15–3.20IC50: 0.88µ andg/mL 0.58 µg/mL [124 ] [106] IntercedensideHemoiedemoside A (66) A (251)Cytotoxic Antifungal HumanC. cucumerinum tumor cell lines 20 µg/disc: ED 2350: mm0.96–4.0 zone µg/mL [113] [49] Fuscocineroside C (237) Cytotoxic Human tumor cell lines IC : 0.88 and 0.58 µg/mL [106] Intercedenside B (67) Cytotoxic Human tumor cell lines 50 ED50: 0.61–2.0 µg/mL [49] Intercedenside A (66) Cytotoxic Human tumor cell lines ED50: 0.96–4.0 µg/mL [49] Intercedenside C (68) Cytotoxic Human tumor cell lines ED50: 0.96–4.0 µg/mL [49] Intercedenside B (67) Cytotoxic Human tumor cell lines ED50: 0.61–2.0 µg/mL [49] 50 HolothurinosideIntercedenside A (195 C) ( 68)Cytotoxic Cytotoxic Human Human tumor tumor cell linescell lines ED50: 0.96–4.0 IC : 0.33–0.71µg/mL µg /mL [49] [93] HolothurinosideHolothurinoside C (229 A) (195)Cytotoxic Cytotoxic Human Human tumor tumor cell linescell lines IC50: 0.33–0.71 IC50: 0.16–0.93µg/mL µg /mL [93] [93] LiouvillosideHolothurinoside A (53) C (229)Virucidal Cytotoxic Human Herpes tumor simplex cell lines virus IC50: 0.16–0.93 <10µg/mL µg /mL [93] [44] Liouvilloside A (53) Virucidal Herpes simplex virus <10 µg/mL [44] Leucospilotaside B (281) Cytotoxic Human tumor cell lines IC50: 0.44–2.62 µg /mL [122] Leucospilotaside B (281) Cytotoxic Human tumor cell lines IC50: 0.44–2.62 µg/mL [122] 50 ArgusideArguside B (164 B) (164)Cytotoxic Cytotoxic Human Human tumor tumor cell linescell lines IC50: 0.38–2.60 IC : 0.38–2.60µg/mL µg/mL [87] [87] ArgusideArguside C (165 C) (165)Cytotoxic Cytotoxic Human Human tumor tumor cell linescell lines IC50: 0.38–2.60 IC50: 0.38–2.60µg/mL µg/mL [87] [87] µ PhilinopsidePhilinopside A (78) A (78)Cytotoxic Cytotoxic Human Human tumor tumor cell linescell lines IC50: 1.70–3.50 IC50: 1.70–3.50g/mL µg/mL [52] [52] Philinopside B (79) Cytotoxic Human tumor cell lines IC50: 0.75–3.0 µg/mL [53] Philinopside B (79) Cytotoxic Human tumor cell lines IC50: 0.75–3.0−6 µg/mL [53] Cucumarioside A2-2 (18) Hemolytic Erythrocyte of mouse ED50: 0.87 at 10 M [136] −6 CucumariosideHolothurin A2-2 B(18 (274) )Hemolytic Antifungal T. Erythrocyte mentagrophytes of mouse MIC-1.5 ED50:µg/mL 0.87 at 10 M [137] [136] HolothurinHolothurin B (274 A)3 (227)Antifungal Cytotoxic HumanT. tumormentagrophytes cell lines IC50 = 0.32–0.87MIC-1.5µg/mL µg/mL [103] [137] HolothurinHolothurin A3 (227 A4) (228)Cytotoxic Cytotoxic Human Human tumor tumor cell linescell lines IC50 = 0.57–1.12 IC50 = 0.32–0.87µg/mL µg/mL [103] [103] Scabraside A (230) Antifungal Eight pathogenic fungal strains MIC80: 2–8 µg/mL [138] Holothurin A4 (228) Cytotoxic Human tumor cell lines IC50 = 0.57–1.12 µg/mL [103] Echinoside A (238) Antifungal Eight pathogenic fungal strains MIC80: 1–8 µg/mL [108] Scabraside A (230) Antifungal Eight pathogenic fungal strains MIC80: 2–8 µg/mL [138] Cucumarioside A2-2 (18) immunomodulatory Increased lysosomal activity 0.2–20 ng/mouse [139] EchinosideFrondoside A (238 A) (37) immunomodulatoryAntifungal EightEnhanced pathogenic phagocytosis fungal strains 0.001 MICµg/mL80: 1–8 µg/mL [140] [108] CucumariosidePhilinopside A2-2 (18 E ()80 )immunomodulatory Cytotoxicity Increased Ten tumor lysosomal cell lines activity ED50: 0.75–3.50 0.2–20µg/mL ng/mouse [54] [139] FrondosideHolotoxin A (37 A)1 (152)immunomodulatory Antifungal Five Enhanced pathogenic phagocytosis fungi MIC: 0.5–1.0 0.001µg/mL µg/mL [22] [140] Cucumarioside A1 (106) Hemolytic Mouse erythrocytes MEC100: 0.7 ± 0.1 µg/mL [66]

Mar. Drugs 2017, 15, 317 26 of 35

6. Mechanisms of Action Natural products derived from marine organisms have incredible structural and functional diversity. The mechanism by which triterpene glycosides exhibit anticancer activity primarily involve induction of tumor cell apoptosis through the activation of intracellular caspase cell death pathways, arrest of the cell cycle at S or G2/M phases and increase of the sub-G0/G1 cell population; regulation of nuclear factor NF-κB expression; reduction in cancer cell adhesion; suppression of cell migration and tube formation; suppression of angiogenesis; inhibition of cell proliferation, colony formation, and tumor invasion [141]. However, the detailed mechanism(s) of the anticancer activities of these glycosides remains largely unclear. Marked membranolytic effects such as increased membrane permeability, loss of barrier function, and the rupture of cell membrane are considered the basic mechanisms underlying a variety of biological activities exerted by triterpene glycosides of sea cucumbers. The glycosides form complex with ∆5(6)-sterols of cellular membrane especially cholesterol. This interaction induces signiﬁcant changes in the physicochemical properties of cell membranes, such as variations in their stability, microviscosity, and permeability. Saponins form complexes with membrane sterols, leading to cell disruption by the formation of pores. Due to this irreversible interaction, the selective permeability of cell membranes is impaired and cell compounds are transferred into the extracellular matrix, ultimately resulting in cell death [142,143].

7. Structure–Activity Relationships (SARs) Both glycone and aglycone parts are important for biological activities of sea cucumber glycosides. The structure–activity relationships among sea cucumber glycosides are presumably more complicated. The most important structural characteristics of glycosides that probably contribute in biological activities are mentioned below. The cytotoxicity not only depends on the chemical structures of the glycosides but also cell types [144]. The presence of 12α-hydroxy and 9(11)-ene structural units in holostane aglycone play key role in cytotoxicity [144]. Number of monosaccharide units in sugar chains and the substitution in side chain of aglycone could affect cytotoxicity. The presence of hydroxy groups in the side chains of glycosides signiﬁcantly reduces cytotoxicity of the glycosides with increasing distance of hydroxy group from the 18(20)-lactone [30,31]. Linear tetraoside unit plays important role in different biological activities of sea cucumber glycosides [144]. Hexaoside chain containing glycosides show stronger cytotoxic activity than pentaoside chain containing glycosides. Glycosides with hexaosides residue with xylose or quinovose in the ﬁfth position are the most active cytotoxins [144]. Different activities test result indicates that the number of sulfate groups and their position in the carbohydrate chains affect cytotoxicity [144]. It has been shown that the sulfate group attached to C-6 of terminal 3-O-methylglucose unit greatly decrease and attached to C-6 of glucose (the third monosaccharide unit) generally increase membranotropic activity [145].

8. Conclusions Sea cucumbers (or holothurians), a class of marine invertebrates, are used as human food and traditional medicine, especially in some parts of Asia. The majority of the sea cucumbers synthesize glycosides with a polycyclic aglycone that contain either 7(8)- or 9(11)-double bond with up to six monosaccharide residues containing carbohydrate chain. A few of them are known to synthesize aglycone with 8(9)-ene. Sea cucumber glycosides are cytotoxic to eukaryotes; probably produce for escaping from predation by marine eukaryotic organisms. These cucumber metabolites have shown profound cytotoxic and hemolytic activities against eukaryotic organisms but not prokaryotic organisms. Due to signiﬁcant cytotoxic and antifungal activities, extensive differential SAR studies of these glycosides can be helpful to develop new drugs and agrochemicals. Mar. Drugs 2017, 15, 317 27 of 35

Acknowledgments: We are also thankful to the World Bank for partial funding of this work through a subproject of Higher Education Quality Enhancement Project (HEQEP), Supplementary Complete Proposal #2071. This research was also supported in part by the Ministry of Oceans and Fisheries (Grant PM60300), Korea. Sincere thanks are due to Prodip Kumar Roy of OIST, Okinawa, Japan for help in literature collection. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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