Naturally occurring triterpenoid saponins

Naturally occurring new triterpenoid saponins reported from mid-1996 to March, 2007 are reviewed including their physical constants and plant sources, and are compiled in Table 1. New saponins are arranged in Table 1 on the basis of the skeletal structures of their aglycones, e.g., oleanane type, ursane type, lupane type, hopane type, taraxastane type, cycloartane type, lanostane type, tirucallane type, dammarane type, cucurbitane type, and holostane type. The known triterpenoid saponins and prosapogenins of the new saponins, the biological and pharmacological activities of which were published during 1996-2007, are also reviewed together with their plant sources listed in Table 2 according to the skeletal structures of their aglycones in the same fashion as in Table 1. The plant and animal sources of both new and known bioactive triterpenoid saponins are collected in Table 3 in alphabetical order. The biological and pharmacological activities such as antiallergic, antiatherosclerosis and antiplatelet, antibacterial, anticomplementary, antidiabetic, contraceptive, antifungal, anti-inflammatory, antileishmanial, antimalarial/antiplasmodial, anti-obesity, anti-proliferative, antipsoriatic, antispasmodic, antisweet, antiviral, cytotoxic/antitumor, detoxication, gastroprotective, haemolytic, hepatoprotective, immunomodulatory, anti-enzyme, anti-osteoporotic, insecticidal, insulin-like, membrane-porosity, molluscicidal, neuropharmacological, anti-endothelial dysfunction, snake venom antidote, and sweet activities of these saponins or derived prosapogenins are discussed briefly after Table 3.     

New triterpenoid saponins from Patrinia scabiosaefolia

Phytochemical investigation of the methanol extract from the whole plants of Patrinia scabiosaefolia Fisch. resulted in the isolation of four new triterpenoid saponins (1–4) along with six known compounds (5–10). On the basis of spectroscopic and chemical methods, the structures of the new compounds were established as 3-O-β-d-xylopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→2)-β-d-xylopyranosyl-12β,30-dihydroxy-olean-28,13β-olide (1), 3-O-α-l-rhamnopyranosyl-(1→2)-β-d-xylopyranosyl-12β,30-dihydroxy-olean-28,13β-olide (2), 3-O-β-d-xylopyranosyl-(1→2)-β-d-glucopyranosyl-12β, 30-dihydroxy-olean-28,13β-olide (3), and 3-O-β-d-glucopyranosyl-(1→4)-β-d-xylopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→2)-β-d-xylopyranosyl-oleanolic acid 28-O-β-d-glucopyranoside (4), respectively. Compounds 1–3 possess a novel 12β,30-dihydroxy-olean-28,13β-lactone aglycone and a 12β-hydroxy substituent that is rarely found in this kind of triterpenoid saponin.     

Haemolytic acylated triterpenoid saponins from Harpullia austro-caledonica

Eight new acylated triterpenoid saponins were isolated from the stem bark of Harpullia austro-caledonica along with the known harpuloside (9). Their structures were established using 1D and 2D NMR and mass spectrometry as 3-O-beta-D-galactopyranosyl-(1-->2)-beta-D-glucuronopyranosyl-21 beta, 22 alpha-di-O-angeloylbarringtogenol C (1), 3-O-alpha-L-rhamnopyranosyl-(1-->3)-[beta-D-galactopyranosyl-(1-->2)]-beta-D-glucuronopyranosyl-21 beta, 22 alpha-di-O-angeloyl barringtogenol C (2), 3-O-alpha-L-arabinofuranosyl-(1-->3)-[beta-D-galactopyranosyl-(1-->2)]-beta-D-glucuronopyranosyl-21 beta, 22 alpha-di-O-angeloylbarringtogenol C (3), 3-O-alpha-L-arabinofuranosyl-(1-->2)-beta-D-glucuronopyranosyl-21 beta, 22 alpha-di-O-angeloylprotoaescigenin (4), 3-O-alpha-L-arabinofuranosyl-(1-->3)-[alpha-L-arabinofuranosyl-(1-->2)]-beta-D-glucuronopyranosyl-21 beta, 22 alpha-di-O-angeloyl protoaescigenin (5), 3-O-alpha-L-arabinofuranosyl-(1-->3)-[beta-D-xylopyranosyl-(1-->2)]-beta-D-glucuronopyranosyl-21 beta, 22 alpha-di-O-angeloylprotoaescigenin (6), 3-O-alpha-L-arabinofuranosyl-(1-->3)-[beta-D-glucopyranosyl-(1-->2)]-beta-D-glucuronopyranosyl-21 beta, 22 alpha-di-O-angeloylprotoaescigenin (7), 3-O-beta-D-xylopyranosyl-(1-->2)-beta-D-glucuronopyranosyl-21 beta, 22 alpha-di-O-angeloylprotoaescigenin (8). The EtOH extract of the stem bark showed in vitro cytotoxic activity against KB cells (90% at 10 microg/ml). At a concentration of 5 microg/ml, the saponin mixture showed haemolytic activity and caused 100% haemolysis of a 10% suspension of sheep erythrocytes.     

New acylated triterpenoid saponins from Maesa lanceolata

Ten new acylated triterpenoid saponins were isolated from the leaves of Maesa lanceolata. For their structure elucidation extensive use was made of homo- and heteronuclear 2D NMR techniques such as COSY, NOESY, HSQC and HMBC. All saponins identified contained the same tetraglycosidic side chain, but the triterpenoid moiety showed a variable esterification pattern. Monoester, diester and triester derivatives were present. Maesasaponin I was a 21-monoester derivative, i.e. ?3 beta-O-[alpha-L-rhamnopyranosyl-(1-->2)-beta-D-galactopyranosyl- (1-->3)]-[beta-D-galactopyranosyl-(1-->2)]-beta-D-glucuronopyranosyl+ ++?-21 beta-angeloyloxy-13 beta, 28-oxidoolean-16 alpha, 22 alpha, 28 alpha-triol. Maesasaponins III, IV3, V3 and VI2 had an additional acetyl, propanoyl, n-butanoyl and angeloyl substituent, respectively, in position 22. Maesasaponins II, IV2, V2, VI3 and VII1 were characterised as the 16-acetyl derivatives of maesasaponins I, III, IV3, V3 and VI2, respectively. Structures of saponins previously reported in M. lanceolata had to be revised.     

Pentacyclic triterpenoid and saponins from Gambeya boukokoensis

Chemical studies of the EtOAc extract of Gambeya boukokoensis Aubr. et Pellegr. stem bark led to the isolation of eight compounds. Three of them were elucidated as new compounds and designated as: gamboukokoensein A, 1alpha,2alpha,3beta,19alpha,23-pentahydroxyurs-12-en-28-oic acid; gamboukokoenside A, 2beta,3beta,6beta,28-tetrahydroxyolean-12-en-23-oic acid 23-O-alpha-L-arabinopyranosyl ester and gamboukokoenside B, 6beta,28-dihydroxy-3-oxoolean-12-en-23-oic acid 23-O-alpha-L-arabinopyranosyl ester. The other five compounds were known and identified as myrianthic acid, protobassic acid, oleanolic acid, erythrodiol and chondrillasterol. Their structures were elucidated on the basis of one and two dimensional NMR spectroscopic techniques, FABMS, ESMS and chemical evidence.     

Two new triterpenoid saponins from Gymnema sylvestre

Two new oleanane-type triterpenoid saponins, gymnemoside-W1 and W2, together with seven known compounds were isolated from the leaves of Gymnema sylvestre R. Br. By means of spectral and chemical analysis, the structures of the new compounds were elucidated as 16 β-hydroxyl olean-12-en-3-O-[β-D-glucopyranosyl (1→6)-β.D-glucopyranosyl]-28-O-β-D-glucopyranoside(1) and 16 β,21 β,28-trihydroxyl-olean-12-ene-3-O-glucoronopyranoside (2). The EtOHIH2O extracts of this plant were shown to be able to inhibit glucose absorption in rats.     

Cytotoxic triterpenoid saponins from Aesculus glabra Willd.

Twenty-four acylated polyhydroxyoleanene saponins were isolated from the seeds of Aesculus glabra. Sixteen of them, namely aesculiosides G1–G16 (1–16), were determined as compounds by spectroscopic and chemical analysis. The structural features of all 24 saponins are: (1) arabinofuranosyl units affixed to C-3 of the glucuronopyranosyl unit in the trisaccharide chain; (2) no 24-OH substitution; (3) C-2 sugar moiety substitution of the 3-O-glucuronopyranosyl unit is either glucopyranosyl or galactopyranosyl. The features of these isolated saponin structures provide more evidence for chemical taxonomy within the genus Aesculus. The cytotoxicity of the aesculiosides (1–16) were tested against A549 and PC-3 cancer cell lines with GI₅₀ from 5.4 to >25 μM.     

Two new oleanane triterpenoid saponins from Elsholtzia bodinieri

Two new oleanane-type triterpenoid saponins, bodiniosides C (1) and D (2), were isolated from the aerial parts of Elsholtzia bodinieri. Their structures were determined by one- and two-dimensional NMR techniques, including HMQC, HMBC and HMQC-TOCSY experiments, as well as acid hydrolysis and GC analysis.     

Esters of new oleanane-type triterpenoid saponins from Schefflera kwangsiensis

Eleven new oleanane-type triterpenoid saponins were isolated from the aerial parts of Schefflera kwangsiensis (1–11), together with nine esters (12–20) of known saponins. The structures of these compounds were elucidated on the basis of spectroscopic data analysis and chemical evidence. Furthermore, in in vitro assays, compounds 2, 3, 5, 7, 8, 11–13, 15, 17 and 18 (10 μM) exhibited moderate hepatoprotective activity against d-galactosamine-induced HL-7702 cell damage.     

Bioactive triterpenoid saponins and phenolic compounds against glioma cells

A total of 54 natural origin compounds were evaluated for their activity in inhibiting the proliferation of glioma cells. Results showed that four Aesculus polyhydroxylated triterpenoid saponins (3–6), six Gleditsia triterpenoid saponins (7–12), and five phenolic compounds (43–46, 51) had dose-dependent activity suppressing the proliferation of both C6 and U251 cells. Structure–activity relationship analysis suggested that the acetyl group at C-28 for the Aesculus saponins and the monoterpenic acid moiety for the Gleditsia saponins could be critical for the activity of these active compounds. Aesculioside H (4), gleditsioside A (7), and feuric acid 3,4-dihydroxyphenethyl ester (FADPE, 46) were the three most active compounds from the different types of the active compounds and induced apoptosis and necrosis in glioma cells.     

New triterpenoid saponins from cacti and anti-type I allergy activity of saponins from cactus

The research in our laboratory focuses on the isolation of saponins from cactus. In this study, we report five new triterpenoid saponins, dumortierinoside A methyl ester (1), pachanoside I1 (2), pachanoside D1 (3), gummososide A (4), and gummososide A methyl ester (5). Compounds 1-3 isolated from Isolatocereus dumortieri Backbg., and compounds 4 and 5 were isolated from Stenocereus alamosensis A. C. Gibson & K. E. Horak. Compound 2 possessed a new pachanane-type triterpene skeleton, pachanol I, in its aglycon. The aglycon of 3 was pachanol D, while those of 4 and 5 were both gummosogenin, which we have previously reported, but this is the first report of pachanol D and gummosogenin in their aglycon forms. Additionally, we evaluated the anti-type I allergy activity of the saponins with RBL-2H3 (Rat basophilic leukemia) cells by measuring the β-hexosaminidase release inhibitory activity. As a result of these studies, gummososide A methyl ester (5) was found to show activity (IC(50)=99.5 μM) and thurberoside A exhibited mild activity (IC(50)=166.9 μM).     

Molecular activities, biosynthesis and evolution of triterpenoid saponins

Saponins are bioactive compounds generally considered to be produced by plants to counteract pathogens and herbivores. Besides their role in plant defense, saponins are of growing interest for drug research as they are active constituents of several folk medicines and provide valuable pharmacological properties. Accordingly, much effort has been put into unraveling the modes of action of saponins, as well as in exploration of their potential for industrial processes and pharmacology. However, the exploitation of saponins for bioengineering crop plants with improved resistances against pests as well as circumvention of laborious and uneconomical extraction procedures for industrial production from plants is hampered by the lack of knowledge and availability of genes in saponin biosynthesis. Although the ability to produce saponins is rather widespread among plants, a complete synthetic pathway has not been elucidated in any single species. Current conceptions consider saponins to be derived from intermediates of the phytosterol pathway, and predominantly enzymes belonging to the multigene families of oxidosqualene cyclases (OSCs), cytochromes P450 (P450s) and family 1 UDP-glycosyltransferases (UGTs) are thought to be involved in their biosynthesis. Formation of unique structural features involves additional biosynthetical enzymes of diverse phylogenetic background. As an example of this, a serine carboxypeptidase-like acyltransferase (SCPL) was recently found to be involved in synthesis of triterpenoid saponins in oats. However, the total number of identified genes in saponin biosynthesis remains low as the complexity and diversity of these multigene families impede gene discovery based on sequence analysis and phylogeny.This review summarizes current knowledge of triterpenoid saponin biosynthesis in plants, molecular activities, evolutionary aspects and perspectives for further gene discovery.     

Arvensoside A and B,triterpenoid saponins from Calendula arvensis

Two new triterpenoid glycosides from the aerial parts of Calendula arvensis were identified as oleanolic acid-28-O-β-D-glucopyranoside-3-β-O-(O-β-D-galactopyranosyl(1 → 3)-β-D-glucopyranoside) and oleanolic acid 3-β-O-(O-β-D-galactopyranosyl(1 → 3)-β-D-glucopyranoside) by FAB, FAB MIKE mass spectrometry and ¹³C NMR spectroscopy.     

Anti-inflammatory activities of triterpenoid saponins from Polygala japonica

Bioassay-guided investigation was performed to identify the active constituents from a methanol extract of Polygala japonica, a folk medicinal plant widely used in China to treat inflammatory diseases. The n-BuOH and EtOAc fractions of the P. japonica methanol extract, which show significant anti-inflammatory activity in in vivo test, were further subjected to column chromatography to afford six triterpene glycosides, marked here as saponins 1–6. All compounds were evaluated for their anti-inflammatory activity in the carageenan-induced mouse paw edema test, and saponins 1, 4 and 5 showed significantly anti-inflammatory effects on both phases of carageenan-induced acute paw edema in mice. Saponin 5 was also found to significantly inhibit the production of inflammatory mediators – nitric oxide (NO) in LPS-stimulated RAW264.7 macrophages, with no obvious effects on macrophage viability.     

Phenolic compounds and rare polyhydroxylated triterpenoid saponins from Eryngium yuccifolium

Phytochemical investigation on the whole plant of Eryngium yuccifolium resulted in the isolation and identification of three phenolic compounds (1-3) and 12 polyhydroxylated triterpenoid saponins, named eryngiosides A-L (4-15), together with four known compounds kaempferol-3-O-(2,6-di-O-trans-p-coumaroyl)-β-d-glucopyranoside (16), caffeic acid (17), 21β-angeloyloxy-3β-[β-d-glucopyranosyl-(1→2)]-[β-d-xylopyranosyl-(1→3)]-β-d-glucuronopyranosyloxyolean-12-ene-15α,16α,22α,28-tetrol (18), and saniculasaponin III (19). This study reports the isolation of these compounds and their structural elucidation by extensive spectroscopic analyses and chemical degradation.     

New triterpenoid saponins from the roots of Gypsophila perfoliata Linn

Nine new triterpenoid saponins (1–9) have been isolated from the roots of Gypsophila perfoliata Linn. Their structures were established on the basis of extensive NMR (¹H, ¹³C, HSQC and HMBC) and ESIMS studies.     

Cytotoxic triterpenoid saponins from the fruits of Aesculus pavia L

Continued chemical investigation on the fruits of North American Aesculus pavia L. resulted in the isolation and identification of 13 polyhydroxyoleanene pentacyclic triterpenoid saponins, named aesculiosides IIe-IIk (1-7), and IIIa-IIIf (8-13), together with 18 known compounds: aesculiosides Ia-Ie (14-18), IIa-IId (19-22), IVa-IVc (23-25), 3-O-[beta-D-galactopyranosyl(1-->2)]-alpha-L-arabinofuranosyl(1-->3)-beta-D-glucuronopyranosyl-21,22-O-diangeloyl-3beta,15 alpha,16 alpha,21 beta,22 alpha,28-hexahydroxyolean-12-ene (26), 3-O-[beta-D-glucopyranosyl(1-->2)]-alpha-L-arabinofuranosyl(1-->3)-beta-D-glucuronopyranosyl-21,22-O-diangeloyl-3beta,16 alpha,21 beta,22 alpha,24 beta,28-hexahydroxyolean-12-ene (27), 3-O-[beta-D-galactopyranosyl(1-->2)]-alpha-L-arabinofuranosyl(1-->3)-beta-D-glucuronopyranosyl-21,22-O-diangeloyl-3beta,16 alpha,21 beta,22 alpha,28-pentahydroxyolean-12-ene (28), R(1)-barrigenol (29), scopolin (30), and 5-methoxyscopolin (31). The structures of these compounds were elucidated by spectroscopic and chemical analyses. Compounds 14-22 and 26-28 were tested in vitro for their activity against 59 cell lines from nine different human cancers including leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast. It was found that compounds with two-acyl groups at C-21 and C-22 had cytotoxic activity for all cell lines tested with GI(50) 0.175-8.71 microM, while compounds without acyl groups at C-21 and C-22 had weak or no cytotoxic activity. These results suggest that the acyl groups at C-21 and C-22 are essential for their activity.     

Four triterpenoid saponins from dried roots of Gypsophila species.

Four new triterpenoid saponins were isolated from the roots of Gypsophila paniculata and G. arrostii. Their structures were elucidated using a combination of homo- and heteronuclear 2D NMR techniques, without having recourse to chemical degradation or modification. The saponins investigated are: 3-O-beta-D-galactopyranosyl-(1----2)-[beta-D-xylopyranosyl-(1----3)]-bet a-D- glucuronopyranosyl quillaic acid 28-O-beta-D-glucopyranosyl-(1----3)-[beta-D-xylopyranosyl-(1----4)]-alph a- L-rhamnopyranosyl-(1----2)-beta-D-fucopyranoside; 3-O-beta-D-galactopyranosyl-(1----2)-[beta-D-xylopyranosyl-(1----3)]-bet a- D-glucuronopyranosyl quillaic acid 28-O-beta-D-arabinopyranosyl-(1----4)-beta-D-arabinopyranosyl++ +-(1----3)-beta-D- xylopyranosyl-(1----4)-alpha-L-rhamnopyranosyl-(1----2)-beta-D-fucopyran oside; 3-O-beta-D-glucopyranosyl-(1----2)-beta-D-glucuronopyranosyl gypsogenin 28-O-beta-D-glucopyranosyl-(1----3)-[beta-D-xylopyranosyl-(1----4)]-alph a- L-rhamnopyranosyl-(1----2)-beta-D-fucopyranoside; 3-O-beta-D-xylopyranosyl-(1----3)-[beta-D-galactopyranosyl-(1----2)]-bet a- D-glucuronopyranosyl gypsogenin 28-O-beta-D-glucopyranosyl-(1----3)-[beta-D-xylopyranosyl-(1----4)-alpha -L- rhamnopyranosyl-(1----2)-beta-D-fucopyranoside.     

Advances in the synthesis and pharmacological activity of lupane-type triterpenoid saponins

Lupeol, betulin and betulinic acid are members of the so-called lupane-type triterpenoids. These natural products found worldwide in quite of lot of vegetables, fruits and plant species exhibit promising pharmacological activities including anti-inflammatory, anti-HIV and antitumor activities. Nevertheless, the poor pharmacokinetic properties of these cholesterol-like triterpenoids hampered further pharmaceutical developments. The synthesis of lupane-type saponins, i.e., sugar-derived lupanes, seems to be a good avenue to improve both their water solubility and pharmacological activity. The aims of this review are twofold: first, to describe the biological activity of naturally occurring lupane-type saponins, and second, report the different methodologies employed for the elaboration of glycosidic linkages at the C-3 and/or C-28 positions on the lupane core. The synthesis of both natural and unnatural lupane-type saponins is discussed with an emphasis on molecules exhibiting relevant biological activities.