Antitumor Activity of Pulsatilla koreana Saponins and Their Structure-Activity Relationship

Bang, Seong‐Cheol; Lee, Ji‐Hyun; Song, Gyu Yong; Kim, Dong Hee; Yoon, Mi Young; Ahn, Byung Zun

doi:10.1248/cpb.53.1451

Cited by 98 publications

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“…5) In addition, a total 17 triterpenoid saponins including six new saponins were isolated from Pullsatilla koreana N. root and the structure-activity relationships of antitumoral saponins was published. 6,7) Among them, Pullsatilla saponin D (1, inhibition ratio (IR): 66.9% against LLC lung carcinoma xengraft model at 6.0 mg/kg/d i.p., ED 50 3.04- 50 1.57-8.36 mM) exhibited highly potent anticancer activity. Pulsatilla saponin D shows five times more active in anticancer test than its aglycone (ED 50 ; Ͼ50 mM).…”

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confidence: 99%

Facile Synthesis of Trisaccharide Moiety Corresponding to Antitumor Activity in Triterpenoid Saponins Isolated from Pullsatilla Roots

Bang

Seo

Yun

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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Saponins, the glycosides of steroids or triterpenes, are widely distributed in plants and animals. 1) They exist in relatively high quantities in many significant food and beverage plants, including oats, peanuts, soybeans, lentils, mung beans, garlic, onions, spinach, asparagus, jujube, quillaja and tea. Saponins also are generally found as active constituents in many well known oriental herbal medicines such as ginseng, notoginseng, licorice, horse chestnut, red clover, senegae, and primula.2) Many previous studies reveal that saponins show various physiological and pharmacological activities, such as anti-cancer, anti-inflammatory, cardiovascular, and cytotoxic activities.3,4) The oligosaccharides integrated into the saponins have a very important role in their bioactivity and thus the interest in this sugar unit is rapidly increasing. For example, when the ether-linked tetrasaccharide was removed from julibrosides, its cytotoxicity dramatically decreased. We recently reported Pulsatilla saponin5) In addition, a total 17 triterpenoid saponins including six new saponins were isolated from Pullsatilla koreana N. root and the structure-activity relationships of antitumoral saponins was published.6,7) Among them, Pullsatilla saponin D (1, inhibition ratio (IR): 66.9% against LLC lung carcinoma xengraft model at 6.0 mg/kg/d i.p., ED 50 3.04-13.17 mM) and oleanolic ]-a -Larabinopyranoside, at C-3 position enhances the activity. It has been postulated that the linked trisaccharide improves the bioavailability in tumor tissue in vivo. Therefore, this moiety could be utilized as a promoiety for the increment of the activity of other antitumoral compounds and their solubility in water as shown in Fig. 1. Indeed, glucose has been integrated into anticancer agents as a conjugate for the improvement of their activity since cancer cells have increased rate of glucose metabolism compared with healthy cells and over-expression of 11) This approach has been also applied to pep- A trisaccharide found in triterpenoid saponins isolated from Pullsatilla roots appears as an important promoiety for the enhancement of anticancer activity of their aglycones. Thus a facile synthetic method for a trisaccharide moiety, allyl-2,3,4-tri-O-benzoyl-a a-L-rhamnopyranosyl-(1→ →2)- [2,3,4,6-, has been firstly developed through the regio-and stereoselective glycosylations from arabinose in total 16% yield via route 2 (eight steps). In this synthetic procedure, the protection of anomeric -OH of L-arabinose with equatorially oriented allyl group unlike with the axial 4-methoxybenzyl protecting group well promoted glycosyl bond formation between a a-L-rhamnopyranosyl trichloroacetimidate and 2-OH of arabinose. As expected, the synthesized trisaccharide moiety 3 has no cytotoxicity (ED 50 : Ͼ100 m mM) against three human cancer cell lines (A-549, SK-OV-3, and SK-MEL-2), respectively.

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Facile Synthesis of Trisaccharide Moiety Corresponding to Antitumor Activity in Triterpenoid Saponins Isolated from Pullsatilla Roots

Bang

Seo

Yun

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…1) not only displayed strong in vitro anticancer activities, but also more potent in vivo antitumor activities in mice bearing Lewis lung carcinoma, exceeding the effects of even taxol and doxorubicin. 8) In addition, we reported total synthesis of Pulsatilla saponin D (PSD). 9) These natural saponin products were obtained in small amounts, which was a limiting factor.…”

Section: ) Saponins With Hederagenin Such As Hederacolchid a {Hederagmentioning

confidence: 99%

Total Synthesis and Anticancer Activity of Novel <i>Pulsatilla</i> Saponin D Analogues

Kim

Park

Chung

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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Novel saponins that retain a free carboxyl group at the C-17 position and various sugars linked at the C-3 position of hederagenin aglycone were synthesized via stereospecific glycosylation. Since these natural products represented by Pulsatilla saponin D (PSD) were obtained in very small amounts, the total synthesis developed in this paper will resolve this problem of scarcity. The two types of synthesized arabinose-and rhamnose-cored saponins showed potent anticancer activity against a human lung cancer cell line (A549), and most disaccharide moiety saponins possessed more potent anti-lung cancer activity. Among the novel PSD analogues containing disaccharide saponins, compound 10i showed anti-lung cancer activity (6.6 µM) that was four-fold more potent than the clinical agent Iressa ® (26.08 µM). Key wordskalopanaxsaponin A, and sapindoside C have been shown to have potent cytotoxic activities toward various cancer cell lines.2-7) Among hederagenins, Pulsatilla saponin D (PSD) 10 ( Fig. 1) not only displayed strong in vitro anticancer activities, but also more potent in vivo antitumor activities in mice bearing Lewis lung carcinoma, exceeding the effects of even taxol and doxorubicin.8) In addition, we reported total synthesis of Pulsatilla saponin D (PSD). 9) These natural saponin products were obtained in small amounts, which was a limiting factor. Chemical synthesis may resolve this problem, and may easily provide suitable compounds for study of structure-activity relationships (SAR) and for the other studies.2,10) The result of SAR showed saponins with hederagenin retaining the free carboxyl group at the C-17 position had stronger anticancer activity than related compounds with other substituents. The hederagenin derivatives, that have sugar moieties on the C-3 position, also showed potent anticancer activity.11,12) Most isolated PSD analogs maintained derivative with sugars bound at the 2-OH of the arabinose moiety.8) Therefore, we proposed to study the effect of derivatization at 3-OH on the anticancer activity for SAR study. In this paper, we report total synthesis of new PSD analogs with various sugar moieties linked at C-3 position of hederagenin and at 3-OH of arabinose moiety. We also evaluated the in vitro anticancer activity of these new compounds. Results and DiscussionWe designed two types of saponin analogues arabinose-and rhamnose-directly glycosylated hederagenins. Stereospecific glycosylation of the glycosyl acceptor, as illustrated by the arabinose moiety 1, with perbenzoylated trichloroacetimidates donors 1a-d [13][14][15][16] was achieved in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) in dichloromethan (CH 2 Cl 2 ) at −78°C to give disaccharides 2a-d (Chart 1). Then, the acetyl group was removed using acetyl chloride/ CH 3 OH to give compounds 3a-d. 17) Glycosylation of compounds 1a-d with the C-4 free hydroxyl group of compounds 3a-d under the TMSOTf as a promoter at −78°C afforded trisaccharide 4a-g. The hydroxyl groups at the C-3, -4 positions in compound 6 as t...

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“…[2][3][4] Oleanane-type triterpenoid saponins, lupane-type triterpenoid saponins, quinones, phenylpropanoids, and flavonoid glycosides have been isolated from the root and aerial parts of P. koreana in previous phytochemical studies. [5][6][7][8][9] However, there have been few studies that have specifically aimed to identify compounds from the flowers of P. Koreana.…”

Section: Introductionmentioning

confidence: 99%

Flavonoid Glycosides from the Flowers ofPulsatilla koreanaNakai

et al. 2016

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− Extraction and fractionation of Pulsatilla koreana flowers followed by, repeated open column chromatography for EtOAc and n-BuOH fractions yielded four flavonoid glycosides, namely, astragalin (1), tiliroside (2), buddlenoide A (3), and apigenin-7-O-(3''-E-p-coumaroyl)-glucopyranoside (4). The chemical structures of these flavonoid glycosides were elucidated on the basis of various spectroscopic methods including electronic ionization mass spectrometry (EI-MS), 1D NMR ( 1 H, 13C, DEPT), 2D NMR (gCOSY, gHSQC, gHMBC), and infrared (IR) spectrometry. This study represents the first report of the isolation of the flavonoid glycosides from the flowers of P. koreana.

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Antitumor Activity of Pulsatilla koreana Saponins and Their Structure-Activity Relationship

Cited by 98 publications

References 10 publications

Facile Synthesis of Trisaccharide Moiety Corresponding to Antitumor Activity in Triterpenoid Saponins Isolated from Pullsatilla Roots

Facile Synthesis of Trisaccharide Moiety Corresponding to Antitumor Activity in Triterpenoid Saponins Isolated from Pullsatilla Roots

Total Synthesis and Anticancer Activity of Novel <i>Pulsatilla</i> Saponin D Analogues

Flavonoid Glycosides from the Flowers ofPulsatilla koreanaNakai

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