Withangulatin A, a New Withanolide from Physalis angulata

Chen, Chiu-Ming; Chen, Zong‐Tsi; Hsieh, Chiu-Hsiang; Li, Wen-Sen; Wen, Say-Yee

doi:10.3987/com-90-5430

Cited by 36 publications

(23 citation statements)

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“…Six (1, 3, 4, 6-8) of ten withanolides have already been isolated from the same plant. [4][5][6][7] They were identified by comparison of the spectral data with those reported. Compounds 2, 5, 9 and 10 are new isolates.…”

Section: Resultsmentioning

confidence: 99%

Trypanocidal Constituents in Plants: 4. Withanolides from the Aerial Parts of Physalis angulata

Nagafuji

Okabe

Akahane

et al. 2004

Biological & Pharmaceutical Bulletin

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In the previous paper in this series, 2) we described the identification of trypanocidal xanthones in Garcinia subelliptica against epimastigotes and trypomastigotes of the protozoan Trypanosoma cruzi, which is the etiologic agent of Chagas' disease (American trypanosomiasis). In the course of our search for trypanocidal constituents in plants, we have found that the MeOH extract of the aerial parts of Physalis angulata L. (Solanaceae) showed considerable activity.P. angulata is indigenous to tropical America and was naturalized in Japan in the Edo era. It is an annual small herb and has been traditionally utilized for antipyretic purposes in Japan.3) The isolation of ergostane-type steroidal compounds, physagulins A-G, 4-6) withangulatin A 7) and physalins, 8) has been reported from this plant.T. cruzi is transformed into three stages in its life cycle: epimastigote in the insect gut; trypomastigote, an infectious form in the mammalian blood stream; and amastigote, a proliferative form in mammalian cells. During the isolation procedure, trypanocidal activity was monitored against epimastigotes, because it is easy to cultivate them and they are not infectious. Ten withanolides (1-10) were isolated from the active fraction. To check the therapeutic possibility of these withanolides, trypanocidal activity against trypomastigotes, an infectious form, was examined. Furthermore, evaluation of the IC 50 value against epimastigotes was performed using Cell Counting Kit-8 in order to compare with cytotoxicity at the IC 50 value. In this paper we describe the structural elucidation of the four new withanolides (2, 5, 9, 10) and the trypanocidal activity of the isolates. The possibility of chemotherapeutic utility is also discussed. MATERIALS AND METHODSPlant Materials P. angulata was cultivated in the medicinal plant garden of Fukuoka University and harvested in September 2002. The aerial parts were air-dried and powdered.Instruments and Reagents The instruments used in this study were a JEOL JNM-A500 for NMR spectra (500 MHz for 1 H-NMR, 125 MHz for 13 C-NMR), a JEOL JMS-HX 110 for MS spectra, a JASCO DIP 360 polarimeter for optical rotations, and a Labsystems Multiskan JX Microplate Reader for measuring the absorbance of a formazan product. The following materials were used for chromatography: Diaion HP-20 (a styrene polymer, Mitsubishi Chemical Industries, Ltd.), Silica gel 60N (Cica), Sephadex LH-20 (Pharmacia Fine Chemicals), and YMC gel (ODS, YMC Co. Ltd.). Newborn calf serum (NCS) was purchased from Nacalai Tesque. Dulbecco's modified Eagle's medium (DMEM) and RPMI 1640 medium were purchased from Sigma. Gentian violet, ketoconazole, and 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were purchased from Wako. A Cell Counting Kit-8 was purchased from Dojindo. Other reagents are the same as in the previous papers. 2,9)Cultivation of T. cruzi The strain of T. cruzi used in this study and the cultivation methods of epimastigotes and trypomastigotes were the same as those described in the previous p...

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Section: Resultsmentioning

confidence: 99%

Trypanocidal Constituents in Plants: 4. Withanolides from the Aerial Parts of Physalis angulata

Nagafuji

Okabe

Akahane

et al. 2004

Biological & Pharmaceutical Bulletin

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“…As in the previously reported procedure, 15) the fractions containing withanolides were combined. The combined fractions were further purified by repeated column chromatography and preparative TLC to afford a minor withanolide, withangulatin I (2).…”

Section: Resultsmentioning

confidence: 99%

“…19) In a previous study, we isolated a withanolide, withangulatin A (1), 15) with significant biological activities 20) from this plant as a part of our search for bioactive constituents from natural sources. Here, we report the isolation and structural elucidation of a minor withanolide, withangulatin I (2), from this plant.…”

Section: )mentioning

confidence: 99%

“…4) To date, phytochemical studies of this plant have described the isolation of numerous phytochemicals, including withasteroids, [4][5][6]8,[13][14][15][16][17] flavonoid glycoside, 18) and alkaloids. 19) In a previous study, we isolated a withanolide, withangulatin A (1), 15) with significant biological activities 20) from this plant as a part of our search for bioactive constituents from natural sources. Here, we report the isolation and structural elucidation of a minor withanolide, withangulatin I (2), from this plant.…”

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Withangulatin I, a New Cytotoxic Withanolide from Physalis angulata

Lee

Pan

Chen

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Physalis angulata L. is an annual herb belonging to the family Solanaceae and is widely distributed in tropical and temperate regions. It is a common herbal plant, known in Chinese as kuzhi, which has been used as a folk medicine with antiinflammatory, antitussive, antipyretic, diuretic, antidotal, and antitumor effects in Taiwan. 1) The extracts and components of this plant were found to have antitumor, 2,3) cytotoxic, [4][5][6][7][8] inhibition of the ubiquitin-proteasome pathway, 9) immunomodulatory, 10) antimycobacterial, 11) antinociceptive, antiinflammatory, and antiallergic activities. 12)Physalis angulata is known to contain a wide variety of pharmacologically important steroidal compounds, such as withasteroids.4) To date, phytochemical studies of this plant have described the isolation of numerous phytochemicals, including withasteroids, [4][5][6]8,[13][14][15][16][17] flavonoid glycoside, 18) and alkaloids. 19) In a previous study, we isolated a withanolide, withangulatin A (1), 15) with significant biological activities 20) from this plant as a part of our search for bioactive constituents from natural sources. Here, we report the isolation and structural elucidation of a minor withanolide, withangulatin I (2), from this plant. Its structure was established as (20S,22R)-15a-acetoxy-5b,6b-epoxy-14a-hydroxy-1,4-dioxo-witha-2,16,24-trienolide on the basis of extensive spectroscopic data interpretation, chemical transformation, and circular dichroism (CD) experiments. The cytotoxic activities of compounds 1 and 2 against human colorectal carcinoma COLO 205 and human gastric carcinoma AGS cell lines were also evaluated in vitro. Results and DiscussionAs in the previously reported procedure, 15) the fractions containing withanolides were combined. The combined fractions were further purified by repeated column chromatography and preparative TLC to afford a minor withanolide, withangulatin I (2). The structure of 2 was established based on detailed spectral analyses, chemical transformation, and comparison with the spectral data reported in the literature.Compound 2 was isolated as a pale yellow, amorphous powder. The IR spectrum of 2 displayed absorption bands of hydroxyl (3450 cm 22) The EI-MS spectrum showed a base peak at m/z 125 which confirmed the presence of the a,b-unsaturated d-lactone moiety.23) These data revealed that compound 2 is a typical withanolide bearing an acetoxyl group and a D 2 -1,4-dione moiety. The deshielding proton A new withanolide, withangulatin I (2), was isolated from the whole plant of Physalis angulata. Its structure was established as (20S,22R)-15a a-acetoxy-5b b,6b b-epoxy-14a a-hydroxy-1,4-

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“…Withanolides are a group of structurally diverse steroids isolated from Physalis angulata and have been reported to exert varied pharmacological activities such as anticancer, immunosuppresive and antioxidant functions [16] . Withagulatin A is a withanolide from Physalis angulata and was demonstrated to inhibit proliferation of several tumor cell lines [17] . However, little is known concerning this compound's detailed pharmacological mechanism.…”

Section: Introductionmentioning

confidence: 99%

Withagulatin A inhibits hepatic stellate cell viability and procollagen I production through Akt and Smad signaling pathways

et al. 2010

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Aim: To investigate the effects of the natural product Withagulatin A on hepatic stellate cell (HSC) viability and type I procollagen production. The potential mechanism underlying the pharmacological actions was also explored. Methods: The effect of Withagulatin A on cell viability was evaluated in HSC and LX-2 cells using a sulforhodamine B (SRB) assay. Cell cycle distribution was analyzed using flow cytometry. Type I procollagen gene expression was determined using real-time PCR. Regulation of signaling molecules by Withagulatin A was detected using Western blotting. Results: Primary rat HSCs and the human hepatic stellate cell line LX-2 treated with Withagulatin A (0.625-20 μmol/L) underwent a dose-dependent decrease in cell viability, which was associated with S phase arrest and the induction of cell apoptosis. In addition, the natural product decreased phosphorylation of the Akt/mTOR/p70S6K pathway that controls cell proliferation and survival. Furthermore, Withagulatin A (1, 2 μmol/L) inhibited transforming growth factor-β (TGF-β) stimulated type I procollagen gene expression, which was attributable to the suppression of TGF-β stimulated Smad2 and Smad3 phosphorylation. Conclusion: Our results demonstrated that Withagulatin A potently inhibited HSC viability and type I procollagen production, thereby implying that this natural product has potential use in the development of anti-fibrogenic reagents for the treatment of hepatic fibrosis.

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Withangulatin A, a New Withanolide from Physalis angulata

Cited by 36 publications

References 0 publications

Trypanocidal Constituents in Plants: 4. Withanolides from the Aerial Parts of Physalis angulata

Trypanocidal Constituents in Plants: 4. Withanolides from the Aerial Parts of Physalis angulata

Withangulatin I, a New Cytotoxic Withanolide from Physalis angulata

Withagulatin A inhibits hepatic stellate cell viability and procollagen I production through Akt and Smad signaling pathways

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