Ceanothic acid

The seeds of Zizyphus jujuba

Two new bioactive triterpenoids from the roots of Colubrina asiatica.[Pubmed:30445837]

Nat Prod Res. 2018 Nov 16:1-7.

Two new ceanothane triterpenes, 3,7-O,O-dibenzoyl Ceanothic acid methylester (1) and 3-O-acetyl-7-O-benzoyl Ceanothic acid methylester (2), along with nine known compounds (3-11), were isolated from the roots of Colubrina asiatica. The isolated compounds were identified by spectroscopic evidence. Compounds 1 and 2 showed antimalarial activity against Plasmodium falciparum with IC50 values of 4.67 and 3.07 microg/mL, respectively. Compound 2 also showed antimycobacterial activity against Mycobacterium tuberculosis (MIC 6.25 microg/mL). In addition, compounds 1, 2, 10 and 11 showed cytotoxicity against three cancer cell lines (KB, NCI-H187 and MCF-7) with IC50 values ranging from 8.32 to 46.72 microg/mL.

Pharmacokinetic Comparisons of Multiple Triterpenic Acids from Jujubae Fructus Extract Following Oral Delivery in Normal and Acute Liver Injury Rats.[Pubmed:30011885]

Int J Mol Sci. 2018 Jul 13;19(7). pii: ijms19072047.

Jujubae Fructus, the dried fruit of Ziziphus jujuba, has been used as Chinese medicine and food for centuries. Triterpenic acids have been found to be the major bioactive constituents in Jujubae Fructus responsible for their hepatoprotective activity in previous phytochemical and biological studies, while few pharmacokinetic studies have been conducted. To reveal the kinetics of the triterpenic acids under the pathological liver injury state, an established ultra-performance liquid chromatography coupled with a mass spectrometry method was applied for the simultaneous quantitation of seven triterpenic acids (Ceanothic acid, epiCeanothic acid, pomonic acid, alphitolic acid, maslinic acid, betulinic acid, and betulonic acid) in plasma samples of normal and acute liver injury rats induced by CCl(4). The results showed that there were significant differences (p < 0.05) in the pharmacokinetic parameters of seven triterpenic acids between model and normal groups. The AUC0(-)t and AUC0(-)infinity of epiCeanothic acid (5227 +/- 334 mug⋅h/L vs. 1478 +/- 255 mug h/L and 6127 +/- 423 mug h/L vs. 1482 +/- 255 mug h/L, respectively) and pomonic acid (4654 +/- 349 mug h/L vs. 1834 +/- 225 mug h/L and 4776 +/- 322 mug h/L vs. 1859 +/- 230 mug h/L, respectively) in model rats were significantly higher than those in normal rats, and the CLz/F of them were significantly decreased (0.28 +/- 0.02 L/h/kg vs. 1.36 +/- 0.18 L/h/kg and 19.96 +/- 1.30 L/h/kg vs. 53.15 +/- 5.60 L/h/kg, respectively). In contrast, the above parameters for alphitolic acid, betulinic acid and betulonic acid exhibited the quite different trend. This pharmacokinetic research might provide useful information for the clinical usage of triterpenic acids from Jujubae Fructus.

Comparative pharmacokinetics of triterpenic acids in normal and immunosuppressed rats after oral administration of Jujubae Fructus extract by UPLC-MS/MS.[Pubmed:29413572]

J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Mar 1;1077-1078:13-21.

The fruit of Ziziphus jujuba (Jujubae Fructus) has been used as food and crude drug for thousands of years. Although several chemical and biological studies have revealed triterpenic acid as the main bioactive constituent of Jujubae Fructus responsible for immune-regulatory activity, only few pharmacokinetic studies have been conducted. To comprehend the kinetics of triterpenic acids and promote their curative application, a sensitive and efficient ultra-performance liquid chromatography coupled with mass spectrometry method (UPLC-MS/MS) was established. UPLC-MS/MS was applied for the simultaneous determination of Ceanothic acid, epiCeanothic acid, pomonic acid, alphitolic acid, maslinic acid, betulinic acid, and betulonic acid in normal and immunosuppressed rat plasma samples. After sample preparation, chromatographic separation was performed on an Acquity UPLC BEH C18 column (2.1x100mm, 1.7mum) with acetonitrile: methanol (1:1, v/v) and 0.5% ammonium acetate in water as mobile phase. The established method was validated and found to be specific, accurate, and precise for the seven triterpenic acids, and was successfully applied for the pharmacokinetic study of rat plasma samples. The results showed that the pharmacokinetic parameters (Cmax, Tmax, AUC0-t, AUC0-infinity, and CLz/F) in the plasma samples of immunosuppressed rats were significantly different from those in normal rats, and might provide an insight for the clinical usage of triterpenic acids from Jujubae Fructus.

[Chemical constituents from seeds of Ziziphus mauritiana].[Pubmed:25174108]

Zhong Yao Cai. 2014 Mar;37(3):432-5.

OBJECTIVE: To study the chemical constituents in the seeds of Ziziphus mauritiana. METHODS: The constituents were isolated by silica column chromatography and their structures were elucidated by physico-chemical properties and spectroscopic analysis. RESULTS: Twelve compounds were isolated from the seeds of Ziziphus mauritiana and identified as betulinic aldehyde (1), betulinic acid (2), Ceanothic acid (3), frangufoline (4), spinosin (5), beta-sitosterol (6), daucosterol (7), daucosterol-6'-octadecanoate (8), sucrose (9), docosanoic acid (10), stearic acid (11), palmitoleic acid (12). CONCLUSION: All the compounds are obtained from Ziziphus mauritiana seeds for the first time and compounds 4,5 and 8 are isolated from this plant for the first time.

Zizimauritic acids A-C, three novel nortriterpenes from Ziziphus mauritiana.[Pubmed:22989532]

Bioorg Med Chem Lett. 2012 Oct 15;22(20):6377-80.

Zizimauritic acids A-C (1-3), three novel nortriterpenes with a unique A-nor-E-seco spiro-lactone ceanothane-type triterpene skeleton, together with 3 known triterpenes ceanothenic acid (4), betulinic acid (5), and Ceanothic acid (6), were isolated from the roots of Ziziphus mauritiana. Compounds 1-4 showed cytotoxicities with the IC(50) values ranging from 5.05 to 11.94 mug/ml, and compounds 1 and 3 showed an inhibitory effect on the growth of Staphylococcus aureus with the IC(50) values 2.17 and 12.79 mug/ml. A plausible biosynthetic pathway of compounds 1-3 was proposed.

Simultaneous qualitative and quantitative analysis of triterpenic acids, saponins and flavonoids in the leaves of two Ziziphus species by HPLC-PDA-MS/ELSD.[Pubmed:21665400]

J Pharm Biomed Anal. 2011 Sep 10;56(2):264-70.

The leaves of Ziziphus jujuba and Z. jujuba var. spinosa have been utilized as crude drugs for their health benefits in China for thousands of years. To control their quality, a reliable method based on high-performance liquid chromatography coupled with photo diode array and electrospray ionization tandem mass spectrometry detection (HPLC-PDA-ESI-MS/MS) was developed for exploration of the chemical profiles of these jujube leaves. As the results, fourteen constituents including three flavonoids, two saponins and nine triterpenic acids were identified or tentatively characterized. Then, twelve of them such as quercetin-3-O-rutinoside, zizyphus saponins I and II, Ceanothic acid, alphitolic acid, maslinic acid, 2alpha-hydroxyursolic acid, zizyberanalic acid, epiCeanothic acid, ceanothenic acid, betulinic acid, and oleanolic acid were selected as the chemical markers and were determined using an HPLC coupled with evaporative light scattering detection (ELSD) method. The separation was carried out on a Waters Sunfire C(1)(8) column with 0.2 % acetic acid and acetonitrile as the mobile phase under gradient elution. The operating conditions of ELSD were set as 80 degrees C for drift tube temperature and 2.7 l/min for nitrogen flow rate. The developed method was fully validated in terms of linearity, sensitivity, precision, repeatability as well as recovery, and subsequently applied to evaluate the quality of eight batches of Z. jujuba and Z. jujuba var. spinosa leaves from different collections.

Cancer preventive agents 9. Betulinic acid derivatives as potent cancer chemopreventive agents.[Pubmed:19481937]

Bioorg Med Chem Lett. 2009 Jul 1;19(13):3378-81.

C-3 esterifications of betulinic acid (BA, 1) and its A-ring homolog, Ceanothic acid (CA, 2), were carried out to provide sixteen terpenoids, 4-19, including nine new compounds (4-12). All synthesized compounds were evaluated in an in vitro antitumor-promoting assay using the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Among them, compounds 4-6, 11-14, 16, and 17 displayed remarkable inhibitory effects of EBV-EA activation. BA analog 6, which contains a prenyl-like group, showed the most potent inhibitory effect (100%, 76%, 37%, and 11% inhibition of EBA activation at 1000, 500, 100, and 10mol ratio/TPA, respectively, with IC(50) value of 285mol ratio/32pmol TPA). Compound 6 merits further development as a cancer preventive agent.

High-performance liquid chromatography--two wavelength detection of triterpenoid acids from the fruits of Ziziphus jujuba containing various cultivars in different regions and classification using chemometric analysis.[Pubmed:19359121]

J Pharm Biomed Anal. 2009 Jul 12;49(5):1296-302.

A simple and sensitive HPLC-DAD method has been developed for the first time to simultaneously determine 10 triterpenoid acids (Ceanothic acid, alphitolic acid, zizyberanal acid, zizyberanalic acid, epiCeanothic acid, ceanothenic acid, betulinic acid, oleanolic acid, ursonic acid and zizyberenalic acid) in the dried fruit of Ziziphus jujuba (called Dazao) which has been widely used as one of the traditional Chinese medicines (TCMs). This HPLC assay was performed on a reversed-phase C(18) column (250 mm x 4.6mm, 5 microm) with the column temperature at 35 degrees C. The mobile phase was composed of A (acetonitrile) and B (0.05% aqueous phosphoric acid, v/v). The flow rate was 1.0 ml/min and the detection wave length was set at 205 nm for reference compounds 1-9 and 238 nm for reference compound 10. All calibration curves showed good linear regression (r(2)>0.9999) within the test range. The established method showed good precision and accuracy with overall intra-day and inter-day variations of 0.43-1.72% and 0.53-2.45%, respectively, and overall recoveries of 94.98-104.09% for the 10 compounds analyzed. The validated method was successfully applied for the simultaneous determination of the 10 triterpenoid acids in 42 batches of Dazao which contained 36 cultivars from 22 cultivation regions, and were investigated and authenticated as Z. jujuba. Hierarchical clustering analysis (HCA) and principal components analysis (PCA) were performed to differentiate and classify the samples based on the contents of the 10 triterpenoid acids. The presented HPLC-DAD method conjugated with chemometrics approach was demonstrated to be very helpful in using Dazao resources, and was possibly useful in chemotaxonomic characterization.

Ceanothane- and lupane-type triterpenes with antiplasmodial and antimycobacterial activities from Ziziphus cambodiana.[Pubmed:16595959]

Chem Pharm Bull (Tokyo). 2006 Apr;54(4):535-7.

One new and eight known ceanothane- and lupane-type triterpenes were isolated from the root bark of Ziziphus cambodiana PIERRE (Rhamnaceae). Based on spectral analyses, the structure of the new compound was elucidated as 3-O-(4-hydroxy-3-methoxybenzoyl)Ceanothic acid (3-O-vanillylCeanothic acid) (1), while the known compounds were identified as lupeol (2), betulinaldehyde (3), betulinic acid (4), 2-O-E-p-coumaroyl alphitolic acid (5), alphitolic acid (6), zizyberanalic acid (7), zizyberenalic acid (8) and Ceanothic acid (9). Compounds 1, 5 and 8 exhibited significant in vitro antiplasmodial activity against the parasite Plasmodium falciparum, with inhibitory concentration (IC50) values of 3.7, 0.9 and 3.0 microg/ml, respectively. Compounds 1 and 3-8 showed antimycobacterial activity against Mycobacterium tuberculosis with respective MIC values of 25, 25, 25, 12.5, 50, 50 and 100 microg/ml.

Preparation and cytotoxic effect of ceanothic acid derivatives.[Pubmed:9834149]

J Nat Prod. 1998 Nov;61(11):1343-7.

Six ceanothane and 1-norceanothane derivatives (1, 2, 8-11) were prepared from Ceanothic acid dibenzyl ester. These ring-A homologues of betulinic acid exhibited cytotoxic effects. Among these, 1-decarboxy-3-oxo-Ceanothic acid (2) was found to be the most cytotoxic against OVCAR-3 and HeLa cancer cell lines, with an IC50 of 2.8 and 6.6 microg/mL, respectively, and an IC50 of 11.3 microg/mL against normal cell line FS-5.

In vitro cytotoxic activity of 1-decarboxy-3-oxo-ceanothic acid in a human ovarian adenocarcinoma cell line.[Pubmed:9730010]

Res Commun Mol Pathol Pharmacol. 1998 Jun;100(3):313-26.

The effect of a novel pentacyclic triterpene, 1-decarboxy-3-oxo-Ceanothic acid (DOCA) on DNA synthesis, DNA degradation and programmed cell death was examined in human ovarian adenocarcinoma (OVCAR-3) cells. OVCAR-3 cells exposed to various concentrations of DOCA for 30 h displayed a dose-dependent inhibition of DNA synthesis. Morphologically, treatment with 10 microg/ml of DOCA for 24 h and 72 h resulted respectively in reduction in cell volume and condensation of nuclear structures. By agarose gel analysis, DNA fragmentation with the characteristic pattern of inter-nucleosomal ladder was observed after cells were treated with 2.5 microg/ml of DOCA for 24 h. Both cell death and DNA fragmentation caused by this compound were partially inhibited by the protein synthesis inhibitor cycloheximide, suggesting that the apoptotic process caused by DOCA requires synthesis of new proteins. On the other hand, no apparent double-stranded DNA breaks were detected after cells were incubated with 2.5 microg/ml of DOCA for 24 h, indicating that DNA damage was not a preceding event for apoptosis induced by this compound. Taken together, our results demonstrate that the cytotoxic effect of DOCA is mediated, at least in part, by the induction of apoptosis.

Antimicrobial compounds from Ceanothus americanus against oral pathogens.[Pubmed:9276981]

Phytochemistry. 1997 Sep;46(1):97-102.

During the search for antimicrobial compounds from higher plant sources, a methanol extract of Ceanothus americanus demonstrated antimicrobial activity against selected oral pathogens. Through further bioassay-guided fractionation and purification, three triterpenes (Ceanothic acid, 27-hydroxy Ceanothic acid and ceanothetric acid) and two flavonoids (maesopsin and maesopsin-6-O-glucoside) were identified. Among these, ceanothetric acid and maesopsin-6-O-glucoside were new compounds. Ceanothic acid and ceanothetric acid demonstrated growth inhibitory effect against Streptococcus mutans, Actinomyces viscosus, Porphyromonas gingivalis, and Prevotella intermedia with MICs ranging from 42 to 625 micrograms ml-1. Maesopsin, its glucoside, and 27-hydroxy Ceanothic acid, were inactive below the concentration of 500 micrograms ml-1.

Ceanothic acid (Emmolic acid) is a ring-A homologue of betulinic acid. Ceanothic acid inhibits OVCAR-3, HeLa, and FS-5 cells with the cell survival of 68%, 65%, and 81%, respectively.

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