- A SAPONIN FROM ASPARAGUS GONOCLADUS
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The ethanolic extract of the aerial part of Asparagus gonocladus yielded a new saponin.It was identified as lup-20(29)-en-28-oic-3-O-α-L-rhamnopyranosyl-(2->1)-O-β-D-glucopyranoside. - Keywords: Asparagus gonocladus; Liliaceae; lup-20(29)-en-28-oic-3-O-α-L-rhamnopyranosyl-(2->1)-O-β-D-glucopyranoside.
- Mandloi, Dilip,Sant, P. G.
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- Toward a benign strategy for the manufacturing of betulinic acid
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We report a novel and efficient strategy for the preparation of the high-value triterpenoid betulinic acid based on extraction and streamlined oxidation of betulin from the industrial by-product birch bark. The initial extraction of betulin relies on a biphasic system and allowed extracting betulin in short times at room temperature. The crude extract could be directly oxidized, thereby providing a chromium-free, time- and energy saving strategy for the manufacturing of betulinic acid in high yield.
- Ressmann, Anna K.,Kremsmayr, Thomas,Gaertner, Peter,Zirbs, Ronald,Bica, Katharina
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- α-L-RHAMNOPYRANOSYL-3β-HYDROXY-LUP-20(29)-EN-28-OIC ACID FROM THE STEM OF DILLENIA PENTAGYNA
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Key Word Index: Dillenia pentagyna; Dilleniaceae; α-L-rhamnopyranosyl-3β-hydroxy-lup-20(29)-en-28-oic acid; a new saponin.
- Tiwari, Kamala P.,Srivastava, Savitri D.,Srivastava, Santosh K.
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- Sulfonation of Betulinic Acid by Sulfamic Acid
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Betulinic acid was sulfonated by sulfamic acid in the presence of urea in homogeneous 1,4-dioxane or DMF solution at 65-75°C in 2.5-3.5 h to give betulinic acid 3-sulfate, the structure of which was confirmed by IR and 13C NMR spectroscopy.
- Levdanskii,Levdanskii,Kuznetsov
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- Design, synthesis and evaluation of antiproliferative activity of fluorinated betulinic acid
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Betulinic acid (BA), a pentacyclic triterpenoid, exhibits broad spectrum antiproliferative activity, but generally with only modest potency. To improve BA's pharmacological properties, fluorine was introduced as a single atom at C-2, creating two diastereomers, or in a trifluoromethyl group at C-3. We evaluated the impact of these groups on antiproliferative activity against five human tumor cell lines. A racemic 2-F-BA (compound 6) showed significantly improved antiproliferative activity, while each diastereomer exhibited similar effects. We also demonstrated that 2-F-BA is a topoisomerase (Topo) I and IIα dual inhibitor in cell-based and cell-free assays. A hypothetical mode of binding to the Topo I-DNA suggested a difference between the hydrogen bonding of BA and 2-F-BA to DNA, which may account for the difference in bioactivity against Topo I.
- Li, Jizhen,Chang, Ling-Chu,Hsieh, Kan-Yen,Hsu, Pei-Ling,Capuzzi, Stephen J.,Zhang, Ying-Chao,Li, Kang-Po,Morris-Natschke, Susan L.,Goto, Masuo,Lee, Kuo-Hsiung
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- Glucosidation of betulinic acid by Cunninghamella species
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Microbial transformation of the antimelanoma agent betulinic acid (1) was studied. Preparative scale biotransformation with resting-cell suspensions of Cunninghamella species NRRL 5695 resulted in the production of a fungal metabolite of 1, which has been characterized as 28-O-β-D- glucopyranosyl 3β-hydroxy-lup-20(29)-en-28-oate (2) based on spectral and enzymic data. The in vitro cytotoxicity assay of metabolite 2 revealed no activity against several human melanoma cell lines.
- Chatterjee, Parnali,Pezzuto, John M.,Kouzi, Samir A.
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- A BETULINIC ACID GLYCOSIDE FROM SCHEFFLERA VENULOSA
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A new betulinic acid glycoside, lup-20(29)-en-28-oic-3-O-β-D-glucopyranosyl (2->1)-O-β-D-glucopyranoside has been characterized from the leaves of Schefflera venulosa.
- Purohit, M. C.,Pant, G.,Rawat, M. S. M.
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- Triterpenoid saponins from the buds of Lonicera similis
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Four new lupane triterpenoid saponins, along with one known lupane and eight hederagenin saponins, were isolated from the EtOH extract of the buds of Lonicera similis Hemsl. The structures of the new compounds were established as 3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl 23-hydroxybetulinic acid 28-O-β-D-glucopyranosyl ester (lonisimilioside A, 1), 3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl 23-hydroxybetulinic acid 28-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl ester (lonisimilioside B, 2), 3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl betulinic acid 28-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl ester (lonisimilioside C, 3) and 3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl betulinic acid 28-O-β-D-glucopyranosyl ester (lonisimilioside D, 4), respectively. The cytotoxic activities of the isolates against human cancer cell lines HepG2, MCF-7 and A-549 were evaluated. Only the monodesmosidic saponin with a free carboxyl group at C-28 (12) exhibited significant cytotoxicities against HepG2, MCF-7 and A-549 cell lines with the IC50 values of 8.98?±?0.19, 12.48?±?0.45 and 11.62?±?0.54?μM, respectively. Furthermore, Hoechst fluorescence 33342 staining was used to demonstrate that 12 could induce HepG2 and A-549 cells apoptosis significantly.
- Zhang, Xiao,Zou, Li-Hua,He, Yu-Lin,Peng, Cheng,Guo, Li,Xiong, Liang
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- Genotoxic and mutagenic properties of synthetic betulinic acid and betulonic acid
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Abstract Betulinic acid was synthesized from birch bark extract (Betula pendula), with betulonic acid being an intermediate of the synthesis. Both compounds were isolated with a purity of 95%. Genotoxicity and mutagenicity of the prepared compounds was analyzed by the Ames test and SOS chromotest and it was found that the substances show no mutagenic and genotoxic activity.
- Frolova,Kukina,Sinitsyna
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- The Effect of Experimental BCG Antigen–Betulin-Derived Conjugates on the Guinea Pig Immunological Response
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Abstract: The immunopotentiating properties of BCG vaccine strain antigen conjugated with betulin derivatives have been evaluated. The experiments were carried out on agouti guinea pigs (n = 20). The animals of the experimental groups (n = 5) were immunized with the following antituberculosis drugs: group 1, with antigens of the BCG vaccine strain conjugated with betulinic acid; group 2, with BCG antigens conjugated with betulonic acid; and group 3, with the BCG vaccine. The animals of the control group (n = 5) were injected with a saline solution. All the animals were infected with a virulent culture of Mycobacterium bovis (strain 8) on day 30 after the administration of antituberculosis drugs. The blood sampling for the assessment of the immune status was conducted on day 30 after the administration of drugs and day 30 after the infection with M. bovis. The designed conjugates were found to display immunopotentiating activity characterized by a 1.7–3.8-fold increase in the number of immunocompetent cells and an increase in the neutrophil functional activity observed to a greater degree in the guinea pig group 2. After infection with M. bovis some key parameters of the immune system, such as a T-lymphocyte count and the activity of enzymatic (myeloperoxidase) and nonenzymatic (cationic proteins) bactericidal systems of neutrophilic granulocytes significantly increased in groups 2 and 3, which implied the highest antituberculosis activity of the agents administered to these animals. The guinea pigs were euthanized 45 days after the infection with M. bovis. The next pathoanatomical experiments proved that the vaccine strain conjugates with betulonic acid and the BCG vaccine induced marked resistance against the pathogenic mycobacteria. The protection indexes for these agents were approximately the same and achieved 66 and 71%, respectively.
- Koshkin, I. N.,Kulakov, I. V.,Vlasenko, V. S.
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p. 837 - 844
(2021/08/25)
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- Catalytic oxidative transformation of betulin to its valuable oxo-derivatives over gold supported catalysts: Effect of support nature
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Liquid-phase oxidation of betulin extracted from birch bark was studied over gold catalysts supported on a range of supports (hydrotalcite, ZrO2, ZnO, MgO, CeO2, La2O3, HMS and various alumina) with different morphology and properties. Gold catalysts as well as the corresponding supports were characterized by XRD, BET, ICP-OES, XPS and TEM. It was found that the nature of the support plays a decisive role in betulin oxidation over gold-based catalysts, expressed in the influence on the average size and distribution of gold nanoparticles and, thereby, on their catalytic performance (activity and selectivity) in betulin oxidation. Moreover, it was revealed that betulin oxidation catalyzed by gold is a structure sensitive reaction, requiring an optimal size of gold nanoparticles of ca. 3.3 nm. The most suitable support for gold was found to be alumina. Kinetic studies allowed determination of reaction orders and conditions favorable for selective formation of a particular oxo-derivative of betulin (betulone, betulinic and betulonic aldehydes, betulinic acid).
- Kolobova,M?ki-Arvela,Grigoreva,Pakrieva,Carabineiro,Peltonen,Kazantsev,Bogdanchikova,Pestryakov,Murzin, D.Yu.
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- Synthesis of a Hexavalent Betulinic Acid Derivative as a Hemagglutinin-Targeted Influenza Virus Entry Inhibitor
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Naturally occurring pentacyclic triterpenes, such as betulinic acid (BA) and its derivatives, exhibit various pharmaceutical activities and have been the subject of great interest, in particular for their antiviral properties. Here, we found a new anti-influenza virus conjugate, hexakis 6-deoxy-6-[4-N-(3β-hydroxy-lup-20(29)-en-28-oate)aminomethyl-1H-1,2,3-triazol-1-yl]-2,3-di-O-acetyl-α-cyclodextrin (CYY1-11, 1), in a mini library of pentacyclic triterpene-cyclodextrin conjugates by performing a cell-based screening assay and then exploring the underlying mechanisms. Our results showed that conjugate 1 possessed a high-level activity against the influenza virus A/WSN/33 with an IC50 value of 5.20 μM (SI > 38.4). The study of the mechanism of action indicated that conjugate 1 inhibited viral replication by directly targeting the influenza hemagglutinin protein (KD = 1.50 μM), thus efficiently preventing the attachment of the virion to its receptors on host cells and subsequent infection. This study suggests that multivalent BA derivatives have possible use as a new class of influenza virus entry inhibitors.
- Chen, Yingying,Si, Longlong,Wang, Xinchen,Xiao, Sulong,Zhang, Bo,Zhang, Lihe,Zhang, Yongmin,Zhou, Demin,Zhu, Yinbiao
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p. 2546 - 2554
(2020/08/14)
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- Rhodamine B-based fluorescent probes for molecular mechanism study of the anti-influenza activity of pentacyclic triterpenes
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The antiviral activity of pentacyclic triterpenes has attracted increasing attention. However, the detailed antiviral mechanism remains fully unclear. In the present study, four C28 or C30 modified pentacyclic triterpene probes via conjugating with rhodamine B were designed and synthesized, and their anti-influenza virus activity was evaluated. The results indicated that two compounds 14 and 23 showed significant antiviral activity to influenza A/WSN/33 (H1N1) virus in Madin-Darby canine kidney (MDCK) cells with IC50 values of 8.36 and 8.24 μM, respectively. The mechanism of action studies of representative probe 23 indicated that it could inhibit the membrane fusion by binding with influenza virus hemagglutinin (HA), and the apparent dissociation constant (KD) value for probe 23-HA interaction was successfully evaluated (1.78 × 10?5 M) using surface plasmon resonance spectroscopy. In addition, the subcellular localization of probe 23 in MDCK cells was determined by confocal microscopy and flow cytometry, and the results suggested that fluorescent probe 23 was rapidly taken up in MDCK cells and accumulated in cytoplasm, but no antiviral activity was observed after its entry into cells. The present study further confirmed our previous finding that pentacyclic triterpenes could tightly bind to the viral envelope HA protein, thus blocking the virus entry into host cells.
- Chen, Yingying,Li, Man,Ma, Wenxiao,Ran, Fuxiang,Xiao, Sulong,Yuan, Lan,Zhang, Lihe,Zhou, Demin
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supporting information
(2020/08/05)
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- Pyrazine-Fused Triterpenoids Block the TRPA1 Ion Channel in Vitro and Inhibit TRPA1-Mediated Acute Inflammation in Vivo
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TRPA1 is a nonselective cation channel, most famously expressed in nonmyelinated nociceptors. In addition to being an important chemical and mechanical pain sensor, TRPA1 has more recently appeared to have a role also in inflammation. Triterpenoids are natural products with anti-inflammatory and anticancer effects in experimental models. In this paper, 13 novel triterpenoids were created by synthetically modifying betulin, an abundant triterpenoid of the genus Betula L., and their TRPA1-modulating properties were examined. The Fluo 3-AM protocol was used in the initial screening, in which six of the 14 tested triterpenoids inhibited TRPA1 in a statistically significant manner. In subsequent whole-cell patch clamp recordings, the two most effective compounds (pyrazine-fused triterpenoids 8 and 9) displayed a reversible and dose- and voltage-dependent effect to block the TRPA1 ion channel at submicromolar concentrations. Interestingly, the TRPA1 blocking action was also evident in vivo, as compounds 8 and 9 both alleviated TRPA1 agonist-induced acute paw inflammation in mice. The results introduce betulin-derived pyrazine-fused triterpenoids as promising novel antagonists of TRPA1 that are potentially useful in treating diseases with a TRPA1-mediated adverse component.
- M?ki-Opas, Ilari,H?m?l?inen, Mari,Moilanen, Lauri J.,Haavikko, Raisa,Ahonen, Tiina J.,Alakurtti, Sami,Moreira, Vania M.,Muraki, Katsuhiko,Yli-Kauhaluoma, Jari,Moilanen, Eeva
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p. 2848 - 2857
(2019/06/24)
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- Oxidation of a wood extractive betulin to biologically active oxo-derivatives using supported gold catalysts
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Betulin (90-94%) was extracted from birch with a non-polar solvent and recrystallized from 2-propanol. Liquid-phase oxidation of betulin aimed at obtaining its biologically active oxo-derivatives (betulone, betulonic and betulinic aldehydes), exhibiting e.g. antitumor, anti-inflammatory, antiparasitic, anticancer and anti-HIV properties, was demonstrated for the first time over gold-based catalysts. Gold was deposited on pristine TiO2 and the same support modified with ceria and lanthana, followed by pretreatment with a H2 or O2 atmosphere. The catalysts were characterized by XRD, BET, ICP, TEM, XPS, DRIFT CO, TPD of NH3 and CO2 methods. The nature of the support, type of modification and the pretreatment atmosphere through the metal-support interactions significantly influenced the average particle size of gold, its distribution and the electronic state of gold, as well as the acid-base properties and, thereby, the catalytic performance (activity and selectivity) in betulin oxidation. Au/La2O3/TiO2 pretreated in H2 displayed the highest catalytic activity in betulin oxidation among the studied catalysts with selectivities to betulone, betulonic and betulinic aldehydes of 42, 32 and 27%, respectively, at 69% conversion. Side reactions resulting in oligomerization/polymerization products occurred on the catalyst surface with the participation of strong acid sites, diminishing the yield of the desired compounds. The latter was improved by adding hydrotalcite with the basic properties to the reaction mixture containing the catalyst. Kinetic modelling through numerical data fitting was performed to quantify the impact of such side reactions and determine the values of rate constants.
- Kolobova, Ekaterina N.,Pakrieva, Ekaterina G.,Carabineiro, Sónia A. C.,Bogdanchikova, Nina,Kharlanov, Andrey N.,Kazantsev, Sergey O.,Hemming, Jarl,M?ki-Arvela, P?ivi,Pestryakov, Alexey N.,Murzin, Dmitry Yu.
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p. 3370 - 3382
(2019/06/24)
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- Preparation of Betulone Via Betulin Oxidation Over Ru Nanoparticles Deposited on Graphitic Carbon Nitride
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Derivatives of betulin obtained by oxidation have broad pharmacological applications, demonstrating anti-inflammatory, antioxidant, hepatoprotective, and anticancer activity. Ru supported catalysts based on graphitic carbon nitride or N-doped carbon were prepared via a mild reduction of the initial Ru precursor with hydrazine. These catalysts along with Ru supported on carbon nanofibers and a mesoporous carbon support Sibunit were studied in catalytic oxidation of betulin. Ru/carbon nitride demonstrated catalytic activity in betulin oxidation higher than Ru/N-doped carbon (conversion of betulin up to ca. 70% and 30%, respectively). Selectivity to different oxidation products was dependent on the properties of the carbon supports.
- Shcherban,M?ki-Arvela,Aho,Sergiienko,Skoryk,Kolobova,Simakova,Er?nen,Smeds,Hemming,Murzin, D. Yu.
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p. 723 - 732
(2019/01/25)
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- Inhibition of influenza virus infection by multivalent pentacyclic triterpene-functionalized per-O-methylated cyclodextrin conjugates
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Multivalent ligands that exhibit high binding affinity to influenza hemagglutinin (HA) trimer can block the interaction of HA with its sialic acid receptor. In this study, a series of multivalent pentacyclic triterpene-functionalized per-O-methylated cyclodextrin (CD) derivatives were designed and synthesized using 1, 3-dipolar cycloaddition click reaction. A cell-based assay showed that three compounds (25, 28 and 31) exhibited strong inhibitory activity against influenza A/WSN/33 (H1N1) virus. Compound 28 showed the most potent anti-influenza activity with IC50 of 4.7?μM. The time-of-addition assay indicated that compound 28 inhibited the entry of influenza virus into host cell. Further hemagglutination inhibition (HI) and surface plasmon resonance (SPR) assays indicated that compound 28 tightly bound to influenza HA protein with a dissociation constant (KD) of 4.0?μM. Our results demonstrated a strategy of using per-O-methylated β-CD as a scaffold for designing multivalent compounds to disrupt influenza HA protein-host receptor protein interaction and thus block influenza virus entry into host cells.
- Tian, Zhenyu,Si, Longlong,Meng, Kun,Zhou, Xiaoshu,Zhang, Yongmin,Zhou, Demin,Xiao, Sulong
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p. 133 - 139
(2017/04/14)
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- Synthesis of Conjugates of Lupane-Type Pentacyclic Triterpenoids with 2-Aminoethane- and N-Methyl-2-Aminoethanesulfonic Acids. Assessment of in vitro Toxicity
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Conjugates of betulin and betulinic and betulonic acids with 2-aminoethane- and N-methyl-2-aminoethanesulfonic acids were synthesized for the first time and were interesting as potential biologically active compounds. Experiments in vitro in MDCK cell culture using the MTT assay found that betulin and betulinic-acid derivatives with aminoethanesulfonic acid bound to triterpene C-3 or C-28 through an ester linker were less toxic than the native compounds.
- Komissarova,Dubovitskii,Shitikova,Vyrypaev,Spirikhin,Eropkina,Lobova,Eropkin, M. Yu.,Yunusov
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p. 907 - 914
(2017/10/16)
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- Synthesis and biological evaluation of novel pentacyclic triterpene α-cyclodextrin conjugates as HCV entry inhibitors
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Hepatitis C virus (HCV) entry is a key target for the treatment of chronic HCV infection. In our continuing efforts to identify novel potential anti-HCV entry inhibitors, a series of water-soluble triazole-bridged α-cyclodextrin-pentacyclic triterpene conjugates were easily synthesized with moderate to good yields. These novel compounds were fully identified and characterized by 1D and 2D NMR spectroscopy and ESI-HRMS. The anti-HCV entry activities were determined based on HCVpp/VSVGpp entry assays. The best results were found for compounds 15 and 18, which displayed the most promising anti-HCV entry activities with average IC50values of 1.18?μM and 0.25?μM, respectively. In addition, the in?vitro cytotoxicity activity of the two compounds against MDCK cells showed no toxicity at 100?μM. Five different binding assays were set up to identify the action mechanism. The results showed that the compounds exert their inhibitory activity at the post-binding step and subsequently prevent virus entry.
- Xiao, Sulong,Wang, Qi,Si, Longlong,Zhou, Xiaoshu,Zhang, Yongmin,Zhang, Lihe,Zhou, Demin
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supporting information
p. 1 - 9
(2016/11/09)
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- Heterocycle-fused lupane triterpenoids inhibit Leishmania donovani amastigotes
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The synthesis of heterocyclic betulin derivatives and their activity against Leishmania donovani is reported. Betulonic acid was used as a versatile intermediate. Several different fused heterocycles were introduced at the 2,3-position of the lupane skeleton including isoxazole, pyrazine, pyridine, indole and pyrazole rings. Also the 28-position was modified. Three compounds, 5, 8 and 25, showed low micromolar activity with IC50 values of 13.2, 4.3 and 7.2 μM, respectively. Compound 8 showed the best activity and selectivity, and its activity was tested on infected macrophages using a concentration, 5 μM, where no macrophage toxicity was exhibited. Interestingly, the activity of compound 8 on axenic amastigotes and Leishmania-infected macrophages was similar.
- Haavikko, Raisa,Nasereddin, Abedelmajeed,Sacerdoti-Sierra, Nina,Kopelyanskiy, Dmitry,Alakurtti, Sami,Tikka, Mari,Jaffe, Charles L.,Yli-Kauhaluoma, Jari
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supporting information
p. 445 - 451
(2014/04/17)
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- Synthesis and anti-HCV entry activity studies of β-cyclodextrin- pentacyclic triterpene conjugates
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In our previous studies, oleanolic acid (OA) and echinocystic acid (EA), isolated from Dipsacus asperoides, were found to have anti-HCV entry properties. The major issue for members of this type of triterpene is their low water solubility. In this study, a series of new water-soluble triazole-bridged β-cyclodextrin (CD)-pentacyclic triterpene conjugates were synthesized via click chemistry. Thanks to the attached β-CD moiety, all synthesized conjugates showed lower hydrophobicity (Alog P) than their parent compounds. Several conjugates exhibited moderate anti-HCV entry activity. With the exception of per-O-methylated β-CD-pentacyclic triterpene conjugates, all other conjugates showed no cytotoxicity based on an alamarBlue assay carried out with HeLa, HepG2, MDCK, and 293T cells. More interestingly, the hemolytic activity of these conjugates disappeared upon the introduction of β-CDs. Easy access to such conjugates that combine the properties of β-CD and pentacyclic triterpenes may provide a way to obtain a new class of anti-HCV entry inhibitors. An awesome CD collection: A series of water-soluble triazole-bridged β-cyclodextrin (CD)-pentacyclic triterpene conjugates were synthesized, and their hydrophobicity, anti-HCV entry activities, and toxicity were studied. Easy access to such conjugates may provide a way to obtain a new class of anti-HCV entry inhibitors.
- Xiao, Sulong,Wang, Qi,Si, Longlong,Shi, Yongying,Wang, Han,Yu, Fei,Zhang, Yongmin,Li, Yingbo,Zheng, Yongxiang,Zhang, Chuanling,Wang, Chunguang,Zhang, Lihe,Zhou, Demin
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supporting information
p. 1060 - 1070
(2014/05/20)
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- METHOD FOR PREPARATION OF BETULINIC ACID
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The present invention relates to a method for preparation of betulinic acid from betulin. The method comprises oxidizing betulin to betulinic and/or betulonic aldehyde with a ruthenium based catalyst catalyzed oxidation process in the presence of an oxidant, and further converting the betulinic and/or betulonic aldehyde to betulinic acid.
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- METHOD FOR PREPARATION OF BETULINIC ACIDcla
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The invention relates a method for preparation of betulonic acid or betulinic acid from betulin wherein the method comprises a stage for oxidizing betulin to betulonic aldehyde and/or betulinic aldehyde with Pd(ll)-catalyst catalyzed oxidation process in the presence of dioxygen.
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(2013/03/28)
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- METHOD FOR PREPARATION OF BETULINIC ACID
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The present invention relates to a method for preparation of betulinic acid from betulin. The method comprises oxidizing betulin to betulinic acid with a catalyst of formula (5), e.g. 2,2,6,6-tetramethylpiperidine 1 - oxyl (TEMPO), in the presence of a hypervalent iodine reagent as oxidant.
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(2013/03/28)
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- Betulin and ursolic acid synthetic derivatives as inhibitors of Papilloma virus
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The synthesis of new betulin and ursolic acid derivatives and evaluation of their antiviral activity in vitro is reported. Betulin was modified at positions C-3, C-20 and C-28 to afford the derivatives with nicotinoyl-, methoxycynnamoyl-, alkyne and aminopropoxy-2-cyanoethyl-moieties. The two stage conversion of betulin to the new ursane-type triterpenoid by treatment of allobetulin with Ac2O-HClO4 is suggested. Cyanoethylation of ursonic acid oxime led to cyanoethyloximinoderivative. According to the results of antiviral screening against human papillomavirus type 11 the selectivity index for tested triterpenoids has a range from 10 to 35 with no cellular cytotoxicite, the most remarkable activity was found for 3β,28-di-O-nicotinoylbetulin. 3β,28-Dihydroxy-29-norlup-20(30)-yne was also active against HCV replicon (EC50 1.32; EC90 16.82; IC50 12.41; IC90 >20; SI50 9.4; SI90 >1.19). 28-O-Methoxycynnamoylbetulin was active against influenza type A virus (H1N1) (Ye{cyrillic}S{cyrillic}50 2; IC50 >200; SI >100).
- Kazakova, Oxana B.,Giniyatullina, Gul'nara V.,Yamansarov, Emil Yu.,Tolstikov, Genrikh A.
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scheme or table
p. 4088 - 4090
(2010/08/06)
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- Dimethylaminopyridine derivatives of lupane triterpenoids are potent disruptors of mitochondrial structure and function
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Development of mitochondrially-targeted drugs is receiving increasing attention because of the central roles these organelles play in energy production, reactive oxygen generation, and regulation of cell death pathways. Previous studies have demonstrated that both natural and synthetic triterpenoids can disrupt mitochondrial structure and function. In this study, we tested the ability of a number of dimethylaminopyridine (DMAP) derivatives of lupane triterpenoids to target mitochochondria in two human melanoma cell lines and an untransformed normal fibroblast line. These compounds induced a striking fragmentation and depolarization of the mitochondrial network, along with an inhibition of cell proliferation. A range of potencies among these compounds was noted, which was correlated with the number, position, and orientation of the DMAP groups. Overall, the extent of proliferation inhibition mirrored the effectiveness of mitochondrial disruption. Thus, DMAP derivatives of lupane triterpenoids can be potent mitochondrial perturbants that appear to suppress cell growth primarily via their mitochondrial effects.
- Holy, Jon,Kolomitsyna, Oksana,Krasutsky, Dmytro,Oliveira, Paulo J.,Perkins, Edward,Krasutsky, Pavel A.
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scheme or table
p. 6080 - 6088
(2010/10/03)
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- SYNTHESIS OF BETULONIC AND BETULINIC ALDEHYDES
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The present invention provides for methods of selectively converting betulin to betulonic aldehyde. The present invention also provides for methods of selectively converting 3-substituted triterpen-28-ols to the corresponding 3-substituted triterpen-28-carboxaldehydes. Additionally, the present invention provides for methods of preparing betulonic aldehyde, betulonic acid, betulinic acid, and corresponding 3-substituted triterpenes.
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(2009/05/28)
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- Betulin-derived compounds as inhibitors of alphavirus replication
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This paper describes inhibition of Semliki Forest virus (SFV) replication by synthetic derivatives of naturally occurring triterpenoid betulin (1). Chemical modifications were made to OH groups at C-3 and C-28 and to the C-20-C-29 double bond. A set of heterocyclic betulin derivatives was also assayed. A free or acetylated OH group at C-3 was identified as an important structural contributor for anti-SFV activity, 3,28-di-O-acetylbetulin (4) being the most potent derivative (IC50 value 9.1 μM). Betulinic acid (13), 28-O-tetrahydropyranylbetulin (17), and a triazolidine derivative (41) were also shown to inhibit Sindbis virus, with IC50 values of 0.5, 1.9, and 6.1 μM, respectively. The latter three compounds also had significant synergistic effects against SFV when combined with 3′-amino-3′-deoxyadenosine. In contrast to previous work on other viruses, the antiviral activity of 13 was mapped to take place in virus replication phase. The efficacy was also shown to be independent of external guanosine supplementation.
- Pohjala, Leena,Alakurtti, Sami,Ahola, Tero,Yli-Kauhaluoma, Jari,Tammela, Paeivi
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supporting information; experimental part
p. 1917 - 1926
(2010/04/29)
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- Synthesis of betulinic acid acyl glucuronide for application in anticancer prodrug monotherapy
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The synthesis of 28-O-β-d-glucuronide betulinic acid, an acyl glucuronide derivative, was successfully carried out for the first time using commercially available peracetylated methyl glucuronate bromide under phase-transfer conditions. The target compound could be used in an anticancer prodrug monotherapy (PMT) strategy since it is non-cytotoxic, non-haemolytic, more water soluble than betulinic acid, it possesses a good in vitro stability in phosphate buffer and can be hydrolyzed in the presence of β-d-glucuronidase releasing in vitro betulinic acid, a promising anticancer agent.
- Gauthier, Charles,Legault, Jean,Rondeau, Simon,Pichette, André
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scheme or table
p. 988 - 991
(2009/05/31)
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- Oxidative transformations of betulinol
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Starting from commercially available betulinol by a combination of several selective oxidation procedures betutinal, betulinic acid, betulonal as well as betulonic acid were obtained in high yields on a multi-gram scale.
- Barthel, Alexander,Stark, Sebastian,Csuk, René
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p. 9225 - 9229
(2008/12/21)
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- BETULIN DERIVED COMPOUNDS USEFUL AS ANTIBACTERIAL AGENTS
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The invention relates to compouns derived from betulin, and to the use thereof as antibacterial agents in pharmaceutical and cosmetic applications.
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Page/Page column 78-79
(2008/06/13)
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- DEPOLYMERIZATION EXTRACTION OF COMPOUNDS FROM BIRCH BARK
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The invention provides improved processes for the extraction of betulin, lupeol, betulinic acid, suberinic acids, and/or other organic compounds and compositions from birch bark.
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Page/Page column 37; 44
(2008/06/13)
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- STEREOSELECTIVE REDUCTION OF TRITERPENONES
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The present invention provides for methods of selectively converting triterpen-3-ones to the corresponding triterpen-3-ols. The selectivity of the methods is at least about 80% of the beta-isomer, at the C-3 position. Specifically, the present invention provides for methods of preparing betulinic acid, lupeol, betulin, allobetulin, and oleanan-3-β-ol-28,19-lactone from betulonic acid, lupeone, betulone, allobetulone and oleanan-3-β-one-28,19- lactone, respectively.
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Page/Page column 19
(2008/06/13)
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- A practical synthesis of betulinic acid
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A new synthetic route for the synthesis of betulinic acid from betulin has been developed. The main step of this procedure is the selective oxidation of the primary alcohol function of betulin without affecting the secondary hydroxyl group. Applying shorter reaction times and lower temperatures results in the exclusive formation of the corresponding aldehyde, betulinal.
- Csuk, René,Schmuck, Kianga,Sch?fer, Renate
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p. 8769 - 8770
(2007/10/03)
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- New 3-O-acyl betulinic acids from Strychnos vanprukii Craib
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Three new betulinic acid derivatives, 3β-O-trans-feruloylbetulinic acid (1), 3β-O-cis-feruloylbetulinic acid (2), and 3β-O-cis- coumaroylbetulinic acid (4), along with two known triterpenes, 3β-O-trans-coumaroylbetulinic acid (3) and ursolic acid (6) were isolated from the leaves and twigs of Strychnos vanprukii Craib. All isolates showed moderate anti-HIV activity with IC50 values ranging from 3 to 7 μg/mL (5 to 15 μM) in an indicator cell line for HIV infectivity. The structures of the new isolates were elucidated by spectroscopic techniques including 1D and 2D NMR spectroscopy. In addition, the structure of 1 was confirmed by X-ray crystallography.
- Chien, Nguyen Quyet,Van Hung, Nguyen,Santarsiero, Bernard D.,Mesecar, Andrew D.,Cuong, Nguyen Manh,Soejarto, D. Doel,Pezzuto, John M.,Fong, Harry H. S.,Tan, Ghee T.
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p. 994 - 998
(2007/10/03)
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- Selective oxidation of betulin for the preparation of betulinic acid, an antitumoral compound
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This paper describes a semisynthetic approach for the preparation of betulinic acid from betulin. The main step of this synthetic approach is the selective oxidation of primary alcohol function of betulin. This reaction is accomplished with chromic oxide adsorbed on silica gel to obtain betulinal in an adequate yield. Betulinal is then almost quantitatively oxidized to betulinic acid by potassium permanganate action.
- Pichette, Andre,Liu, Hongyan,Roy, Christian,Tanguay, Steve,Simard, Francois,Lavoie, Serge
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p. 3925 - 3937
(2007/10/03)
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- Submicron-liposome containing triterpenoid and a method for preparing the same
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Disclosed herein is submicron-liposome containing highly concentrated triterpenoid prepared by using nontoxic solvent without intense mechanical treatment and a method for preparing the same.
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- Triterpenoid derivatives
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The present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, crystal form, complex, hydrate, or hydrolysable ester thereof, in the preparation of a medicament for treating a patient suffering from leukaemia, cancer or other proliferative disorder. A further embodiment relates to the use a compound of formula (I) in an assay for detecting the phosphorylation state of cellular substrates. The present invention also relates to novel compounds of formula (I), and the chemical synthesis thereof.
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- Submicron-liposome containing triterpenoid and a method for preparing the same
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Disclosed herein is submicron-liposome containing highly concentrated triterpenoid prepared by using non-toxic solvent without intense mechanical treatment and a method for preparing the same.
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- Epimerization of Hydroxyl Group in Lupan Series Triterpenoids
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Two methods of obtaining 3α-betulinic acid and related compounds from their 3β-epimers were studied: the reaction of bimolecular substitution and the stereoselective reduction of 3-ketoderivatives. The substitution of acyloxy by formyloxy group in 3-O-tosyllupeol or of the belulin hydroxyl by benzoyloxy group resulted only in Δ2, 3-elimination products, with none of the expected products of bimolecular substitution being found. The catalytic hydrogenation of betulonic acid over Raney nickel resulted only in reduction of the isopropenyl double bond, whereas the use of 5% Ru/C gave a 60:40 mixture of epimers of dihydrobetulinic acid. Practically the same mixture of betulinic acid epimers was obtained when reducing betulonic acid with L-Selectride. The cytotoxic activity of 3α-betulinic acid increased toward the Bro melanoma cells and decreased toward the MS melanoma cells.
- Symon,Kaplun,Vlasenkova,Gerasimova,Shon, Le Bang,Litvin,Kozlova,Surkova,Shvets
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p. 185 - 189
(2007/10/03)
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- Synthesis and Antiviral Activity of Hydrazides and Substituted Benzalhydrazides of Betulinic Acid and Its Derivatives
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New nitrogen-containing derivatives of betulinic and betulonic acids, hydrazides and N′-benzalhydrazides, were synthesized. Their antiviral activities toward viruses of influenza A virus, herpes simplex type I virus, enterovirus ECHO6, and HIV-1 were studied in vitro. Betulinic acid 3-oxime was found to have the highest activity against the influenza virus. Betulonic acid, betulinic acid 4-chlorobenzalhydrazide, betulonic acid 3-oxime benzalhydrazide, and betulinic acid hydrazide inhibited the replication of herpes simplex type I virus. Betulinic acid hydrazide also showed antiviral activity toward HIV-1. All the derivatives of betulinic acid under study displayed a low antiviral activity toward enterovirus ECHO6.
- Flekhter,Boreko,Nigmatullina,Pavlova,Nikolaeva,Savinova,Eremin,Baltina,Galin,Tolstikov
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p. 296 - 301
(2007/10/03)
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- Lupane triterpenes and derivatives with antiviral activity
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Betulin and betulinic acid have been modified at the C-3 and C-28 positions and the antiviral activity of derivatives has been evaluated in vitro. It was found that simple modifications of the parent structure of lupane triterpenes produced highly effective agents against influenza A and herpes simplex type 1 viruses.
- Baltina,Flekhter,Nigmatullina,Boreko,Pavlova,Nikolaeva,Savinova,Tolstikov
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p. 3549 - 3552
(2007/10/03)
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- Synthesis of glycosides of lupane-type triterpene acids
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A preparative synthesis of glucosides of the lupane-type triterpene acids betulinic, dihydrobetulinic, betulonic, dihydrobetulonic, and 3,20-dioxo-30-norlupan-28-oic was proposed. Glycosylation of 3-hydroxyacids by α-acetobromoglucose (ABG) with Ag2O was performed in pyridine (Py) to form glycosides at C-28, repeated glycosylation of which by these same reagents but in CH2Cl2 generated a glycoside bond at C-3 to form bisglucosides. 28-Glucosides of ketoacids were formed in high yields in both Py and CH2Cl2.
- Samoshina,Denisenko,Denisenko,Uvarova
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p. 575 - 582
(2007/10/03)
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- Process for obtaining betulinic acid
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The invention relates to an improved process for obtaining highly pure, crystalline betulinic acid from a methanolic extract of ground plane tree cortex and/or plane tree bark, as well as highly pure crystalline betulinic acid which is solvated with one equivalent of ethanol.
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- Methods for manufacturing betulinic acid
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The present invention provides a method for preparing betulin-3-acetate including alcoholyzing betulin 3,28-dibenzoate; a process for preparing betulin-3-acetate including: (1) acylating betulin to provide betulin 3,28-dibenzoate and (2) alcoholyzing betulin 3,28-dibenzoate to provide betulin-3-acetate; and a process for preparing betulinic acid including: (1) acylating betulin to provide betulin 3,28-dibenzoate; (2) alcoholyzing betulin 3,28-dibenzoate to provide betulin-3-acetate; (3) oxidizing betulin-3-acetate to provide betulinic aldehyde-3-acetate; (4) oxidizing betulinic aldehyde-3-acetate to provide betulinic acid-3-acetate; and (5) deprotecting betulinic acid-3-acetate to provide betulinic acid.
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- Birch bark processing and the isolation of natural products from birch bark
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The invention provides methods for separating outer birch bark from inner birch bark. The invention also provides methods for isolating betulin; lupeol; betulinic acid; 9,10-epoxy-18-hydroxyoctadecanoic acid; 9,10,18-trihydroxyoctadecanoic acid; polyphenolic polymers and fatty acids from birch bark.
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- Extracting betulinic acid from Ziziphus jujuba
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A process for isolating betulinic acid from Ziziphus jujuba is disclosed. The process involves the steps of:a) extracting bark of Ziziphus jujuba in a solvent to obtain an extract containing betulinic acid,b) semi-concentrating the extract containing betulinic acid,c) chilling said semi-concentrated extract overnight to obtain a solid in the extract,d) separating the solid from the extract by filtration or centrifugation,e) dissolving the separated solid from step d) in hot methanol, refluxing with activated charcoal and filtering through a celite bed to obtain a methanolic solution,f) partially concentrating the methanolic solution of step e), adding halogenated hydrocarbon solvent and chilling overnight to obtain a solid in the solution,g) separating the solid of step f) by filtration or centrifugation and drying the solid to obtain a solid enriched in betulinic acid,h) dissolving the dried solid step g) in a solvent containing pyridine and acetic anhydride, separating an organic layer and drying to obtain a crude 3-acetoxy betulinic acid,i) washing the crude solid 3-acetoxy betulinic acid obtained in step h) with an alcohol to yield pure solid 3-acetoxy betulinic acid obtained in step i) in an aqueous alcoholic alkali solution to yield pure betulinic acid.
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- Synthesis of betulinic acid derivatives with activity against human melanoma
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Betulinic acid has been modified at C-3, C-20, and C-28 positions and the toxicity of the derivatives has been evaluated against cultured human melanoma (MEL-2) and human epidermoid carcinoma of the mouth (KB) cell lines. This preliminary investigation demonstrates that simple modifications of the parent structure of betulinic acid can produce potentially important derivatives, which may be developed as antitumor drugs.
- Kim, Darrick S. H. L.,Pezzuto, John M.,Pisha, Emily
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p. 1707 - 1712
(2007/10/03)
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- The synthesis of betulinic acid from betulin and its solubilization with liposomes
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A method for betulinic acid synthesis from betulin was developed. Betulin was oxidized with chromium oxide (VI) into betulonic acid, which was reduced with sodium borohydride to yield a mixture of 3-hydroxy epimers containing 85% of the natural β-epimer. Studying changes in light scattering by dispersions of liposomes with different contents of betulinic acid revealed that up to 10 mol % of this compound may be entrapped in liposomes. The dependence of the efficiency of the betulinic acid entrapment on liposome composition was studied. The presence of polyvinylpyrrolidone or Proxanol increased the resistance of betulinic acid-containing liposomes to aggregation. These polymers solubilized betulinic acid with the same efficiency as liposomes.
- Son, Le Bang,Kaplun,Shpilevskii,Andiya-Pravdivyi,Alekseeva,Grigor'ev,Shvets
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p. 700 - 705
(2007/10/03)
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- Simple synthesis of allobetulin, 28-oxyallobetulin and related biomarkers from betulin and betulinic acid catalysed by solid acids
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Allobetulin (3a) and allobetulin acetate (3b) were efficiently prepared in excellent yield from betulin (2a) and betulin 3-acetate (2b) catalysed by a number of solid acids in refluxing dichloromethane. Sulfuric acid on silica, montmorillonite clays (both K10 and KSF), kaolinite, bleaching clay and toluene-p-sulfonic acid on silica are efficient catalysts for these conversions. Similarly, 28-oxyallobetulin (3c) and 28-oxyallobetulin acetate (3d) were obtained in good and excellent yield from betulinic acid (2c) and betulinic acid acetate (2d) respectively catalysed by montmorillonite K10. Two allobetulin related biomarkers, 19β,28-epoxy-A-neo-18α-olean-3(5)-ene (4a) and A-neo-18α-olean-3(5)-en-28→19β-olide (4b) were synthesised either from 3a and 3c or directly from 2a and 2c in refluxing benzene or cyclohexane catalysed by montmorillonite K10. Two other biomarkers, 19β,28-epoxy-18α-olean-2-ene (10a) and 18α-olean-2-en-28→19β-olide (10b) were also synthesised based on the above transformations. The direct formation of allobetulane related biomarkers from natural betulin 2a and betulinic acid 2c catalysed by clay mineral (montmorillonite) is of great geochemical interest.
- Li, Tong-Shuang,Wang, Jian-Xin,Zheng, Xue-Jing
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p. 3957 - 3965
(2007/10/03)
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- A concise semi-synthetic approach to betulinic acid from betulin
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Betulin was convert to betulinic acid using two different synthetic routes. The first approach involved an oxidation of betulin using Jones' reagent to betulinic acid and subsequent NaBH4 reduction to betulinic acid. The second approach involved steps utilizing different protecting groups on the alcohol functional groups of betulin and Jones' oxidation to circumvent the isomerization of the secondary alcohol of betulinic acid.
- Kim, Darrick S.H.L.,Chen, Zhidong,Van Nguyen, Tuyen,Pezzuto, John M.,Qiu, Shengxiang,Lu, Zhi-Zhen
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p. 1607 - 1612
(2007/10/03)
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