- N-methylated diazabicyclo[3.2.2]nonane substituted triterpenoic acids are excellent, hyperbolic and selective inhibitors for butyrylcholinesterase
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Triterpenoic acids (oleanolic, ursolic, betulinic, platanic and glycyrrhetinic acid) were acetylated and coupled with 1,3- or 1,4-diazabicyclo[3.2.2]nonanes to yield amides. Reaction of these amides with methyl iodide at the distal nitrogen of the bicyclic system gave the corresponding quaternary ammonium salts. These compounds were shown to act as excellent inhibitors of the enzyme butyrylcholinesterase (BChE) while being only weak inhibitors for acetylcholinesterase (AChE). Evaluation of the enzyme kinetics revealed these compounds to act as hyperbolic inhibitors for BChE while the results from molecular modeling gave an explanation for their selectivity between AChE and BChE.
- Heise, Niels,Friedrich, Sander,Temml, Veronika,Schuster, Daniela,Siewert, Bianka,Csuk, René
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supporting information
(2021/11/08)
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- Discovery and radiosensitization research of ursolic acid derivatives as SENP1 inhibitors
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SUMOylation and deSUMOylation plays an important role in DNA damage response and the formation of radiotherapy resistance. SENP1 is the main specific isopeptidase to catalyze deSUMOylation modification. Inhibiting SENP1 upregulates cancer cell radiosensitivity and it becomes a promising target for radiosensitization. Herein, based on the structure of ursolic acid (UA), a total of 53 pentacyclic triterpene derivatives were designed and synthesized as SENP1 inhibitors. Ten derivatives exhibited better SENP1 inhibitory activities than UA and the preliminary structure-activity relationship was discussed. Most of the UA derivatives were low-cytotoxic, among which compound 36 showed the best radiosensitizing activity with the SER value of 1.45. It was the first study to develop small molecular SENP1 inhibitors as radiosensitizers.
- Wei, Huiqiang,Guo, Jianghong,Sun, Xiao,Gou, Wenfeng,Ning, Hongxin,Fang, Zhennan,Liu, Qiang,Hou, Wenbin,Li, Yiliang
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- Pentacyclic triterpenoid TGR5 receptor stimulant, preparation method and application thereof
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The invention discloses a pentacyclic triterpenoid TGR5 receptor stimulant, a preparation method and application of the pentacyclic triterpenoid TGR5 receptor stimulant. The structure of the pentacyclic triterpenoid TGR5 receptor stimulant is as shown in a formula I, and the definition of each substituent is as shown in the specification and claims. According to the pentacyclic triterpenoid compound, the solubility is increased, the permeability is improved, the TGR5 receptor agonist activity is remarkably improved, Caco-2 monolayer cells can be penetrated, and the in-vivo drug effect exertion of the compound after oral administration is guaranteed. The TGR5 receptor stimulant is expected to be further developed into a medicine for treating metabolic diseases represented by diabetes.
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Paragraph 0123; 0329; 0335; 0336-0337
(2021/04/26)
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- Design, Synthesis and Biological Activity of C3 Hemisynthetic Triterpenic Esters as Novel Antitrypanosomal Hits
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Research for innovative drugs is crucial to contribute to parasitic infections control and eradication. Inspired by natural antiprotozoal triterpenes, a library of 12 hemisynthetic 3-O-arylalkyl esters was derived from ursolic and oleanolic acids through one-step synthesis. Compounds were tested on Trypanosoma, Leishmania and the WI38 cell line alongside with a set of triterpenic acids. Results showed that the triterpenic C3 esterification keeps the antitrypanosomal activity (IC50≈1.6–5.5 μm) while reducing the cytotoxicity compared to parent acids. Unsaturation of the ester alkyl chain leads to an activity loss interestingly kept when a sterically hindered group replaces the double bond or shields the ester group. An ursane/oleanane C3 hydroxylation was the only important feature for antileishmanial activity. Two candidates, dihydrocinnamoyl and 2-fluorophenylpropionyl ursolic acids, were tested on an acute mouse model of African trypanosomiasis with significant parasitemia reduction at day 5 post-infection for the dihydrocinnamoyl derivative. Further evaluation on other alkyl/protective groups should be investigated both in vitro and in vivo.
- Beaufay, Claire,Bonneau, Natacha,Girardi, Cynthia,Leverrier, Aurélie,Ortiz, Sergio,Palermo, Jorge,Poupaert, Jacques H.,Quetin-Leclercq, Jo?lle,Sanchez, Marianela,Schioppa, Laura
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p. 896 - 903
(2021/09/28)
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- MSBA-S – A pentacyclic sulfamate as a new option for radiotherapy of human breast cancer cells
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Many pentacyclic triterpenoids show anti-cancer and anti-inflammatory properties. Recently, we detected a pronounced cytotoxicity and radiosensitivity of two betulinyl sulfamates in human breast cancer cells. Besides betulinic acid scaffold (BSBA-S), we synthesized several new sulfamate-coupled scaffolds from oleanolic acid (OSBA-S), ursolic acid (USBA-S), platanic acid (PSBA-S) and maslinic acid (MSBA-S). Highest cytotoxicity was monitored in breast cancer cell lines after MSBA-S treatment showing in SRB assays IC50 values between 3.7 μM and 5.8 μM. Other sulfamate/triterpene conjugates, however, were less cytotoxic holding IC50 values between 6.6 μM and >50 μM, respectively. MSBA-S-treated breast cancer cells displayed significantly reduced clonogenic survival and an increased rate of apoptosis as compared to the other conjugates. In addition, MSBA-S in combination with irradiation resulted in effects on radiosensitivity in MDA-MB-231 cells (DMF10 = 1.14). In particular, ROS formation was strongly assessed in MSBA-S-treated breast cancer cells. Our findings suggest that the sulfamate derivative of maslinic acid MSBA-S might be a new option for the radiation therapy in breast cancer cells.
- Bache, Matthias,Eiselt, Yvonne,Funtan, Anne,Kahnt, Michael,Paschke, Reinhard,Petrenko, Marina,Serbian, Immo,Vordermark, Dirk,Csuk, René,Güttler, Antje,Ke?ler, Jacqueline,Pflüger, Elena
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- Cytotoxic triterpenoid–safirinium conjugates target the endoplasmic reticulum
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Safirinium P and Q fluorescence labels were synthesized and conjugated with spacered triterpenoic acids to access hybrid structures. While the parent safirinium compounds were not cytotoxic at all, many triterpenoid safirinium P and Q conjugates showed moderate cytotoxicity. An exception, however, was safirinium P derived compound 30 holding low EC50 = 5.4 μM (for A375 cells) to EC50 = 7.5 μM (for FaDu cells) as well as EC50 = 6.6 μM for non-malignant fibroblasts NIH 3T3. Fluorescence imaging showed that the safirinium core structures cannot enter the cells (not even after a prolonged incubation time of 24 h), while the conjugates (as exemplified for 30) are accumulating in the endoplasmic reticulum but not in the mitochondria. The development of safirinium–hybrids targeting the endoplasmic reticulum can be regarded as a promising strategy in the development of cytotoxic agents.
- Kraft, Oliver,Kozubek, Marie,Hoenke, Sophie,Serbian, Immo,Major, Daniel,Csuk, René
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- COMPOSITIONS AND METHODS FOR TREATMENT OF PLATINUM-BASED CHEMOTHERAPEUTIC RESISTANT TUMORS
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Embodiments of the instant disclosure relate to novel methods and compositions for treating tumors resistant to platinum-based chemotherapy. In certain embodiments, methods of treating tumors herein can include administering an effective amount of at least one ursolic acid derivative. In certain embodiments, methods of treating tumors herein can include administering an effective amount of at least one ursolic acid derivative in combination with at least one platinum-based chemotherapeutic separately or in a combination therapy. In some embodiments, methods of treating tumors disclosed herein can include screening and/or selecting a subject suitable for treatment on the basis of SENP1 tumor expression. In other embodiments, methods of treating tumors can include administering a composition disclosed herein to a subject, the composition having a combination of at least one ursolic acid derivative and at least one platinum-based chemotherapeutic.
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Paragraph 0114-0116
(2021/09/11)
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- The presence of a cyclohexyldiamine moiety confers cytotoxicity to pentacyclic triterpenoids
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Pentacyclic triterpenoids oleanolic acid, ursolic acid, betulinic acid, and platanic acid were acetylated and converted into several amides 9–31; the cytotoxicity of which has been determined in sulforhodamine B assays employing seral human tumor cell lines and nonmalignant fibrob-lasts. Thereby, a betulinic acid/trans-1,4-cyclohexyldiamine amide showed excellent cytotoxicity (for example, EC50 = 0.6 μM for HT29 colon adenocarcinoma cells).
- Al-Harrasi, Ahmed,Brandes, Benjamin,Christoph, Martin A.,Csuk, René,Deigner, Hans-Peter,Friedrich, Sander,Heise, Niels,Hoenke, Sophie
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- Antimicrobial properties of amine- and guanidine-functionalized derivatives of betulinic, ursolic and oleanolic acids: Synthesis and structure/activity evaluation
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A series of 34 new amine- and guanidine-functionalized derivatives of betulinic, ursolic, and oleanolic acids were synthesized and tested for their antimicrobial activity against the growth of four bacterial strains (Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus (MRSA)) and two fungal strains (Candida albicans and Cryptococcus neoformans). The obtained compounds were also tested for the cytotoxic effect against HEK293 human embryonic kidney cell line and hemolytic activity against human red blood cells. Most of the prepared amino and guanidinium derivatives of betulinic, ursolic, and oleanolic acids showed a considerably higher bacteriostatic activity against methicillin-resistant S. aureus than the parent compounds. The most active compounds (MICs ≤ 0.25 μg/ml or 0.4–0.5 μM) were superior over the clinically used antibiotic vancomycin in the antibacterial effect (MIC of 1 μg/ml or 0.7 μM). Apart from antibacterial activity, new triterpene acid derivatives exhibited excellent antifungal activity against Cryptococcus neoformans, with MICs values being as low as 0.25 μg/ml (0.4 μM), and were approximately 65 times as active as fluconazole, a known antifungal agent. Four most promising compounds we identified (7, 13, 24, and 33) showed not only high bacteriostatic effect, but also low cytotoxicity against mammalian HEK293 cells and high hemolytic selectivity.
- Spivak, Anna Yu.,Khalitova, Rezeda R.,Nedopekina, Darya A.,Gubaidullin, Rinat R.
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- Acetoxyl ursolic acid piperazine compound containing isopropanolamine substructure, and preparation method and application of acetoxyl ursolic acid piperazine compound
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The invention relates to an acetoxyl ursolic acid piperazine compound containing an isopropanolamine substructure, and a preparation method and application of the acetoxyl ursolic acid piperazine compound. The compound has a structure disclosed in a following general formula (I): an ursolic acid compound is taken as a basis, a nitrogen-containing fragment is introduced into the system to synthesize one series of 3[beta]-acetoxyl ursolic acid-28-piperazine compound containing the isopropanolamine substructure, and the compound has a good inhibition effect on plant pathogenic bacteria, includingxanthomonas oryzaepv. oryzae, xanthomonas axonopodis pv. Citri and the like.
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Paragraph 0054-0055
(2020/02/29)
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- The presence of a cationic center is not alone decisive for the cytotoxicity of triterpene carboxylic acid amides
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3-O-Acetyl-ursolic acid (2) and 3-O-acetyl oleanolic acid (8) were converted into piperazinylamides holding a distal NH, NMe or a NMe2 group. These compounds as well as the corresponding N-methyl-N-oxides were accessed. Their cytotoxicity was assessed in SRB assays employing a panel of human tumor cell lines and non-malignant fibroblasts (NIH 3T3). As a result, compounds holding a quaternary distal N-substituent were less cytotoxic that those holding a NH-moiety. Hence, the presence of a distal cationic center seems not to be a sufficient criterion for obtaining triterpenoids of high cytotoxicity and selectivity.
- Brandes, Benjamin,Deigner, Hans-Peter,Hoenke, Sophie,Koch, Lukas,Csuk, René
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- Synthesis and cytotoxic evaluation of malachite green derived oleanolic and ursolic acid piperazineamides
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The coupling of acetylated piperazinylamide spacered triterpenoic oleanolic acid and ursolic acid with meta or para substituted carboxylated malachite green analogs gave conjugates 10, 11, 15, and 16 that were cytotoxic for several human tumor cell lines. Especially, an oleanolic acid-derived compound 10 was cytotoxic for MCF-7 human breast carcinoma cells (EC50 = 0.7 μM). These derivatives represent first examples of triterpenoic acid derivatives holding a cationic scaffold derived from malachite green. [Figure not available: see fulltext.]
- Csuk, René,Friedrich, Sander,Hoenke, Sophie,Serbian, Immo,Wolfram, Ratna Kancana
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p. 926 - 933
(2020/04/23)
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- Spermine amides of selected triterpenoid acids: Dynamic supramolecular system formation influences the cytotoxicity of the drugs
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Cancer is a global disease of great importance, and the need for novel cytotoxic drugs is still eminent. A series of spermine amides of several selected triterpene acids (betulonic, heterobetulonic, oleanolic, ursolic and platanic acid) have been synthesized to search for new cytotoxic and antimicrobial agents. The compounds have also been subjected to the investigation of their physico-chemical characteristics (ability to self-assemble), and to an in silico comparative calculation of their physico-chemical and ADME parameters. In the in vitro screening tests with several target compounds (8a-8c and 11c), their cytotoxicity changed with prolonged time, which appeared to be a result of formation of dynamic supramolecular networks. This phenomenon is important in investigation of the effect of self-assembly on biological activity. The most important compounds in this series were spermine derivatives of heterobetulonic acid (3b) and ursolic acid (8b), showing cytotoxicity 5 μM and 10 μM, respectively, on all tested cancer cell lines. Comparable cytotoxicity was also displayed by 13b, formerly a model compound prepared for testing of the synthetic procedures, the 1,2-diaminoethane derivative. The target compounds 3b and 8b displayed antimicrobial activity on Staphylococcus aureus, Streptococcus mutans and Listeria monocytogenes at a concentration 6.25 μM. Supramolecular characteristics of several compounds were documented by the TEM and SEM micrographs showing fibrous, partially helical, networks, and UV measurements showing changes in the intensity of UV signals, also indicating formation of supramolecular systems.
- Bildziukevich, Uladzimir,Malík, Matěj,?zdemir, Zulal,Rárová, Lucie,Janovská, Lucie,?louf, Miroslav,?aman, David,?arek, Jan,Nonappa,Wimmer, Zdeněk
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p. 484 - 491
(2020/02/04)
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- Triterpene-based carboxamides act as good inhibitors of butyrylcholinesterase
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A set of overall 40 carboxamides was prepared from five different natural occurring triterpenoids including oleanolic, ursolic, maslinic, betulinic, and platanic acid. All of which were derived from ethylene diamine holding an additional substituent connected to the ethylene diamine group. These derivatives were evaluated regarding their inhibitory activity of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) employing Ellman’s assay. We further determined the type of inhibition and inhibition constants. Carboxamides derived from platanic acid have been shown to be potent and selective BChE inhibitors. Especially the mixed-type inhibitor (3β)-N-(2-pyrrolidin-1-ylethyl)-3-acetyloxy-20-oxo-30-norlupan-28-amide (35) showed a remarkably low Ki of 0.07 ± 0.01 μM (Ki0 = 2.38 ± 0.48 μM) for the inhibition of BChE.
- Loesche, Anne,Kahnt, Michael,Serbian, Immo,Brandt, Wolfgang,Csuk, René
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- With anti-tumor activity of ursolic acid derivative and its preparation method
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The invention discloses an ursolic acid derivative with antitumor activity and a preparation method and application thereof. A series of ursolic acid derivatives with antitumor activity is synthesized. An in-vitro pharmacological test shows that the ursolic acid derivative synthesized in the invention has remarkable antiproliferative activity on Hela and MNK45 tumor cells, and has wide application in preparing an antitumor drug.
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Paragraph 0037-0039
(2019/05/08)
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- Synthesis and cytotoxicity evaluation of DOTA-conjugates of ursolic acid
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In this study, we report the synthesis of several amine-spacered conjugates of ursolic acid (UA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Thus, a total of 11 UA-DOTA conjugates were prepared holding various oligo-methylene diamine spacers as well as different substituents at the acetate units of DOTA including tert-butyl, benzyl, and allyl esters. Furthermore, three synthetic approaches were compared for the ethylenediamine-spacered conjugate 29 regarding reaction steps, yields, and precursor availability. The prepared conjugates were investigated regarding cytotoxicity using SRB assays and a set of human tumor cell lines. The highest cytotoxicity was observed for piperazinyl spacered compound 22. Thereby, EC50 values of 1.5 μM (for A375 melanoma) and 1.7 μM (for A2780 ovarian carcinoma) were determined. Conjugates 22 and 24 were selected for further cytotoxicity investigations including fluorescence microscopy, annexin V assays and cell cycle analysis.
- Kahnt, Michael,Hoenke, Sophie,Fischer, Lucie,Al-Harrasi, Ahmed,Csuk, René
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- Inhibitor for specific deSUMOylation protease 1 and preparation method and application thereof
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The invention discloses a novel inhibitor, as shown in a formula I, for the specific deSUMOylation protease 1 (SENP1) and a preparation method and application thereof. The inhibitor improves the sensitivity of tumor cells to irradiation by inhibiting the activity of the SENP1 and is expected to become a novel sensitizing drug for tumor radiotherapy.
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Paragraph 0101-0103
(2020/01/12)
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- Design, synthesis, and biological evaluation of novel nitrogen heterocycle-containing ursolic acid analogs as antitumor agents
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Nineteen ursolic acid analogues were designed, synthesized, and evaluated for their antiproliferative activity against the Hela and MKN45 cell lines. Some compounds containing a piperazine moiety displayed moderate to high levels of antitumor activities against the tested cancer cell lines. The most potent compound shares the IC50 value of 2.1 μM and 2.6 μM for the Hela and MKN45 cell lines, respectively. Further mechanism studies and in vivo antitumor studies have shown that it decreased the apoptosis regulator (BCL2/BAX) ratio, disrupted mitochondrial potential and induced apoptosis, and suppressed the growth of Hela xenografts in nude mice.
- Wang, Wenzhi,Lei, Lei,Liu, Zhi,Wang, Hongbo,Meng, Qingguo
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- Ursolic Acid Isolated from the Leaves of Loquat (Eriobotrya japonica) Inhibited Osteoclast Differentiation through Targeting Exportin 5
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One of the conventional strategies for treating osteoporosis is to eliminate the multinucleated osteoclasts that are responsible for bone resorption. Our previous study revealed that ursolic acid, isolated from leaves of loquat that is used as tasty tea in Japan, suppressed osteoclastogenesis. We confirmed that ursolic acid exhibited osteoclast differentiation inhibitory activity with an 50% inhibitory concentration (IC50) value of 5.4 ± 0.96 μM. To disclose its mechanism of action, this study first uses polymer-coated magnetic nanobeads to identify potential target proteins. As a result, we identified a nuclear exporter protein named exportin 5 (XPO5). Further studies demonstrated that knockdown of XPO5 significantly blocks osteoclast differentiation (P 0.01). Expression profiling of mature microRNAs in the cells revealed that downregulation of XPO5 by small interfering RNA or by ursolic acid could downregulate the expression of mature microRNA let-7g-5p during osteoclast differentiation (P 0.01). Collectively, our findings suggest that ursolic acid inhibits osteoclast differentiation through targeting XPO5, which provides further evidence for the healthy function of the tea. This study also provides new insights into the role of XPO5 and its mediated microRNAs in treatment for bone resorption diseases.
- Tan, Hui,Zhao, Chong,Zhu, Qinchang,Katakura, Yoshinori,Tanaka, Hiroyuki,Ohnuki, Koichiro,Shimizu, Kuniyoshi
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- Ursolic Acid Isolated from the Leaves of Loquat (Eriobotrya japonica) Inhibited Osteoclast Differentiation through Targeting Exportin 5
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One of the conventional strategies for treating osteoporosis is to eliminate the multinucleated osteoclasts that are responsible for bone resorption. Our previous study revealed that ursolic acid, isolated from leaves of loquat that is used as tasty tea in Japan, suppressed osteoclastogenesis. We confirmed that ursolic acid exhibited osteoclast differentiation inhibitory activity with an 50% inhibitory concentration (IC50) value of 5.4 ± 0.96 μM. To disclose its mechanism of action, this study first uses polymer-coated magnetic nanobeads to identify potential target proteins. As a result, we identified a nuclear exporter protein named exportin 5 (XPO5). Further studies demonstrated that knockdown of XPO5 significantly blocks osteoclast differentiation (P 0.01). Expression profiling of mature microRNAs in the cells revealed that downregulation of XPO5 by small interfering RNA or by ursolic acid could downregulate the expression of mature microRNA let-7g-5p during osteoclast differentiation (P 0.01). Collectively, our findings suggest that ursolic acid inhibits osteoclast differentiation through targeting XPO5, which provides further evidence for the healthy function of the tea. This study also provides new insights into the role of XPO5 and its mediated microRNAs in treatment for bone resorption diseases.
- Tan, Hui,Zhao, Chong,Zhu, Qinchang,Katakura, Yoshinori,Tanaka, Hiroyuki,Ohnuki, Koichiro,Shimizu, Kuniyoshi
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p. 3333 - 3340
(2019/04/03)
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- Synthesis and evaluation of the HIF-1α inhibitory activities of novel ursolic acid tetrazole derivatives
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The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of cancers. Here, we designed and synthesized 31 ursolic acid (UA) derivatives containing a tetrazole moiety and evaluated them for their potential anti-tumor activities as HIF-1α transcriptional inhibitors. Of these, compound 14d (IC50 0.8 ± 0.2 μM) displayed the most potent activity and compounds 14a (IC50 4.7 ± 0.2 μM) exhibited the most promising biological profile. Analysis of the structure–activity relationships of these compounds with HIF-1α suggested that the presence of a tetrazole group located at C-28 of the UA derivatives was critical for their inhibitory activities.
- Zhang, Lin-Hao,Zhang, Zhi-Hong,Li, Ming-Yue,Wei, Zhi-Yu,Jin, Xue-Jun,Piao, Hu-Ri
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supporting information
p. 1440 - 1445
(2019/04/25)
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- Cytotoxicity of oleanolic and ursolic acid derivatives toward hepatocellular carcinoma and evaluation of NF-κB involvement
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Oleanolic and ursolic acids are two ubiquitous isomeric triterpene phytochemicals known for their anticancer activity. A set of derivatives of the two compounds with a modified oxidation state and lipophylicity at C-3 and C-28 positions, were prepared and tested as anticancer agents versus the lines HepG2, Hep3B and HA22T/VGH of hepatocarcinoma, a strongly aggressive tumor that is not responsive toward the standard therapies. New derivatives containing a three carbons side chain on the C-3 position were synthetized in both stereoisomeric forms by the Barbier-Grignard procedure and three of them were found to be active toward all of the three targets. The implication of the transcriptional nuclear factor NF?κB in the mechanism of action was assessed for the more active compounds in the set, as hepatocellular carcinoma (HCC) cyto-types are known to overexpress NF?κB.
- Fontana, Gianfranco,Bruno, Maurizio,Notarbartolo, Monica,Labbozzetta, Manuela,Poma, Paola,Spinella, Alberto,Rosselli, Sergio
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- Ursolic acid derivatives as potential agents against acanthamoeba Spp
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The current chemotherapy of Acanthamoeba keratitis relies on few drugs with low potential and limited efficacy, for all this there is an urgent need to identify new classes of anti-Acanthamoeba agents. In this regard, natural products play an important role in overcoming the current need and medicinal chemistry of natural products represents an attractive approach for the discovery and development of new agents. Ursolic acid, a natural pentacyclic triterpenoid compound, possesses a broad spectrum of activities including anti-Acanthamoeba. Herein, we report on the development by chemical transformation of an ursolic acid-based series of seven compounds (2-8), one of them reported for the first time. The structure-activity relationship (SAR) analysis of their anti-Acanthamoeba activity revealed that acylation/ether formation or oxidation enhances their biological profile, suggesting that the hydrophobic moiety contributes to activity, presumably by increasing the affinity and/or cell membrane permeability. These ursolic acid derivatives highlight the potential of this source as a good base for the development of novel therapeutic agents against Acanthamoeba infections.
- Sifaoui, Ines,Rodríguez-Expósito, Rubén L.,Reyes-Batlle, María,Rizo-Liendo, Aitor,Pi?ero, José E.,Bazzocchi, Isabel L.,Lorenzo-Morales, Jacob,Jiménez, Ignacio A.
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- Targeting mitochondria: Esters of rhodamine B with triterpenoids are mitocanic triggers of apoptosis
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Triterpenoic acids, ursolic acid (1), oleanolic acid (2), glycyrrhetinic acid (3) and betulinic acid (4) were converted into their corresponding methyl 5–8 and benzyl esters 9–12 or benzyl amides 21–24. These derivatives served as starting materials for the synthesis of pink colored rhodamine B derivatives 25–36 which were screened for cytotoxicity in colorimetric SRB assays. All of the compounds were cytotoxic for a variety of human tumor cell lines. The activity of the benzyl ester derivatives 29–32 was lower than the cytotoxicity of the methyl esters 25–28. The benzyl amides 33–36 were the most cytotoxic compounds of this series. The most potential compound was a glycyrrhetinic acid rhodamine B benzyl amide 35. This compound showed activity against the different cancer cell lines in a two-digit to low three-digit nano-molar range. Staining experiments combined with fluorescence microscopy showed that this compound triggered apoptosis in A2780 ovarian carcinoma cells and acted as a mitocan.
- Wolfram, Ratna Kancana,Heller, Lucie,Csuk, René
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supporting information
p. 21 - 30
(2018/04/26)
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- Ursolic acid derivatives as potential antidiabetic agents: In vitro, in vivo, and in silico studies
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(Table presented.). Protein tyrosine phosphatase 1B (PTP-1B) has attracted interest as a novel target for the treatment of type 2 diabetes, this because its role in the insulin-signaling pathway as a negative regulator. Thus, the aim of current work was to obtain seven ursolic acid derivatives as potential antidiabetic agents with PTP-1B inhibition as main mechanism of action. Furthermore, derivatives 1–7 were submitted in vitro to enzymatic PTP-1B inhibition being 3, 5, and 7 the most active compounds (IC50?=?5.6, 4.7, and 4.6?μM, respectively). In addition, results were corroborated with in silico docking studies with PTP-1B orthosteric site A and extended binding site B, showed that 3 had polar and Van der Waals interactions in both sites with Lys120, Tyr46, Ser216, Ala217, Ile219, Asp181, Phe182, Gln262, Val49, Met258, and Gly259, showing a docking score value of ?7.48?Kcal/mol, being more specific for site A. Moreover, compound 7 showed polar interaction with Gln262 and Van der Waals interactions with Ala217, Phe182, Ile219, Arg45, Tyr46, Arg47, Asp48, and Val49 with a predictive docking score of ?6.43?kcal/mol, suggesting that the potential binding site could be localized in the site B adjacent to the catalytic site A. Finally, derivatives 2 and 7 (50?mg/kg) were selected to establish their in vivo antidiabetic effect using a noninsulin-dependent diabetes mice model, showing significant blood glucose lowering compared with control group (p?.05).
- Guzmán-ávila, Ricardo,Flores-Morales, Virginia,Paoli, Paolo,Camici, Guido,Ramírez-Espinosa, Juan José,Cerón-Romero, Litzia,Navarrete-Vázquez, Gabriel,Hidalgo-Figueroa, Sergio,Yolanda Rios, Maria,Villalobos-Molina, Rafael,Estrada-Soto, Samuel
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- Ethylenediamine derived carboxamides of betulinic and ursolic acid as potential cytotoxic agents
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Two easily accessible, natural occurring triterpenoids, betulinic and ursolic acid, were used as starting materials for the synthesis of novel cytotoxic agents. A set of 28 ethylenediamine-spacered carboxamides was prepared holding an additional substituent connected to the ethylenediamine group. The compounds were screened in SRB assays to evaluate their cytotoxic activity employing several human tumor cell lines. Betulinic acid-derived carboxamides 17-30 showed significantly higher cytotoxicity than their ursolic acid analogs 3-16. In particular, compounds 25 and 26 were highly cytotoxic, as indicated by EC50 values lower than 1 μM.
- Kahnt, Michael,Heller, Lucie Fischer Née,Al-Harrasi, Ahmed,Csuk, René
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- Homopiperazine-rhodamine B adducts of triterpenoic acids are strong mitocans
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Parent pentacyclic triterpenoic acids such as ursolic-, oleanolic, glycyrrhetinic, betulinic and boswellic acid were converted into their acetylated piperazinyl amides that were coupled with rhodamine B. SRB assays to evaluate their cytotoxicity showed all of these triterpene-homopiperazinyl-rhodamine adducts 16–20 being highly cytotoxic for a panel of human tumor cell lines even in nanomolar concentrations while being significantly less cytotoxic for non-malignant cells. Interestingly enough, these compounds were even more cytotoxic than previously prepared piperazinyl analogs, thus making the homopiperazinyl spacer a very interesting scaffold for the development of biologically active compounds. Extra staining experiments showed that the cytostatic effect of compounds 18 and 20 onto A2780 cancer cells is due to their ability to act as a mitocan.
- Wolfram, Ratna Kancana,Fischer, Lucie,Kluge, Ralph,Str?hl, Dieter,Al-Harrasi, Ahmed,Csuk, René
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p. 869 - 879
(2018/07/03)
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- Semisynthesis, cytotoxicity, antimalarial evaluation and structure-activity relationship of two series of triterpene derivatives
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In this report, we describe the semisynthesis of two series of ursolic and betulinic acid derivatives through designed by modifications at the C-3 and C-28 positions and demonstrate their antimalarial activity against chloroquine-resistant P. falciparum (W2 strain). Structural modifications at C-3 were more advantageous to antimalarial activity than simultaneous modifications at C-3 and C-28 positions. The ester derivative, 3β-butanoyl betulinic acid (7b), was the most active compound (IC50 = 3.4 μM) and it did not exhibit cytotoxicity against VERO nor HepG2 cells (CC50 > 400 μM), showing selectivity towards parasites (selectivity index > 117.47). In combination with artemisinin, compound 7b showed an additive effect (CI = 1.14). While docking analysis showed a possible interaction of 7b with the Plasmodium protease PfSUB1, with an optimum binding affinity of ?7.02 kcal/mol, the rather low inhibition displayed on a Bacillus licheniformis subtilisin A protease activity assay (IC50 = 93 μM) and the observed accumulation of ring forms together with a delay of appearance of trophozoites in vitro suggests that the main target of 3β-butanoyl betulinic acid on Plasmodium may be related to other molecules and processes pertaining to the ring stage. Therefore, compound 7b is the most promising compound for further studies on antimalarial chemotherapy. The results obtained in this study provide suitable information about scaffolds to develop novel antimalarials from natural sources.
- Cargnin, Simone Tasca,Staudt, Andressa Finkler,Medeiros, Patrícia,de Medeiros Sol Sol, Daniel,de Azevedo dos Santos, Ana Paula,Zanchi, Fernando Berton,Gosmann, Grace,Puyet, Antonio,Garcia Teles, Carolina Bioni,Gnoatto, Simone Baggio
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supporting information
p. 265 - 272
(2018/02/15)
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- Discovery of antitumor ursolic acid long-chain diamine derivatives as potent inhibitors of NF-κB
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A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing long-chain diamine moieties were designed and synthesized as well as evaluated the antitumor effects. These compounds exhibited significant inhibitory activity to the NF-κB with IC50 values at micromolar concentrations in A549 lung cancer cell line. Among them, compound 8c exerted potent activity against the test tumor cell lines including multidrug resistant human cancer lines, with the IC50 values ranged from 5.22 to 8.95 μM. Moreover, compound 8c successfully suppressed the migration of A549 cells. Related mechanism study indicated compound 8c caused cell cycle arrest at G1 phase and triggered apoptosis in A549 cells through blockage of NF-κB signalling pathway. Molecular docking study revealed that key interactions between 8c and the active site of NF-κB in which the bulky and strongly electrophilic group of long-chain diamine moieties were important for improving activity.
- Jiang, Wei,Huang, Ri-Zhen,Zhang, Jing,Guo, Tong,Zhang, Meng-Ting,Huang, Xiao-Chao,Zhang, Bin,Liao, Zhi-Xin,Sun, Jing,Wang, Heng-Shan
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p. 265 - 276
(2018/05/24)
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- Synthesis of three triterpene series and their activity against respiratory syncytial virus
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The human respiratory syncytial virus (hRSV) is a leading cause of hospitalization due to acute lower respiratory infection especially in infants and young children, sometimes causing fatal cases. The monoclonal antibody palivizumab is one of the available options for preventing this virus, and at the moment there are several hRSV vaccine trials underway. Unfortunately, the only drug option to treat hRSV infection is ribavirin, which can be used in severe high-risk cases. For this reason, new medicines are needed and, in this context, the triterpenes and their derivatives are promising alternatives, since many of them have shown important antiviral activity, such as bevirimat. Therefore, we report three series of triterpene (betulin (BE), betulinic acid (BA), and ursolic acid (UA)) derivatives tested against hRSV. The derivatives were synthesized by using commercial anhydrides in an easy and inexpensive step reaction. For the antiviral assay, A549 cells were infected by hRSV and after 96 h of compound or ribavirin (positive control) treatment, the cell viability was tested by MTT assay. DMSO, non-infected cells and infected cells without treatment were used as negative control. The triterpene esterification at the hydroxyl group resulted in 17 derivatives. The 3,28-di-O-acetylbetulin derivative (1a) showed the best results for cell viability, and real-time PCR amplification was performed for 1a treatment. Remarkably, one new anti-hRSV prototype was obtained through an easy synthesis of BE, which shall represent an alternative for a new lead compound for anti-hRSV therapy.
- Santos da Silva, Gloria N.,Monti Atik, Diana,Antunes Fernandes, Jheini L.,de Freitas do Nascimento, Deise,Fazolo, Tiago,Duarte de Souza, Ana Paula,Baggio Gnoatto, Simone C.
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- Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors
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Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular end-points with low to moderate affinity. To explore the biological space associated with PCTTAs, we have investigated the carboxylate-to-hydroxamate transformation, discovering that it de-emphasizes affinity for the transcription factors targeted by the natural compounds (NF-κB, STAT3, Nrf2, TGR5) and selectively induces inhibitory activity on HIF prolyl hydrolases (PHDs). Activity was reversible, isoform-selective, dependent on the hydroxamate location, and negligible when this group was replaced by other chelating elements or O-alkylated. The hydroxamate of betulinic acid (5b) was selected for further studies, and evaluation of its effect on HIF-1α expression under normal and hypoxic conditions qualified it as a promising lead structure for the discovery of new candidates in the realm of neuroprotection.
- Minassi, Alberto,Rogati, Federica,Cruz, Cristina,Prados, M. Eugenia,Galera, Nuria,Jinénez, Carla,Appendino, Giovanni,Bellido, M. Luz,Calzado, Marco A,Caprioglio, Diego,Mu?oz, Eduardo
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p. 2235 - 2243
(2018/10/20)
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- With anti-inflammatory activity of ursolic acid derivatives and its preparation and use (by machine translation)
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The invention discloses a has anti-inflammatory activity of ursolic acid derivative and its preparation method, use. The invention synthesizes a series has anti-inflammatory activity of ursolic acid derivatives. In-vitro pharmacological experiment shows that, in the Patent of synthetic ursolic acid derivatives has significant anti-inflammatory activity, anti-inflammatory drug in the preparation has wide application. (by machine translation)
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Paragraph 0032; 0034
(2017/09/05)
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- Rhodamine B conjugates of triterpenoic acids are cytotoxic mitocans even at nanomolar concentrations
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Triterpenoic acids 1–6 exhibited very low or no cytotoxicity at all, but their corresponding 2,3-di-O-acetyl-piperazinyl amides 13–18 showed low EC50values for several human tumor cell lines. Their cytotoxicity, however, was also high for the non-malignant mouse fibroblasts NIH 3T3. A significant improvement was achieved by preparing the rhodamine B derivatives 19–24. While rhodamine B is not cytotoxic (up to a concentration of 30μM – cut-off of the assay), the triterpenoid piperazine-spacered rhodamine B derivatives were cytotoxic in nano-molar concentration. Compound 24 (a diacetylated maslinic acid derivative) was most toxic for several human tumor cell lines but less toxic for mouse fibroblasts NIH 3T3. Staining and double-staining experiments revealed 24 to act as a mitocan.
- Sommerwerk, Sven,Heller, Lucie,Kerzig, Christoph,Kramell, Annemarie E.,Csuk, René
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- Synthesis of novel oleanolic acid and ursolic acid in C-28 position derivatives as potential anticancer agents
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A series of nitrogen-containing derivatives of oleanolic acid and ursolic acid were prepared by a modification at C-28 position via esterification with 2-hydroxyacetic acid followed by amidation with amines, such as piperazine, N-methylpiperazine, and alkane-1, 2-diamines, alkane-1, 4-diamines, alkane-1, 6-diamines. In vitro antiproliferative activities of the compounds prepared towards MCF-7, Hela and A549 cell lines were evaluated by a MTT method to show that OA-5a, OA-5b, OA-5c and UA-5a showed somewhat improved antiproliferative activities against MCF-7, Hela and A549 cells comparing to that of the positive control, gefitinib.
- Tian, Tian,Liu, Xinyu,Lee, Eung-Seok,Sun, Jingyang,Feng, Zhonghua,Zhao, Longxuan,Zhao, Chunhui
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p. 458 - 468
(2017/04/13)
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- Side chain-functionalized aniline-derived ursolic acid derivatives as multidrug resistance reversers that block the nuclear factor-kappa B (NF-κB) pathway and cell proliferation
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A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing functionalized aniline or amide side chains were synthesized and evaluated for inhibition of NF-κB as well as their antitumor effects. These compounds exhibited significant inhibition activity toward NF-κB with IC50 values at micromolar concentrations in the NCI-H460 lung adenocarcinoma cell line. A docking study of the most active compound 5Y8 revealed key interactions between 5Y8 and the active site of NF-κB in which the functionalized amide moiety at the C-28 position and an ester group at the C-3 position were important for improving the activity. In particular, compound 5Y8 appeared to be the most potent compound against the NCI-H460 cell line, and displayed similar efficiency in drug-sensitive versus drug-resistant cancer cell lines, at least partly, by blocking the NF-κB signaling pathway and inducing apoptosis. Mechanistically, compound 5Y8 might trigger the apoptotic signaling pathway. Thus, the rational design of UA derivatives with functionalized aniline or amide side chains offers significant potential for the discovery of a new class of NF-κB inhibitors with the ability to induce apoptosis and reverse multidrug resistance in the NCI-H460 lung adenocarcinoma cell line.
- Huang, Ri-Zhen,Hua, Shi-Xian,Liao, Zhi-Xin,Huang, Xiao-Chao,Wang, Heng-Shan
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p. 1421 - 1434
(2017/07/25)
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- Modulators of ROR-gamma Receptors, Composition and Use Thereof
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The present invention provides novel methods to treat disease by modulating retinoid-related orphan receptor gamma (ROR-gamma) in vitro and in vivo with ursolic acid analogs, and compositions thereof. The methods and compounds disclosed herein are useful for inhibiting the differentiation of a population of T cells, or treating a disease related to Th17 cell responses in a subject. Examples of such diseases include, but are not limited to, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, psoriasis and diabetes.
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Paragraph 0149; 0150; 0153; 0154
(2017/11/07)
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- Hyaluronidase inhibitory activity of pentacylic triterpenoids from prismatomeris tetrandra (Roxb.) K. schum: Isolation, synthesis and QSAR Study
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The mammalian hyaluronidase degrades hyaluronic acid by the cleavage of the β-1,4-glycosidic bond furnishing a tetrasaccharide molecule as the main product which is a highly angiogenic and potent inducer of inflammatory cytokines. Ursolic acid 1, isolated from Prismatomeris tetrandra, was identified as having the potential to develop inhibitors of hyaluronidase. A series of ursolic acid analogues were either synthesized via structure modification of ursolic acid 1 or commercially obtained. The evaluation of the inhibitory activity of these compounds on the hyaluronidase enzyme was conducted. Several structural, topological and quantum chemical descriptors for these compounds were calculated using semi empirical quantum chemical methods. A quantitative structure activity relationship study (QSAR) was performed to correlate these descriptors with the hyaluronidase inhibitory activity. The statistical characteristics provided by the best multi linear model (BML) (R2 = 0.9717, R2cv = 0.9506) indicated satisfactory stability and predictive ability of the developed model. The in silico molecular docking study which was used to determine the binding interactions revealed that the ursolic acid analog 22 had a strong affinity towards human hyaluronidase.
- Abdullah, Nor Hayati,Thomas, Noel Francis,Sivasothy, Yasodha,Lee, Vannajan Sanghiran,Liew, Sook Yee,Noorbatcha, Ibrahim Ali,Awang, Khalijah
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- Targeting cancer cells with oleanolic and ursolic acid derived hydroxamates
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Oleanolic and ursolic acid derived hydroxamates were easily obtained from their parent compounds; they were screened for their cytotoxicity applying SRB assays employing several human tumor cell lines. Low EC50values were determined for compounds in which the nitrogen as well as the oxygen in the hydroxamic acid part still holds acidic hydrogens. Thus, ursolic acid derived compounds having at least an OH and/or NH moiety in the hydroxamate part of the molecule showed good cytotoxicity but they are significantly less selective for the tumor cells than oleanolic acid derived compounds. Good results were determined for oleanolic acid derived 7 for tumor cell lines 518A2 (melanoma, EC50= 3.3 μM), A2780 (ovarian carcinoma, EC50= 3.4 μM) and HT29 (colon adenocarcinoma, EC50= 5.6 μM) while being significantly less cytotoxic for fibroblasts (EC50= 20.4 μM).
- Wiemann, Jana,Heller, Lucie,Csuk, René
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supporting information
p. 907 - 909
(2016/05/24)
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- Selective killing of cancer cells with triterpenoic acid amides - The substantial role of an aromatic moiety alignment
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2,3-Di-O-acetyl-triterpenoic acid derived amides possessing a (2β, 3β) configuration in ring A and two acetyl groups were previously shown to possess high cytotoxicity for human tumor cell lines but to exhibit low cytotoxicity for non-malignant mouse fibroblasts. In this study, augustic acid (1) and 2-epi-corosolic acid (2) were chosen as starting points for the synthesis of analogs. While augustic acid derived 3-quinolinyl amide 9 gave low EC50values in SRB assays but was cytotoxic for all lines, the isomeric 4-isoquinolinyl amide 21 was very cytotoxic for the tumor cell lines but significantly less cytotoxic for the mouse fibroblasts NIH 3T3. In addition, a triacetylated 4-isoquinolinyl derivative of asiatic acid (28) gave EC50?=?80?nM (for A2780 ovarian cancer cells). As shown by additional experiments (acridine orange/propidium iodide staining, fluorescence spectroscopy and cell cycle investigations) these compounds act mainly by apoptosis.
- Sommerwerk, Sven,Heller, Lucie,Kuhfs, Julia,Csuk, René
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p. 452 - 464
(2016/07/15)
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- Polishing wusu acidifies ornament and its preparation method and application
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The invention discloses chemically modified ursolic acid and its preparation method and use. The chemically modified ursolic acid has a structural formula shown in the following formula, and in the formula, R1 represents acyloxy and R2 represents an amino group. The preparation method comprises the following steps that ursolic acid and acid anhydride undergo a reaction under the catalyst condition to produce 3 beta-acyloxy-ursane-12-ene-28-carboxylic acid compounds 2-5, the compounds 2-5 are acylated by oxalyl chloride under the ice bath condition to form 3-acetoxy-ursane-12-ene-28-acyl chloride, and the 3-acetoxy-ursane-12-ene-28-acyl chloride and aniline undergo a reaction under the acid binding agent condition to produce N-(3 beta-acyloxy-ursane-12-ene-28-acyl)-amine compound. The N-(3 beta-acyloxy-ursane-12-ene-28-acyl)-amine compound has enzymatic activity inhibition effects, can be used in drugs, drinks, foods and health products for preventing, controlling or treating high-blood sugar level diabetes or obesity and belongs to the technical field of drug synthesis.
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Paragraph 0048; 0049
(2017/01/23)
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- Novel pH-sensitive polysialic acid based polymeric micelles for triggered intracellular release of hydrophobic drug
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Polysialic acid (PSA), a non-immunogenic and biodegradable natural polymer, is prone to hydrolysis under endo-lysosomal pH conditions. Here, we synthesized an intracellular pH-sensitive polysialic acid-ursolic acid conjugate by a condensation reaction. To further test the drug loading capability, we prepared paclitaxel-loaded polysialic acid-based amphiphilic copolymer micelle (PTX-loaded-PSAU) by a nanoprecipitation method. Results showed PTX-loaded-PSAU exhibited well-defined spherical shape and homogeneous distribution. The drug-loading was 4.5% with an entrapment efficiency of 67.5%. PTX released from PTX-loaded-PSAU was 15% and 42% in 72 h under simulated physiological condition (pH 7.4) and mild acidic conditions (pH 5.0), respectively. In addition, In vitro cytotoxicity assay showed that PTX-loaded-PSAU retained anti-tumor (SGC-7901) activity with a cell viability of 53.8% following 72 h incubation, indicating PTX-loaded-PSAU could efficiently release PTX into the tumor cells. These results indicated that the pH-responsive biodegradable PTX-loaded-PSAU possess superior extracellular stability and intracellular drug release ability.
- Zhang, Wuxia,Dong, Dongqi,Li, Peng,Wang, Dongdong,Mu, Haibo,Niu, Hong,Duan, Jinyou
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- Discovery of ursolic acid prodrug (NX-201): Pharmacokinetics and in vivo antitumor effects in PANC-1 pancreatic cancer
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The aim of our study was to develop ursolic acid (UA) prodrugs in order to overcome UA's weakness, which has an extremely low bioavailability. UA-medoxomil (NX-201), one of our UA prodrugs, showed an improved bioavailability about 200 times better than UA in rodent model. According to in vivo test performed with PANC-1 xenograft SCID mouse model, tumor growth rate decreased dose-dependently and 100 mg/kg dose of NX-201 had an anticancer effect comparable to gemcitabine. Most of all the combination of NX-201 (50 mg/kg, po, daily) and gemcitabine (40 mg/kg, iv, 2 times per week) even reduced tumor size after three weeks.
- Yoon, Yeohong,Lim, Jee Woong,Kim, Jiyoung,Kim, Younggi,Chun, Keun Ho
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p. 5524 - 5527
(2016/11/05)
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- Inhibitory effects of IL-6-induced STAT3 activation of bio-active compounds derived from Salvia plebeia R.Br
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Salvia plebeia R.Br. (SPRB) is a natural resource that exhibits various biological activities. However, its effects on inflammatory diseases are not yet well characterized. This study aimed to evaluate the inhibitory effects of a compound derived from SPRB on interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) activation. The chemical structure of active compounds isolated from the EtOAc-soluble fraction of SPRB were elucidated by comparison with spectroscopic nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI–MS) data in the literature, which resulted in the identification of 22 known compounds. All of the isolated compounds were evaluated for potentially higher inhibitory effects on IL-6-induced STAT3 activation in Hep3B cells using a luciferase reporter assay. Furthermore, the protein levels of p-STAT3, p-ERK, and p-JAK2 in IL-6 induced U266 cells were regulated in the presence of cirsimaritin from SPRB by western blot assay. Based on these findings, we suggest that SPRB has the potential to inhibit IL-6-induced STAT3 activation and should be considered in functional food and pharmaceutical applications.
- Lee, Seung-Jae,Jang, Hyun-Jae,Kim, Yesol,Oh, Hyun-Mee,Lee, Soyoung,Jung, Kyungsook,Kim, Young-Ho,Lee, Woo-Song,Lee, Seung-Woong,Rho, Mun-Chual
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p. 2222 - 2229
(2016/12/16)
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- Synthesis and evaluation of novel triterpene analogues of ursolic acid as potential antidiabetic agent
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Ursolic acid (UA) is a naturally bioactive compound that possesses potential anti-diabetic activity. The relatively safe and effective molecule intrigued us to further explore and to improve its anti-diabetic activity. In the present study, a series of novel UA analogues was synthesized and their structures were characterized. Their bioactivities against the α-glucosidase from baker's yeast were determined in vitro. The results suggested that most of the analogues exhibited significant inhibitory activity, especially analogues 8b and 9b with the IC50 values of 1.27 ± 0.27 μM (8b) and 1.28 ± 0.27 μM (9b), which were lower than the other analogues and the positive control. The molecular docking and 2D-QSAR studies were carried out to prove that the C-3 hydroxyl could interact with the hydrophobic region of the active pocket and form hydrogen bonds to increase the binding affinity of ligand and the homology modelling protein. Thus, these results will be helpful for understanding the relationship between binding mode and bioactivity and for designing better inhibitors from UA analogues.
- Wu, Panpan,Zheng, Jie,Huang, Tianming,Li, Dianmeng,Hu, Qingqing,Cheng, Anming,Jiang, Zhengyun,Jiao, Luoying,Zhao, Suqing,Zhang, Kun
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- COMPOSITION FOR PREVENTING HAIR LOSS AND ACCELERATING HAIR GROWTH
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Disclosed is a composition for prevention of hair loss and promotion of hair growth. The composition includes a compound represented by Formula 1, wherein A is derived from polycyclic compounds, and R is a hydroxyl group, or a saturated or unsaturated straight or branched alkyloxy or acyloxy group having 1 to 20 carbon atoms.
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Paragraph 0017
(2015/10/05)
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- Design, synthesis and in vitro evaluation of novel ursolic acid derivatives as potential anticancer agents
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A series of novel ursolic acid (UA) derivatives modified at the C-3 and the C-28 positions were designed and synthesized in an attempt to develop potential antitumor agents. The in vitro cytotoxicity were evaluated against five cancer cell lines (MGC-803, HCT-116, T24, HepG2 and A549 cell lines) and a normal cell (HL-7702) by MTT assay. The screening results indicated that some of these target compounds displayed moderate to high levels of antiproliferative activities compared with ursolic acid and 5-fluorouracil (5-FU), and exhibited much lower cytotoxicity than 5-FU, indicating that the targeted compounds had selective and significant effect on the cell lines. The induction of apoptosis and affects on the cell cycle distribution of compound 6r were investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which revealed that the antitumor activity of 6r was possibly achieved through the induction of cell apoptosis by G1 cell-cycle arrest. Western blot and qRT-PCR (quantitative real-time PCR) experiments demonstrated that compound 6r may induce apoptosis through both of intrinsic and extrinsic apoptosis pathway.
- Hua, Shi-Xian,Huang, Ri-Zhen,Ye, Man-Yi,Pan, Ying-Ming,Yao, Gui-Yang,Zhang, Ye,Wang, Heng-Shan
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p. 435 - 452
(2015/04/14)
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- NOVEL URSOLIC ACID DERIVATIVE AND METHOD FOR PREPARING SAME
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The present invention relates to a novel ursolic acid derivative as an ursolic acid prodrug form, and to a method for preparing same, wherein the novel ursolic acid derivative as an ursolic acid prodrug can have excellent pharmacokinetic characteristics such as stability and oral absorptivity and exhibit excellent pharmaceutical activities by being converted into an ursolic acid in vivo, and. The ursolic acid derivative can be in an ester form in which C28 carboxylic acid in the ursolic acid is combined with a prodrug of a certain pharmaceutical compound.
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Paragraph 0051-0054
(2015/09/22)
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- Drug resistance reversal potential of ursolic acid derivatives against nalidixic acid- and multidrug-resistant Escherichia coli
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As a part of our drug discovery program, ursolic acid was chemically transformed into six semi-synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with conventional antibiotic nalidixic acid against the nalidixic acid-sensitive and nalidixic acid-resistant strains of Escherichia coli. Although ursolic acid and its all semi-synthetic derivatives did not show antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration of nalidixic acid up to eightfold. The 3-O-acetyl-urs-12-en-28-isopropyl ester (UA-4) and 3-O-acetyl-urs-12-en-28-n-butyl ester (UA-5) derivatives of ursolic acid reduced the minimum inhibitory concentration of nalidixic acid by eightfold against nalidixic acid-resistant and four and eightfold against nalidixic acid-sensitive, respectively. The UA-4 and UA-5 were further evaluated for their synergy potential with another antibiotic tetracycline against the multidrug-resistant clinical isolate of Escherichia coli-KG4. The results showed that both these derivatives in combination with tetracycline reduced the cell viability in concentration-dependent manner by significantly inhibiting efflux pump. This was further supported by the in silico binding affinity of UA-4 and UA-5 with efflux pump proteins. These ursolic acid derivatives may find their potential use as synergistic agents in the treatment of multidrug-resistant Gram-negative infections. Drug resistance reversal potential and mechanism of natural compound ursolic acid and its derivative UA-4 were deduced through inhibition of ATP-dependent efflux pumps. Inhibition of efflux pumps is useful in (i) lowering the dose of antibiotics; (ii) reducing the drug resistance development frequency; and (iii) increasing the efficacy of antibiotics against multidrug-resistant Escherichia coli strains.
- Dwivedi, Gaurav Raj,Maurya, Anupam,Yadav, Dharmendra Kumar,Khan, Feroz,Darokar, Mahendra P.,Srivastava, Santosh Kumar
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p. 272 - 283
(2015/02/19)
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- Towards cytotoxic and selective derivatives of maslinic acid
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Several novel esters and amides of maslinic acid were prepared. Their evaluation for cytotoxic activity with a panel of human cancer cell lines using a sulforhodamine B (SRB) assay revealed for some of them a noteworthy activity. The results from annexinV-FITC and caspase-assays as well as from DNA laddering experiments provided evidence for an apoptotic cell death. A diacetylated benzylamide (15) induced a G1/G0 arrest in tumor cells. It also displayed an extraordinary cytotoxicity against human ovarian cancer cells but a 300 times lower toxicity for non-malignant primary human fibroblasts.
- Siewert, Bianka,Pianowski, Elke,Obernauer, Anja,Csuk, René
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p. 594 - 615
(2014/01/17)
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