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Discovery and radiosensitization research of ursolic acid derivatives as SENP1 inhibitors
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
supporting information

(2021/10/22)

Pentacylic triterpenes from Lavandula coronopifolia: structure related inhibitory activity on α-glucosidase
Ten pentacyclic triterpenes (1-10) were isolated from Lavandula coronopifolia. We evaluated their α-glucosidase inhibitory activity, and found that the aglycones, 1, 2, 3, 4, 7 and 10 showed superior IC50 values to the positive control. In order to explain the structural requirements for α-glucosidase inhibitory activity, eleven derivatives were prepared, including one new compound, 2-formyl-(A)1–19α-hydroxy-1-norursane-2, 12-dien-28-oic acid 10c. The results demonstrated that a free hydroxyl at ring-A and a free carboxylic group at position 28 are key structural features for the α-glucosidase inhibitory activity, also that an ursane skeleton is optimum for the activity. Additionally, enzyme kinetic analysis of pomolic acid 2, the most potent compound, revealed that it inhibited α-glucosidase in a mixed-type manner. The molecular docking simulation validated this type of inhibition and highlighted the role of the C-3 hydroxyl and C-28 carboxylic groups in interaction with the enzyme in silico.
Elsbaey, Marwa,Mwakalukwa, Rogers,Shimizu, Kuniyoshi,Miyamoto, Tomofumi
p. 1436 - 1444
(2019/08/26)

The Novel Synthetic Triterpene Methyl 3β-O-[4-(2-Aminoethylamino)-4-oxo-butyryl]olean-12-ene-28-oate Inhibits Breast Tumor Cell Growth in Vitro and in Vivo
Oleanolic and ursolic acids were used as lead compounds to synthesize a series of pentacyclic triterpenoid derivatives bearing ethylenediamine, butanediamine, or hexanediamine groups at the C-3 position. The potential antiproliferative activity of these compounds was examined in A549 (human non-small cell lung cancer cells), MCF-7 (human breast cancer cells), and HeLa (human cervical carcinoma cells) cells. Methyl 3β-O-[4-(2-aminoethylamino)-4-oxo-butyryl]olean-12-ene-28-oate (DABO-Me) was identified as a promising antiproliferative agent in vitro and in vivo. DABO-Me strongly suppressed the proliferation of A549, MCF-7, and HeLa cells (IC50=4–7μM). In MCF-7 cells, DABO-Me upregulated the pro-apoptotic protein Bax, downregulated the anti-apoptotic protein Bcl-2, promoted the release of cytochrome c, and activated caspase-3/9. Transwell and flow cytometry assays showed that DABO-Me inhibited MCF-7 cell proliferation, migration, and invasion, and induced apoptosis and S phase arrest. In vitro and in vivo experiments indicated that DABO-Me inhibited MCF-7 cell proliferation and suppressed tumor growth. Taken together, these results indicate that DABO-Me could be developed as an effective antitumor drug.
Feng, Bin,Li, Jiaqi,Tian, Tian,Yu, Jiawen,Zhang, Xiyue,Zhang, Yang,Zhao, Chunhui,Zhao, Longxuan
p. 962 - 970
(2020/11/03)

Ursolic Acid Isolated from the Leaves of Loquat (Eriobotrya japonica) Inhibited Osteoclast Differentiation through Targeting Exportin 5
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
(2019/03/29)

Ursolic Acid Isolated from the Leaves of Loquat (Eriobotrya japonica) Inhibited Osteoclast Differentiation through Targeting Exportin 5
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
p. 3333 - 3340
(2019/04/03)

Cytotoxicity of oleanolic and ursolic acid derivatives toward hepatocellular carcinoma and evaluation of NF-κB involvement
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
(2019/06/19)

Ursolic acid derivatives as potential agents against acanthamoeba Spp
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.
(2019/10/22)

Ursolic and oleanolic acid derivatives with cholinesterase inhibiting potential
Triterpenoids are in the focus of scientific interest, and they were evaluated for many pharmacological applications among them their ability to act as inhibitors of cholinesterases. These inhibitors are still of interest as drugs that improve the life quality of patients suffering from age-related dementia illnesses especially of Alzheimer's disease. Herein, we prepared several derivatives of ursolic and oleanolic acid and screened them in Ellman's assays for their ability to inhibit acetylcholinesterase and/or butyrylcholinesterase, and for each of the active compounds the type of inhibition was determined. As a result, several compounds were shown as good inhibitors for acetylcholinesterase and butyrylcholinesterase even in a micromolar range. An ursolic acid derived hydroxyl-propinyl derivative 10 was a competitive inhibitor for butyrylcholinesterase with an inhibition constant of Ki = 4.29 μM, and therefore being twice as active as gold standard galantamine hydrobromide. The best inhibitor for acetylcholinesterase, however, was 2-methyl-3-oxo-methyl-ursoloate (18), acting as a mixed-type inhibitor showing Ki = 1.72 μM and Ki′ = 1.28 μM, respectively.
Loesche, Anne,K?witsch, Alexander,Lucas, Susana D.,Al-Halabi, Zayan,Sippl, Wolfgang,Al-Harrasi, Ahmed,Csuk, René
p. 23 - 32
(2019/01/04)

An improved scalable synthesis of α- and β-amyrin
The synthesis of α- and β-amyrin was accomplished starting from easily accessible starting materials, oleanolic, and ursolic acid. The procedures allow the preparation of β-amyrin in an exceptionally short scalable manner via selective iodation and reduction. For α-amyrin, a different synthetic approach had to be chosen providing access to α-amyrin in medium-to-large scale.
Serbian, Immo,Csuk, René
(2018/07/13)

Targeting mitochondria: Esters of rhodamine B with triterpenoids are mitocanic triggers of apoptosis
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
supporting information
p. 21 - 30
(2018/04/26)

Ursolic acid derivatives as potential antidiabetic agents: In vitro, in vivo, and in silico studies
(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
p. 70 - 80
(2018/02/06)

Compound 3 - O - (2 - (5 - fluoro uracil - 1 -) acetyl) - ursolic acid methyl ester synthesis and its application used as antineoplastic (by machine translation)
The invention discloses new compound 3 - O - (2 - (5 - fluoro uracil - 1 -) acetyl) - ursolic acid methyl ester and their use as anti-tumor medicament. The synthetic method is the 5 - fluoro uracil - 1 - yl acetic acid and ursolic acid methyl ester to carry out the esterification reaction can obtain 3 - O - (2 - (5 - fluoro uracil - 1 -) acetyl) - ursolic acid methyl ester. This compound to the BEL - 7402 and Hela growth of the cancer cell has very strong inhibiting effect. (by machine translation)
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Paragraph 0033; 0034; 0035; 0039; 0040

(2017/08/25)

Hyaluronidase inhibitory activity of pentacylic triterpenoids from prismatomeris tetrandra (Roxb.) K. schum: Isolation, synthesis and QSAR Study
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
(2016/02/26)

Structure-activity relationships of 3-O-β-chacotriosyl ursolic acid derivatives as novel H5N1 entry inhibitors
A series of methyl ursolate 3-O-β-chacotrioside analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on a small molecule inhibitor saponin 3 previously discovered by us. Detailed structureeactivity relationships (SARs) studies on the aglycone of compound 3 indicated that both the type of pentacyclic triterpene and the subtle modification of ursolic acid as an aglycon had key influences on the antiviral activity. These results suggested that either the introduction of a disubstituted amide structure at the 17-COOH of ursolic acid or alteration of the C-3 configuration of ursolic acid from 3β-to 3α-forms was helpful to significantly improve the selective index while keeping their antiviral activities.
Song, Gaopeng,Shen, Xintian,Li, Sumei,Li, Yibin,Liu, Yunpeng,Zheng, Yushan,Lin, Ruheng,Fan, Jihong,Ye, Hanming,Liu, Shuwen
p. 431 - 442
(2015/03/04)

Design, synthesis, and biofunctional evaluation of novel pentacyclic triterpenes bearing O-[4-(1-piperazinyl)-4-oxo-butyryl moiety as antiproliferative agents
A series of pentacyclic triterpenoids derivatives bearing O-[4-(1-piperazinyl)-4-oxo-butyryl moiety has been synthesized and investigated for their potential antiproliferative activities. Pentacyclic triterpenoids derivative compounds were synthesized by a four or six step synthetic procedure. The activity studies were evaluated using Cell Counting Kit-8 method, and Western blotting analysis on A549 cells, MCF-7 cells and Hela cells. Compounds methyl 3-O-[4-(1-piperazinyl)-4-oxo-butyryl]olean-12-ene-28-oate (OA-4) and compound 2-O-[4-(1-piperazinyl)-4-oxo-butyryl]-3,23-dihydroxyurs-12-ene-28-oate (AA-5) were found to be promising antiproliferative agents. These compounds show potentiality for further optimization as antitumor drugs.
Zhao, Chun-Hui,Zhang, Cui-Li,Shi, Jin-Jie,Hou, Xi-Yan,Feng, Bin,Zhao, Long-Xuan
supporting information
p. 4500 - 4504
(2015/10/12)

The chemical and biological potential of C ring modified triterpenoids
A convenient and elegant route has been developed to separate the natural regioisomers triterpenoids ursolic acid (UA) and oleanolic acid (OA) as well as derivatives thereof. Eleven unknown derivatives of OA were designed, synthesized, and their cytotoxicity was investigated. Further sixteen compounds were prepared to correlate all compounds in a SAR study. It could be shown that C-ring modifications of OA and UA have only a moderate influence onto the cytotoxic activity of the compounds but a significant impact onto the ability to trigger apoptosis in ovarian cancer cells (cell line A2780).
Siewert, Bianka,Wiemann, Jana,K?witsch, Alexander,Csuk, René
p. 84 - 101
(2014/01/06)

An efficient synthesis of methyl 2-cyano-3,12-dioxoursol-1,9-dien-28-oate (CDDU-methyl ester): Analogues, biological activities, and comparison with oleanolic acid derivatives
An efficient synthesis of methyl 2-cyano-3,12-dioxoursol-1,9-dien-28-oate (CDDU-methyl ester) from commercially available ursolic acid, which features an oxidative ozonolysis-mediated C-ring enone formation, and provides the first access to ursolic acid-derived cyano enone analogues with C-ring activation. These new ursolic acid analogues show potent biological activities, with potency of approximately five-fold less than the corresponding oleanolic acid derivatives.
Fu, Liangfeng,Lin, Qi-Xian,Liby, Karen T.,Sporn, Michael B.,Gribble, Gordon W.
supporting information
p. 5192 - 5200
(2014/07/08)

Inhibition of human enterovirus 71 replication by pentacyclic triterpenes and their novel synthetic derivatives
A large number of bioactive pentacyclic triterpenoids have been shown to have multiple biological activities. This study was conducted to evaluate the inhibitory activities of 6 newly synthesized and novel pentacyclic triterpenoids against enterovirus 71 (EV71). The parent compound, ursolic acid (UA), showed the greatest inhibitory activity against EV71, while oleanolic acid (OA), asiatic acid (AA), and synthetic derivatives of 18-β-glycyrrhetinic acid (GA) and OA also exhibited inhibitory effects, although to lesser extents. The results suggest these compounds show potential for further optimization as antiviral candidates for treatment of EV71 infections.
Zhao, Chun-Hui,Xu, Jie,Zhang, Ying-Qiu,Zhao, Long-Xuan,Feng, Bin
p. 764 - 771
(2016/10/06)

Sulfamates of methyl triterpenoates are effective and competitive inhibitors of carbonic anhydrase II
Carbonic anhydrase II, belonging to one of the most important enzyme groups of the human body, is a well-studied isozyme from the family of the carbonic anhydrases. Since it is involved in several physiological processes, it has been a pharmaceutical target for many years. In this study we synthesized a number of sulfamates derived from pentacyclic methyl triterpenoates, and we demonstrate their potential as carbonic anhydrase II inhibitors using the well-established photometric 4-nitrophenyl acetate assay. Inhibition constants, as an indicator of their inhibition strength, were in the micromolar range; one compound (10, methyl (3β) 3-(aminosulfonyloxy)-oleanoate) showed a Ki value as low as 0.3 μM. This Ki value is comparable to that of acetazolamide which is a potent carbonic anhydrase inhibitor and a drug for the treatment of glaucoma.
Schwarz, Stefan,Sommerwerk, Sven,Lucas, Susana D.,Heller, Lucie,Csuk, René
p. 95 - 102
(2014/10/16)

Synthesis and anti-cancer activity of some novel C-17 analogs of ursolic and oleanolic acids
A series of seventeen novel analogs of ursolic and oleanolic acid were synthesized (60-98 %), and evaluated for their anti-cancer potential against a panel of eight human cancer cell lines. Compounds (3-10) showed comparable or better activities than their respective parent compounds against SiHa and HeLa (Cervix), A-549 (Lung), and IMR-32 (Neuroblastoma) cancer cell lines. Significantly, among the bromoalkyl esters (11-19), compound 13 showed promising anti-cancer activity against Leukemia THP-1 cell line at 10 μM concentration. In this series, it is interesting to note that the increase in chain length has an adverse effect on the activity.
Mallavadhani, Uppuluri V.,Mahapatra, Anita,Pattnaik, Banita,Vanga, Nagireddy,Suri, Nitasha,Saxena, Ajit K.
p. 1263 - 1269
(2013/04/10)

Synthesis of novel 8,14-secoursane derivatives: Key intermediates for the preparation of chiral decalin synthons from ursolic acid
The novel 8,14-secoursatriene derivative 6 was synthesized starting from ursolic acid (1) via methyl esterification of the 17-carboxylic acid group and benzoylation of the 3-hydroxy group (→ 2; Scheme 1), ozone oxidation of the C(12)=C(13) bond (→ 3), dehydrogenation with Br2/HBr (→ 4), enol acetylation of the resulting carbonyl group (→ 5; Scheme 2), and ring-C opening with the aid of UV light (→ 6). Ring-C-opened dienone derivative 7 of ursolic acid was also obtained via selective hydrolysis of 6 (Scheme 2). Both compounds 6 and 7 are key intermediates for the preparation of chiral decalin synthons from ursolic acid.
Zhang, Chongnan,Yang, Haijun,Lue, Guangying,Liu, Cailin,Tang, Yun,Liu, Laibao
scheme or table
p. 1026 - 1032
(2012/08/08)

Synthesis of novel ursolic acid heterocyclic derivatives with improved abilities of antiproliferation and induction of p53, p21waf1 and NOXA in pancreatic cancer cells
A series of new heterocyclic derivatives of ursolic acid 1 were synthesized and evaluated for their antiproliferative activity against AsPC-1 pancreatic cancer cells. Compounds 24-32, with an α,β unsaturated ketone in conjugation with an heterocyclic ring in ring A have improved antiproliferative activities. Compound 32 is the most active compound with an IC50 of 1.9 μM which is sevenfold more active than ursolic acid 1. Compound 32 arrests cell cycle in G1 phase and induces apoptosis in AsPC-1 cells with upregulation of p53, p21waf1 and NOXA protein levels.
Leal, Ana S.,Wang, Rui,Salvador, Jorge A.R.,Jing, Yongkui
p. 5774 - 5786
(2012/11/06)

Semisynthetic Ursolic Acid Fluorolactone Derivatives Inhibit Growth with Induction of p21waf1 and Induce Apoptosis with Upregulation of NOXA and Downregulation of c-FLIP in Cancer Cells
A series of ursolic acid ((1S,2R,4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-1,2,6a,6b,9,9,12a-heptamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydro-1H-picene-4a-carboxylic acid) derivatives with a 12-fluoro-13,28β-lactone moiety were synthesized using the electrophilic fluorination reagent Selectfluor. The antiproliferative effects of these novel compounds were evaluated in AsPC-1 pancreatic cancer cells, and the structure-activity relationships (SARs) were evaluated. Of the compounds synthesized, ursolic acid derivatives carrying a heterocyclic ring, such as imidazole or methylimidazole, and cyanoenones were among the more potent inhibitors of AsPC-1 pancreatic cancer cell growth. 2-Cyano-3-oxo-12α-fluoro-urs-1-en-13,28β-olide, compound 20, was the most effective inhibitor with IC50 values of 0.7, 0.9 and 1.8μM in pancreatic cancer cell lines AsPC-1, MIA PaCa-2 and PANC-1, respectively. This compound also exhibited better antiproliferative activities against breast (MCF7), prostate (PC-3), hepatocellular (Hep G2) and lung (A549) cancer cell lines, with IC50 values lower than 1μM. The mechanism of action by which these compounds exert their biological effect was evaluated in AsPC-1 cells using the most potent inhibitor synthesized, compound 20. At 1μM, the cell cycle arrested at the G1 phase with upregulation of p21waf1. Apoptosis was induced at an inhibitor concentration of 8μM with upregulation of NOXA and downregulation of c-FLIP. These data indicate that fluorolactone derivatives of ursolic acid have improved antiproliferative activity, acting through arrest of the cell cycle and induction of apoptosis.
Leal, Ana S.,Salvador, Jorge A. R.,Wang, Rui,Jing, Yongkui
p. 1635 - 1646,12
(2020/08/31)

Synthesis and biological evaluation of analogs of methyl ursolate 3-o-chacotrioside as H5N1 viral entry inhibitors
The earliest stage of influenza virus infection is the viral entry to the host cell. In our previous work, we discovered the first three small molecule H5N1 viral entry inhibitors 1-3. Here, based on saponin 3, methyl ursolate 3-O-chacotrioside, several analogs were synthesized and evaluated to understand the structure-activity relationships of this type of compound on the H5N1 viral entry inhibitory activity. The preliminary studies demonstrated that unlike saponins 1 and 2, it is possible to reduce the 3-O-chacotriosyl residue of compound 3 to a disaccharide without affecting the viral entry activities significantly. The results obtained will render new clues to the understanding of the antiviral profile for these types of compounds.
Ren, Sumei,Chen, Qing,Ding, Ning,Zhang, Wei,Li, Yingxia,Guo, Ying
p. 647 - 658
(2013/01/16)

Antileishmanial activity of the hydroalcoholic extract of miconia langsdorffii, isolated compounds, and semi-synthetic derivatives
The in vitro activity of the crude hydroalcoholic extract of the aerial parts of Miconia langsdorffii Cogn. was evaluated against the promastigote forms of L. amazonensis, the causative agent of cutaneous leishmaniasis in humans. The bioassayguided fractionation of this extract led to identification of the triterpenes ursolic acid and oleanolic acid as the major compounds in the fraction that displayed the highest activity. Several ursolic acid semi-synthetic derivatives were prepared, to find out whether more active compounds could be obtained. Among these ursolic acid-derived substances, the C- 28 methyl ester derivative exhibited the best antileishmanial activity.
Peixoto, Juliana A.,Silva, Marcio Luis Andrade E,Crotti, Antonio E. M.,Veneziani, Rodrigo Cassio Sola,Gimenez, Valeria M. M.,Januario, Ana H.,Groppo, Milton,Magalhaes, Lizandra G.,Dos Santos, Fransergio F.,Albuquerque, Sergio,Da Silva Filho, Ademar A.,Cunha, Wilson R.
body text
p. 1825 - 1833
(2011/05/02)

URSOLIC ACID DERIVATIVE AND PHARMACEUTICAL COMPOSITION THEREOF
Several ursolic acid derivatives and pharmaceutical compositions thereof are provided. The ursolic acid derivatives and the pharmaceutical compositions thereof have at least one of an anticancer and an anti-inflammatory effects. A method for increasing a reactive oxygen species in a cell is also provided. The method comprises a step of providing the cell with a pharmaceutical composition including an ursolic acid derivative.
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(2011/08/08)

Ursolic acid derivatives induce cell cycle arrest and apoptosis in NTUB1 cells associated with reactive oxygen species
Twenty-three ursolic acid (1) derivatives 2-24 including nine new 1 derivatives 5, 7-11, 20-22 were synthesized and evaluated for cytotoxicities against NTUB1 cells (human bladder cancer cell line). Compounds 5 and 17 with an isopropyl ester moiety at C-17-COOH and a succinyl moiety at C-3-OH showed potent inhibitory effect on growth of NTUB1 cells. Compounds 23 and 24 with seco-structures prepared from 1 also showed the increase of the cytotoxicity against NTUB1 cells. Exposure of NTUB1 to 5 (40 μM) and 23 (20 and 50 μM) for 24 h significantly increased the production of reactive oxygen species (ROS) while exposure of NTUB1 to 5 (20 and 40 μM) and 23 (20 and 50 μM) for 48 h also significantly increased the production of ROS while exposure of cells to 17 did not increase the amount of ROS. Flow cytometric analysis exhibited that treatment of NTUB1 with 5 or 17 or 23 led to the cell cycle arrest accompanied by an increase in apoptotic cell death after 24 or 48 h. These data suggest that the presentation of G1 phase arrest and apoptosis in 5- and 23-treated NTUB1 for 24 h mediated through increased amount of ROS in cells exposed with 5 and 23, respectively, while the presence of G2/M arrest before accumulation of cells in sub-G1 phase in 5-treated cells for 48 h also due to increased amount of ROS in cells exposed with 5. The inhibition of tubulin polymerization and cell cycle arrest at G2/M following by apoptosis presented in the cell cycle of 23 also mediates through the increase amount of ROS induced by treating NTUB1 with 23 for 48 h.
Tu, Huang-Yao,Huang, A-Mei,Wei, Bai-Luh,Gan, Kim-Hong,Hour, Tzyh-Chyuan,Yang, Shyh-Chyun,Pu, Yeong-Shiau,Lin, Chun-Nan
experimental part
p. 7265 - 7274
(2010/03/24)

Structure-dependent inhibition of bladder and pancreatic cancer cell growth by 2-substituted glycyrrhetinic and ursolic acid derivatives
Derivatives of oleanolic acid, ursolic acid and glycyrrhetinic acid substituted with electron-withdrawing groups at the 2-position in the A-ring which also contains a 1-en-3-one structure are potent inhibitors of cancer cell growth. In this study, we have compared the effects of several 2-substituted analogs of triterpenoid acid methyl esters derived from ursolic and glycyrrhetinic acid on proliferation of KU7 and 253JB-V bladder and Panc-1 and Panc-28 pancreatic cancer cells. The results show that the 2-cyano and 2-trifluoromethyl derivatives were the most active compounds. The glycyrrhetinic acid derivatives with the rearranged C-ring containing the 9(11)-en-12-one structure were generally more active than the corresponding 12-en-11-one isomers. However, differences in growth inhibitory IC50 values were highly variable and dependent on the 2-substituent (CN vs CF3) and cancer cell context.
Chadalapaka, Gayathri,Jutooru, Indira,McAlees, Alan,Stefanac, Tom,Safe, Stephen
p. 2633 - 2639
(2008/12/21)

METHOD FOR PREPARING 2-IODO TRITERPENOID COMPOUNDS
The present invention relates to a new method of preparing 2-iodo triterpenoid and related compounds via the reaction of the corresponding 1 ene-3-ones in the presence of iodine and pyridine in an ether solvent. The method is particularly suited to steroids such as cholesterol derivatives and pentacyclic triterpenoids such as ursolic acid derivatives.
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Page/Page column 12-13

(2008/06/13)

Chemical phenotypes of the hmg1 and hmg2 mutants of Arabidopsis demonstrate the in-planta role of HMG-CoA reductase in triterpene biosynthesis
Plants produce a wide variety of cyclic triterpenes, such as sterols and triterpenoids, which are the major products of the mevalonate (MVA) pathway. It is important to understand the physiological functions of HMG-CoA reductase (HMGR) because HMGR is the rate-limiting enzyme in the MVA pathway. We have previously isolated Arabidopsis mutants in HMG1 and HMG2. Although the biochemical function of HMGR2 has been thought to be almost equal to that of HMGR1, based on similarities in their sequences, the phenotypes of mutants in these genes are quite different. Whereas hmg2 shows no abnormal phenotype under normal growth conditions, hmg1 shows pleiotropic phenotypes, including dwarfing, early senescence, and male sterility. We previously postulated that the 50% decrease in the sterol content of hmg1, as compared to that in the wild type, was a cause of these phenotypes,1) but comprehensive triterpene profiles of these mutants had not yet been determined. Here, we present the triterpene profiles of hmg1 and hmg2. In contrast to hmg1, hmg2 showed a sterol content 15% lower than that of the wild type. A precise triterpenoid quantification using synthesized deuterated compounds of β-amyrin (1), α-amyrin (2), and lupeol (3) showed that the levels of triterpenoids in hmg1 and hmg2 were 65% and 25% lower than in the wild type (WT), respectively. These results demonstrate that HMGR2 as well as HMGR1 is responsible for the biosynthesis of triterpenes in spite of the lack of visible phenotypes in hmg2.
Ohyama, Kiyoshi,Suzuki, Masashi,Masuda, Kazuo,Yoshida, Shigeo,Muranaka, Toshiya
p. 1518 - 1521
(2008/12/23)

Suppression of the SOS-inducing activity of mutagenic heterocyclic amine, Trp-P-1, by triterpenoid from Uncaria sinensis in the Salmonella typhimurium TA1535/pSK1002 umu test
The methanol extract from Uncaria sinensis showed a suppressive effect on umu gene expression of the SOS response in Salmonella typhimurium TA1535/pSK1002 against the mutagen 3-amino-1,4-dimethyl-5H-pyrido[4,3b]indole (Trp-P-1), which requires liver metabolizing enzymes. The methanol extract from U. sinensis was re-extracted with hexane, CH2Cl2, BuOH, and water, respectively. CH2-Cl2 extract showed a suppressive effect. A suppressive compound 1 in CH2Cl2 extract was isolated by SiO2 column chromatography. Compound 1 was identified as ursolic acid by IR, electron ionization EI-MS, and NMR spectroscopy. Suppressive effects of ursolic acid (1) and its derivatives, methyl ursolate (1M), acetylursolic acid (1A), and methyl acetylursolate (1MA), were determined in the umu test. These compounds suppressed 61.3, 37.7, 71.5, and 37.8% of the Trp-P-1-induced SOS response at a concentration of 0.4 μmol/mL, respectively. The ID 50 values of compounds 1 and 1A were 0.17 and 0.20 μmol/mL. In addition, these compounds were assayed with the activated Trp-P-1. Suppressive effects on activated Trp-P-1 were decreased as compared with those of Trp-P-1.
Miyazawa, Mitsuo,Okuno, Yoshiharu,Imanishi, Koji
p. 2312 - 2315
(2007/10/03)

The cytotoxic activity of ursolic acid derivatives
Ursolic acid and 2α-hydroxyursolic acid isolated from apple peels were found to show growth inhibitory activity against four tumor cell lines, HL-60, BGC, Bel-7402 and Hela. Structural modifications were performed on the C-3, C-28 and C-11 positions of ursolic acid and the cytotoxicity of the derivatives was evaluated. The SAR revealed that the triterpenes possessing two hydrogen-bond forming groups (an H-donor and a carbonyl group) at positions 3 and 28 exhibit cytotoxic activity. The configuration at C-3 was found to be important for the activity. Introduction of an amino group increased the cytotoxicity greatly. A 3β-amino derivative was 20 times more potent than the parent ursolic acid. The 28-aminoalkyl dimer compounds showed selective cytotoxicity.
Ma, Chao-Mei,Cai, Shao-Qing,Cui, Jing-Rong,Wang, Rui-Qing,Tu, Peng-Fei,Hattori, Masao,Daneshtalab, Mohsen
p. 582 - 589
(2007/10/03)

Novel biotransformation of pentacyclic triterpenoid acids by Nocardia sp. NRRL 5646
Six pentacyclic triterpene acids, ursolic acid, oleanolic acid, betulinic acid, 23-hydroxybetulinic acid, glycyrrhetinic acid, and senegenin, were metabolized by the microbe Nocardia sp. NRRL 5646 to selectively furnish their corresponding 28-methyl esters. Notably, ursolic acid (1) was converted to oleanolic acid methyl ester (4) via two intermediates, oleanolic acid (2), and ursolic acid methyl ester (3), which are formed by participation of 'retro-biosynthetic' methyl migration from C-19 to C-20. Senegenin (11) was selectively converted to a nortriterpene methyl ester, senegenic acid methyl ester (12), via an unprecedented C-C bond cleavage. The stereochemical assignments of compounds 11 and 12 were made unambiguously for the first time using 2D NMR spectroscopy.
Zhang, Jian,Cheng, Zhi-Hong,Yu, Bo-Yang,Cordell, Geoffrey A.,Qiu, Samuel X.
p. 2337 - 2340
(2007/10/03)

Studies on the Himalayan yew Taxus wallichiana: Part IX - The chemical constituents of the seeds of Taxus wallichiana
The systematic investigation on the seeds of Taxus wallichiana has resulted in the isolation of three non-taxoid constituents, ursolic acid 1, the cyanogenic glycoside amygdalin 2 and β-sitosterol glucoside 3. It is a very important finding that the seeds of the Himalayan yew did not contain any taxoids in contrast to the presence of taxoids in the seeds of other species of Taxus and amygdalin is the major constituent of the seeds. The detailed NMR data of amygdalin are also provided.
Chattopadhyay,Tripathi,Sashidhara,Mehta,Joshi,Roy
p. 225 - 227
(2007/10/03)

Microbial transformation of cadina-4,10(15)-dien-3-one, aromadendr-1(10)-en-9-one and methyl ursolate by Mucor plumbeus ATCC 4740
The sesquiterpenes cadina-4,10(15)-dien-3-one (1) and aromadendr-1(10)-en-9-one (squamulosone) (14) along with the triterpenoid methyl ursolate (21) were incubated with the fungus Mucor plumbeus ATCC 4740. Substrates 1,14 and ursolic acid (20) were isolated from the plant Hyptis verticillata in large quantities. M. plumbeus hydroxylated 1 at C-12 and C-14. When the iron content of the medium was reduced, however, hydroxylation at these positions was also accompanied by epoxidation of the exocyclic double bond. In total nine new oxygenated cadinanes have been obtained. Sesquiterpene 14 was converted to the novel 2α,13-dihydroxy derivative along with four other metabolites. Methyl ursolate (21) was transformed to a new compound, methyl 3β,7β,21β-trihydroxyursa-9(11),12-dien-28-oate (22). Two other triterpenoids, 3β,28-dihydroxyurs-12-ene (uvaol) (23) and 3β,28-bis(dimethylcarbamoxy)urs-12-ene (24) were not transformed by the microorganism, however.
Collins, Dwight O.,Ruddock, Peter L. D.,Grasse, Jessica Chiverton de,Reynolds, William F.,Reese, Paul B.
p. 479 - 488
(2007/10/03)

Identification of three triterpenoids in almond hulls
Three triterpenoids, betulinic acid, oleanolic acid, and ursolic acid, were isolated as their methyl esters (treatment with diazomethane) from diethyl ether extracts of almond hulls (Nonpareil variety) using flash chromatography and preparative high-performance liquid chromatography. The triterpenoids, which comprised ~1% of the hulls, were characterized using chromatographic and spectroscopic methods. These studies demonstrate that almond hulls are a rich source of these triterpenoids, which have reported anti-inflammatory, anti-HIV, and anti-cancer activities.
Takeoka,Dao,Teranishi,Wong,Flessa,Harden,Edwards
p. 3437 - 3439
(2007/10/03)

Synthesis of β-boswellic acid analogues with a carboxyl group at c-17 isolated from the bark of Schefflera octophylla
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Bore, Lothar,Honda, Tadashi,Gribble, Gordon W.
p. 6278 - 6282
(2007/10/03)

Inhibitory effects of constituents from Cynomorium songaricum and related triterpene derivatives on HIV-1 protease
From CH2Cl2 and MeOH extracts of the stems of Cynomorium songaricum RUPR. (Cynomoriaceae), ursolic acid and its hydrogen malonate were isolated as inhibitors of human immunodeficiency virus type 1 (HIV-1) protease, with 50% inhibitory concentrations (IC50) of 8 and 6 μM, respectively. Amongst various synthesized dicarboxylic acid hemiesters of related triterpenes, inhibitory activity tended to increase in the order of oxalyl, malonyl, succinyl and glutaryl hemiesters, for triterpenes such as ursolic acid, oleanolic acid and betulinic acid. The most potent inhibition was observed for the glutaryl hemiesters, with an IC50 of 4 μM. From the water extract of the stems of C. songaricum, flavan-3-ol polymers, consisting of epicatechin as their extender flavan units, were also found to be potent inhibitory principles against HIV-1 protease.
Ma, Chaomei,Nakamura, Norio,Miyashiro, Hirotsugu,Hattori, Masao,Shimotohno, Kunitada
p. 141 - 145
(2007/10/03)

Chemical Examination of Local Plants. XVII. Some New Triterpenoids from the Peels of Egyptian Pear (Pyrus communis L.)
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Younes, M. E.,Amer, M. S.,El-Safty, M. A. E.,Hassanein, M. M.,Samra, M. M. H.
p. 573 - 586
(2007/10/03)

New enone derivatives of oleanolic acid and ursolic acid as inhibitors of nitric oxide production in mouse macrophages
New derivatives of 3-oxoolean-1-en-28-oic acid and 3-oxours-1-en-28-oic acid were synthesized. Nine of them showed significant inhibitory activity against interferon-γ-induced nitric oxide production in mouse macrophages when assayed at the 1 μM level. 3,12-Dioxoolean-1,9-dien-28-oic acid (3) had the highest activity (IC50, 0.9 μM).
Honda, Tadashi,Finlay, Heather J.,Gribble, Gordon W.,Suh, Nanjoo,Sporn, Michael B.
p. 1623 - 1628
(2007/10/03)

Photochemical and electrochemical deoxygenation studies on S-methyl-dithiocarbonate derivatives
The deoxygenation of alcohols by photochemical and electrochemical methods has been studied using the 3-O-S-methyldithiocarbonate derivatives of oleanolic and ursolic methyl esters as models. The use of diethyl phosphite as hydrogen donor was analyzed. Springer-Verlag Iberica 1997.
Rodriguez-Hahn, Lydia,Manriquez, Maria E.,Frontana, Bernardo A.,Cardenas, Joerge
p. 291 - 294
(2007/10/03)

Isolation of 2',3',6-trihydroxy-4'-methoxy-7-O-neohesperidoside, a novel flavone glycoside from Cassia siamea
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Shafiullah,Khan, Mohammad Bohrab,Parveen, Mehtab,Kamil, Mohammad,Ilyas, Mohammad
p. 101 - 115
(2007/10/03)

Chemical Constituents from the Root and Aerial Parts of Rosa taiwanensis
The root and aerial parts of Rosa taiwanensis Nakai contain the chemical constituents phenols, unsaturated acids, liolide, abscisic acid, flavones, sterols, lupeol, betulin, betulinic acid, oleanolic acid and ursolic acid derivatives.Among them, 2α,3α-dihydroxyurs-12,19-dien-28-oic acid and its C-3 epimer are new compounds.Key Words Rosa taiwanensis; Rosaceae; Aerial part; Root; Flavones; Ursolic acid derivatives; Lupeol; Betulin; Oleanolic acid.
Yang, Shen-Chyun,Fang, Jim-Min,Cheng, Yu-Shia
p. 573 - 578
(2007/10/02)

3β,24-DIHYDROXYOLEAN-12-EN-28-OIC ACID, A PENTACYCLIC TRITERPENE ACID FROM LANTANA INDICA
A new oleanane derivative, 3β,24-dihydroxy olean-12-en-28-oic acid, in addition to oleanolic and ursolic acids, has been isolated from the roots of Lantana indica.The structure of the new triterpene acid has been established by chemical and spectroscopic methods.
Singh, S. K.,Tripathi, V. J.,Singh, R. H.
p. 3360 - 3362
(2007/10/02)

URSANE TRITERPENOIDS FROM NEPETA ERIOSTACHIYA
From the aerial parts of Nepeta eriostachiya two rare ursane triterpenoids, 2α,3α-dihydroxyurs-12-en-28-oic acid and 2α,3β-dihydroxyurs-12-en-28-oic acid, together with a new triterpene, nepetoic acid identified as 2α-methoxy-3β-hydroxyurs-12-en-28-oic acid were isolated as their methyl esters.Their structures were established by chemical and spectroscopic means.
Bhandari, S. P. S.,Garg, H. S.,Agrawal, P. K.,Bhakuni, D. S.
p. 3956 - 3958
(2007/10/02)

Sesquiterpene glycosides and saponins from Cynara cardunculus L.
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Shimizu,Ishihara,Umehara,Miyase,Ueno
p. 2466 - 2474
(2007/10/02)

Synthesis of Amino Derivates of Ursolic Acid
Methyl ester of 3β-amino-18β-H-urs-12-en-28-oic acid (VI) has been obtained from methyl ursolate (II) by oxidation with Kiliani reagent (CrO3) to methyl ursonate (IV) followed by treatment of IV with NH2OH/HCl and reduction of the resultant oxime (V) with alkali metal in 1-propanol.Refluxing of acetylursolic acid (III) with thionyl chloride followed by treatment with dry ammonia gas yields the amide (VII) which on LAH reduction affords 3β-acetoxy-18β-H-urs-12-en-28-methyl amine (VIII).Compound III on Curtius rearrangement gives 28-amino-3β-acetoxy-18β-H-urs-12-ene (IX).
Jain, S. M.,Atal, C. K.
p. 427 - 428
(2007/10/02)

Chemical Investigation on Finlaysonia obovata Wall.
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Pradhan, B. P.,Mukhopadhyay, M. M.
p. 629
(2007/10/02)

Chemical Examination of the Leaves, Stem Bark and Root Bark of Morinda tinctoria Var. Tomentosa
The leaves of M. tinctoria var. tomentosa yielded ursolic acid while its stem bark gave alizarin-1-methyl ether, rubiadin and D-mannitol.Anthragallol-2,3-dimethyl ether, soranjidiol and ibericin were obtained from the root bark besides the glycoside 6-primeveroside of morindone.
Venkateshwar Rao, G.,Rao, P. S.
p. 585 - 586
(2007/10/02)

INVESTIGATION ON LIPID FRACTION COMPOUNDS OF HEATHER FLOWERS (CALLUNA VULGARIS L.)
In the lipid fraction from heather flowers the presence of seven fatty acids was found.From the unhydrolyzed extract n-nonacosane, β-sitosterol and a mixture of triterpenoic compounds were obtained, from which in addition to ursolic acid another incompletely defined compound which has no COOH group, but contains the groups CH2OH and CHOH was separated.
Olechnowicz-Stepien, Waleria,Rzadkowska-Dodalska, Halina,Grimshaw, James
p. 153 - 157
(2007/10/02)