- Synthesis and antitumor potential of new arylidene ursolic acid derivatives via caspase-8 activation
-
Continuing our studies on NO-donating ursolic acid–benzylidene derivatives as potential antitumor agents, we designed and synthesized a series of new arylidene derivatives containing NO-donating ursolic acid and aromatic heterocyclic units. Compounds 5c and 6c showed a significant broad-spectrum antitumor activity. Compound 5c exhibited nearly three- to nine-fold higher cytotoxicity as compared with the parent drug in A549, MCF-7, HepG-2, HT-29, and HeLa cells, and it was also found to be the most potent apoptosis inducer of MCF-7 cells. More importantly, compound 5c arrested the MCF-7 cell cycle in the G1 phase, which was associated with caspase activation and a decrease of the Bcl-2/Bax ratio. Meanwhile, compound 5c caused changes in morphological features, dissipation of the mitochondrial membrane potential, and accumulation of reactive oxygen species. A docking study revealed that the nitroxyethyl moiety of compound 5c may form hydrogen bonds with caspase-8 amino acid residues (SER256 and HIS255). Together, these data suggest that NO-donating ursolic acid–arylidene derivatives are potent apoptosis inducers in tumor cells.
- He, Baoen,Zhu, Zuchang,Chen, Fenglian,Zhang, Rong,Chen, Weiqiang,Zhang, Te,Wang, Tao,Lei, Jiamei
-
-
Read Online
- Evaluation of ursolic acid derivatives with potential anti-Toxoplasma gondii activity
-
Toxoplasma gondii is an important pathogen that causes serious public health problems. Currently, therapeutic drugs for toxoplasmosis cause serious side effects, and more effective and novel substances with relatively low toxicity are urgently needed. Ursolic acid (UA) has many properties that can be beneficial to healthcare. In this study, we synthesized eight series of UA derivatives bearing a tetrazole moiety and evaluated their anti-T. gondii activity in vitro using spiramycin as a positive control. Most of the synthesized derivatives exhibited better anti-T. gondii activity in vitro than UA, among which compound 12a exhibited the most potent anti-T. gondii activity. Furthermore, the results of biochemical parameter determination indicated that 12a effectively restored the normal body weight of mice infected with T. gondii, reduced hepatotoxicity, and exerted significant anti-oxidative effects compared with the findings for spiramycin. Additionally, our molecular docking study indicated that the synthesized compounds could act as potential inhibitors of T. gondii calcium-dependent protein kinase 1 (TgCDPK1), with 12a possessing strong affinity for TgCDPK1 via binding to the key amino acids GLU129 and TYR131.
- Jin, Chun-Mei,Jin, Chunmei,Jin, Li-Li,Liu, Fang,Wei, Zhi-Yu,Zhang, Lin-Hao
-
-
Read Online
- Synthesis and antitumor activity evaluation of ursolic acid derivatives
-
Eighteen uronic acid derivatives were designed and synthesized, and the cytotoxicities in vitro of two cancer cell lines (BEL7402 and SGC7901) were evaluated by MTT assay. The results showed that the inhibitory rate of the compounds on both cell lines was
- Meng, Yan-Qiu,Xu, Chuan-Dong,Yu, Ting-Ting,Li, Wei,Li, Qian-Wen,Li, Xiao-Xiao
-
-
Read Online
- Design, synthesis, and screening of novel ursolic acid derivatives as potential anti-cancer agents that target the HIF-1α pathway
-
The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role in tumor angiogenesis, growth, and metastasis and is recognized as an important potential therapeutic target for cancer. Here, we designed and synthesized three novel series of ursolic acid derivatives containing an aminoguanidine moiety and evaluated them as HIF-1α inhibitors and anti-cancer agents using human cancer cell lines. Most of the compounds exhibited significant inhibition of HIF-1α transcriptional activity, as measured using a Hep3B cell-based luciferase reporter assay. Among these compounds, 7b was the most potent inhibitor of HIF-1α expression under hypoxic conditions (IC50 4.0 μM) and did not display significant cytotoxicity against any cell lines tested. The mechanism of action of 7b was investigated, we found that 7b downregulated HIF-1α protein expression, possibly by suppressing its synthesis, reduced production of vascular endothelial growth factor, and inhibited the proliferation of cancer cells.
- Wu, Jie,Zhang, Zhi-Hong,Zhang, Lin-Hao,Jin, Xue-Jun,Ma, Juan,Piao, Hu-Ri
-
-
Read Online
- Cytotoxic triterpenes from the aerial roots of Ficus microcarpa
-
Six triterpenes, 3β-acetoxy-12,19-dioxo-13(18)-oleanene (1), 3β-acetoxy-19(29)-taraxasten-20α-ol (2), 3β-acetoxy-21α, 22α-epoxytaraxastan-20α-ol (3), 3,22-dioxo-20-taraxastene (4), 3β-acetoxy-11α,12α-epoxy-16-oxo-14-taraxerene (5), 3β-acetoxy-25-methoxylanosta-8,23-diene (6) along with nine known triterpenes, 3β-acetoxy-11α,12α-epoxy-14-taraxerene (7), 3β-acetoxy-25-hydroxylanosta-8,23-diene (8), oleanonic acid (9), acetylbetulinic acid (10), betulonic acid (11), acetylursolic acid (12), ursonic acid (13), ursolic acid (14), and 3-oxofriedelan-28-oic acid (15) were isolated from the aerial roots of Ficus microcarpa, and their structures elucidated by spectroscopic methods. The in vitro cytotoxic efficacy of these triterpenes was investigated using three human cancer cell lines, namely, HONE-1 nasopharyngeal carcinoma, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells. Compound 8 and pentacyclic triterpenes 9-15 possessing a carboxylic acid functionality at C-28 showed significant cytotoxic activities against the aforementioned cell lines and gave IC50 values in the range 4.0-9.4 μM.
- Chiang, Yi-Ming,Chang, Jang-Yang,Kuo, Ching-Chuan,Chang, Chi-Yen,Kuo, Yueh-Hsiung
-
-
Read Online
- Synthesis and Antitumor Evaluation in Vitro of NO-Donating Ursolic Acid-Benzylidene Derivatives
-
Antitumor activity of triterpenoid and its derivatives has attracted great attention recently. Our previous efforts led to the discovery of a series of NO-donor betulin derivatives with potent antitumor activity. Herein, we prepared eight compounds derived from ursolic acid (UA). All the compounds were evaluated for their in vitro cytotoxicity against four human cancer cell lines (HepG-2, MCF-7, HT-29 and A549). Among the compounds tested, compound 4a was found to be most active against HT-29 (IC50=4.28 μm). Further biological assays demonstrated that compound 4a could induce cell cycle arrest at G1 phase and apoptosis in a dose-dependent manner. In addition, compound 4a was found to upregulate pro-apoptotic Bax, p53 and downregulate anti-apoptotic Bcl-2. All these results suggested that compound 4a is a potential candidate drug for the therapy of colon cancer.
- Zhang, Te,He, Baoen,Yuan, Huan,Feng, Gaili,Chen, Fenglian,Wu, Aizhi,Zhang, Lili,Lin, Huiran,Zhuo, Zhenjian,Wang, Tao
-
-
Read Online
- Fluorescent labeling of ursolic acid with FITC for investigation of its cytotoxic activity using confocal microscopy
-
Fluorescent labeling is a widely-used approach in the study of intracellular processes. This method is becoming increasingly popular for studying small bioactive molecules of natural origin; it allows us to estimate the vital intracellular changes which occur under their influence. We propose a new approach for visualization of the intracellular distribution of triterpene acids, based on fluorescent labeling by fluoresceine isothiocyanate. As a model compound we took the most widely-used and best-studied acid in the ursane series – ursolic acid, as this enabled us to compare the results obtained during our research with the available data, in order to evaluate the validity of the proposed method. Experimental tracing of the dynamics of penetration and distribution of the labeled ursolic acid has shown that when the acid enters the cell, it initially localizes on the inner membranes where the predicted target Akt1/protein kinase B – a protein that inhibits apoptosis – is located.
- Frolova, Tatiana S.,Lipeeva, Alla V.,Baev, Dmitry S.,Baiborodin, Sergey I.,Orishchenko, Кonstantin E.,Kochetov, Alexey V.,Sinitsyna, Olga I.
-
-
Read Online
- Synthesis and antitumor activity evaluation of novel ursolic acid derivatives
-
Eleven novel ursolic acid (UA) derivatives were designed and synthesized with modification at positions of C-2, C-3, and C-28 of UA. Their structures were confirmed by MS, 1H NMR, and elemental analysis. Their in vitro cytotoxicities against various cancer cell lines (HeLa, HepG2, and BGC-823) were evaluated by MTT assay. The results indicated that all compounds could inhibit cell proliferation of HeLa, HepG2, and BGC-823 cells. Among them, compounds I3 and I4 showed more potent cytotoxicity on these three tumor cells than gefitinib (positive control), worthy to be studied further.
- Meng, Yan-Qiu,Zhang, Liang-Feng,Liu, Dong-Ying,Liu, Li-Wei,Zhang, Yi,Zhao, Min-Jie
-
-
Read Online
- Synthesis and biological evaluation of ursolic acid derivatives containing an aminoguanidine moiety
-
Three series of ursolic acid derivatives containing an aminoguanidine moiety were designed, synthesized, and evaluated for anti-bacterial and anti-inflammatory activity. Some compounds displayed potent anti-bacterial activity against Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-negative bacterial strains, with minimum inhibitory concentration (MIC) values in the range of 2–64 μg/mL. Compounds 3a, 5a, and 7l showed significant inhibitory activity against the Gram-positive bacterial strain Staphylococcus aureus RN 4220, the Gram-negative bacterial strain Escherichia coli 1924, and four multidrug-resistant Gram-positive bacterial strains, with MIC values of 2 and 4 μg/mL. In anti-inflammatory tests, most of the compounds exhibited potent activity, in particular compound 3a displayed the most potent activity with 81.61% inhibition after intraperitoneal administration, which was more potent than ursolic acid and the reference drugs (ibuprofen and indomethacin). The cytotoxic activity of compound 3a was assessed in HeLa, Hep3B, and A549 cells.
- Wu, Jie,Ma, Song,Zhang, Tian-Yi,Wei, Zhi-Yu,Wang, Hui-Min,Guo, Fang-Yan,Zheng, Chang-Ji,Piao, Hu-Ri
-
-
Read Online
- Ursolic acid derivatives as bone anabolic agents targeted to tryptophan hydroxylase 1 (Tph-1)
-
Abstract Tryptophan hydroxylase 1 (Tph-1) initiates the biosynthesis of peripheral serotonin. As peripheral serotonin suppresses bone formation, inhibitor of Tph-1 provides a useful tool to discover anabolic agents for osteoporosis. In the present study, series of ursolic acid (UA) derivatives were synthesized, and their inhibitory activity on serotonin biosynthesis and cytotoxicity were evaluated. Among the derivatives, 8d with potent inhibitory activity on serotonin was applied for further research. The data revealed that 8d significantly inhibited protein and mRNA expressions of Tph-1, and an SPR study indicated that 8d directly interacted to Tph-1 with a binding affinity of KD = 15.09 μM. Oral administration of 8d significantly prevented bone loss via suppressing serotonin biosynthesis without estrogenic side-effects in ovariectomized (OVX) rats.
- Fu, Hai-Jian,Zhao, Yang,Zhou, Yu-Ren,Bao, Bei-Hua,Du, Yun,Li, Jian-Xin
-
-
Read Online
- Preventive effect of ursolic acid derivative on particulate matter 2.5-induced chronic obstructive pulmonary disease involves suppression of lung inflammation
-
Respiratory diseases like chronic obstructive pulmonary disease (COPD) are associated with the presence of particulate matter 2.5 (PM2.5) in the air. In the present study, the effect of synthesized ursolic acid derivatives on mice model of PM2.5-induced COPD was investigated in vivo. The mice model of COPD was established by the administration of 25 μL of PM2.5 suspension through intranasal route daily for 1 week. The levels of oxidative stress markers and inflammatory cytokines like tumor necrosis factors-α and interleukin-6 in the mice bronchoalveolar fluids increased markedly on administration with PM2.5. However, treatment with ursolic acid derivative caused a significant suppression in PM2.5-induced increase in oxidative stress markers and inflammatory cytokines in dose-dependent manner. Hematoxylin and eosin staining showed excessive inflammatory cell infiltration in pulmonary tissues in mice with COPD. The inflammatory cell infiltration was inhibited on treatment of the mice with ursolic acid derivative. The ursolic acid derivative treatment increased level of superoxide dismutase in mice with COPD. The lung injury induced by PM2.5 in mice was also prevented on treatment with ursolic acid derivative. Thus, ursolic acid derivative inhibits pulmonary tissues damage in mice through suppression of inflammatory cytokine and oxidative enzymes. Therefore, ursolic acid derivative can be of therapeutic importance for treatment of PM2.5-induced COPD.
- Li, Cuini,Chen, Junxian,Yuan, Weiwei,Zhang, Wei,Chen, Hong,Tan, Hongtao
-
-
Read Online
- Design, synthesis, and anticancer evaluation of novel indole derivatives of ursolic acid as potential topoisomerase II inhibitors
-
In this study, a series of new indole derivatives of ursolic acid bearing different N-(aminoalkyl)carboxamide side chains were designed, synthesized, and evaluated for their in vitro cytotoxic activities against two human hepatocarcinoma cell lines (SMMC-7721 and HepG2) and normal hepatocyte cell line (LO2) via MTT assay. Among them, compound 5f exhibited the most potent activity against SMMC-7721 and HepG2 cells with IC50 values of 0.56 ± 0.08 μM and 0.91 ± 0.13 μM, respectively, and substantially lower cytotoxicity to LO2 cells. A follow-up enzyme inhibition assay and molecular docking study indicated that compound 5f can significantly inhibit the activity of Topoisomerase IIα. Further mechanistic studies performed in SMMC-7721 cells revealed that compound 5f can elevate the intracellular ROS levels, decrease mitochondrial membrane potential, and finally lead to the apoptosis of SMMC-7721 cells. Collectively, compound 5f is a promising Topoisomerase II (Topo II) inhibitor, which exhibited the potential as a lead compound for the discovery of novel anticancer agents.
- Li, A-Liang,Hao, Yun,Wang, Wen-Yan,Liu, Qing-Song,Sun, Yue,Gu, Wen
-
-
Read Online
- Synthesis and biological evaluation of ursolic acid-triazolyl derivatives as potential anti-cancer agents
-
A series of ursolic acid-1-phenyl-1H-[1,2,3]triazol-4-ylmethylester congeners have been designed and synthesized in an attempt to develop potent antitumor agents. A regioselective approach using Huisgen 1,3-dipolar cycloaddition reaction of ursolic acid-alkyne derivative with various aromatic azides was employed to target an array of triazolyl derivatives in an efficient manner. Their structures were confirmed by using 1H NMR, 13C NMR, IR and MS analysis. All the compounds were evaluated for anticancer activity against a panel of four human cancer cell lines including A-549 (lung), MCF-7 (breast), HCT-116 (colon), THP-1 (leukemia) and a normal human epithelial cell line (FR-2) using sulforhodamine-B assay. The pharmacological results showed that most of the compounds displayed high level of antitumor activities against the tested cancer cell lines compared with ursolic acid. Compounds 7b, 7g, 7p and 7r were found to be the most potent compounds in this study.
- Rashid, Showkat,Dar, Bilal Ahmad,Majeed, Rabiya,Hamid, Abid,Bhat, Bilal Ahmad
-
-
Read Online
- Discovery of FZU-03,010 as a self-assembling anticancer amphiphile for acute myeloid leukemia
-
Recently various drug candidates with excellent anticancer potency have been demonstrated, whereas their clinical application largely suffers from several limitations especially poor solubility. Ursolic acid (UA) as one of ubiquitous pentacyclic triterpenes in plant kingdom exhibited versatile antiproliferative effects in various cancer cell lines. However, the unfavorable pharmaceutical properties became the main obstacle for its clinical development. With the aim of development of novel derivatives with enhanced potency, a series of diversified UA amphiphiles have been designed, synthesized, and pharmacologically evaluated. Amphiphile 10 (FZU-03,010) with significant improved antiproliferative effect can self-assemble into stable nanoparticles in water, which may serve as a promising candidate for further development.
- Chen, Yingyu,Li, Cailong,Zheng, Yunquan,Gao, Yu,Hu, Jianda,Chen, Haijun
-
-
Read Online
- Synthesis and evaluation of ursolic acid-based 1,2,4-triazolo[1,5-a]pyrimidines derivatives as anti-inflammatory agents
-
Here, two series of novel ursolic acid-based 1,2,4-triazolo[1,5-a]pyrimidines derivatives were synthesized and screened for their anti-inflammatory activity by evaluating their inhibition effect of using LPS-induced inflammatory response in RAW 264.7 macrophages in vitro; the effects of different concentrations of the compounds on the secretion of nitric oxide (NO) and inflammatory cytokines including TNF-α and IL-6 were evaluated. Their toxicity was also assessed in vitro. Results showed that the most prominent compound 3 could significantly decrease production of the above inflammatory factors. Docking study was performed for the representative compounds 3, UA, and Celecoxib to explain their interaction with cyclooxygenase-2 (COX-2) receptor active site. In vitro enzyme study implied that compound 3 exerted its anti-inflammatory activity through COX-2 inhibition.
- Zhang, Tian-Yi,Li, Chun-Shi,Li, Ping,Bai, Xue-Qian,Guo, Shu-Ying,Jin, Ying,Piao, Sheng-Jun
-
-
Read Online
- Anti-AIDS agents 38. Anti-HIV activity of 3-O-acyl ursolic acid derivatives
-
Based on our previous finding that 3-O-acyl-betulinic and -oleanolic acids, especially the 3-O-(3′,3′- dimethyl)-succinyl derivatives (2 and 4), demonstrated potent anti-HIV activity [EC50 20 000 and 22 326, respectively], several 3-O-acyl-ursolic acids were prepared and evaluated for anti-HIV activity. Ursolic acid (6) was equipotent (EC50 4.4 μM) with oleanolic acid (EC50 3.7 μM), although it was slightly toxic (IC50 14.3 μM, TI 3.3). 3-O-Diglycoryl-ursolic acid (10) demonstrated relatively potent anti-HIV-activity with an EC50 of 0.31 μM and a TI of 155.5. In contrast, 3-O-(3′,3′-dimethylsuccinyl)-ursolic acid (8), which is analogous to the extremely potent anti-HIV betulinic acid and oleanolic acid derivatives 2 and 4, displayed only weak anti-HIV activity (EC50 2.1 μM, TI 23.6).
- Kashiwada,Nagao,Hashimoto,Ikeshiro,Okabe,Cosentino,Lee
-
-
Read Online
- New derivatives of ursolic acid through the biotransformation by Bacillus megaterium CGMCC 1.1741 as inhibitors on nitric oxide production
-
Microbial transformation of ursolic acid (1) by Bacillus megaterium CGMCC 1.1741 was investigated and yielded five metabolites identified as 3-oxo-urs-12-en-28-oic acid (2); 1β,11α-dihydroxy-3-oxo-urs-12-en-28-oic acid (3); 1β-hydroxy-3-oxo-urs-12-en-28, 13-lactoe (4); 1β,3β, 11α-trihydroxyurs-12-en-28-oic acid (5) and 1β,11α-dihydroxy-3-oxo-urs-12-en-28-O-β-D-glucopyranoside (6). Metabolites 3, 4, 5 and 6 were new natural products. Their nitric oxide (NO) production inhibitory activity was assessed in lipopolysaccharide (LPS) – stimulated RAW 264.7 cells. Compounds 3 and 4 exhibited significant activities with the IC50 values of 1.243 and 1.711?μM, respectively. A primary structure-activity relationship was also discussed.
- Zhang, Chao,Xu, Shao-Hua,Ma, Bai-Ling,Wang, Wei-wei,Yu, Bo-Yang,Zhang, Jian
-
-
Read Online
- Synthesis and screening of ursolic acid-benzylidine derivatives as potential anti-cancer agents
-
Ursolic acid present abundantly in plant kingdom is a well-known compound with various promising biological activities including, anti-cancer, anti-inflammatory, hepatoprotective, antiallergic and anti-HIV properties. Herein, a library of ursolic acid-benzylidine derivatives have been designed and synthesized using Claisen Schmidt condensation of ursolic acid with various aromatic aldehydes in an attempt to develop potent antitumor agents. The compounds were evaluated against a panel of four human carcinoma cell lines including, A-549 (lung), MCF-7 (breast), HCT-116 (colon), THP-1 (leukemia) and a normal human epithelial cell line (FR-2). The results from MTT assay revealed that all the compounds displayed high level of antitumor activities compared with the triazole analogs (previously reported) and the parent ursolic acid. However, compound 3b, the most active derivative was subjected to mechanistic studies to understand the underlying mechanism. The results revealed that compound 3b induced apoptosis in HCT-116 cell lines, arrest cell cycle in the G1 phase, caused accumulation of cytochrome c in the cytosol and increased the expression levels of caspase-9 and caspase-3 proteins. Therefore, compound 3b induces apoptosis in HCT-116 cells through mitochondrial pathway.
- Dar, Bilal Ahmad,Lone, Ali Mohd,Shah, Wajaht Amin,Qurishi, Mushtaq Ahmad
-
-
Read Online
- Design, synthesis, anticancer activity and mechanism studies of novel 2-amino-4-aryl-pyrimidine derivatives of ursolic acid
-
A series of novel 2-amino-4-aryl-pyrimidine derivatives of ursolic acid were designed, synthesized, and evaluated for their anticancer activities against four cancer cell lines (MCF-7, HeLa, HepG2, and A549) and a human hepatocyte cell line (LO2) via MTT assay. Among these derivatives, compound 7b exhibited potent cytotoxic activity against MCF-7 and HeLa cells with IC50 values of 0.48 ± 0.11 and 0.74 ± 0.13 μM, respectively, and substantially lower cytotoxicity to LO2 cells. Further cellular mechanism studies in MCF-7 cells elucidated that compound 7b could inhibit cell migration, induce cell cycle arrest at S phase and trigger mitochondrial-related apoptosis by increasing the generation of intracellular ROS and decreasing the mitochondrial membrane potential (MMP), which was associated with upregulation of the protein expression level of Bax and downregulation the level of Bcl-2 and the activation of caspase cascade. Western blot analyses also revealed that compound 7b could simultaneously suppress RAS/Raf/MEK/ERK and PI3K/AKT/mTOR signaling pathways, which could be responsible for the induction of apoptosis. Molecular docking study revealed that MEK1 kinase could be one of the possible targets of the title compounds. These results offered a promising scaffold for the investigation of novel targeted anticancer agents.
- Gu, Wen,Li, A-Liang,Liu, Qing-Song,Sun, Yue,Wang, Wen-Yan,Yang, Zi-Hui
-
p. 2335 - 2350
(2022/02/16)
-
- Discovery of triterpenoids as potent dual inhibitors of pancreatic lipase and human carboxylesterase 1
-
Pancreatic lipase (PL) is a well-known key target for the prevention and treatment of obesity. Human carboxylesterase 1A (hCES1A) has become an important target for the treatment of hyperlipidaemia. Thus, the discovery of potent dual-target inhibitors based on PL and hCES1A hold great potential for the development of remedies for treating related metabolic diseases. In this study, a series of natural triterpenoids were collected and the inhibitory effects of these triterpenoids on PL and hCES1A were determined using fluorescence-based biochemical assays. It was found that oleanolic acid (OA) and ursolic acid (UA) have the excellent inhibitory effects against PL and hCES1A, and highly selectivity over hCES2A. Subsequently, a number of compounds based on the OA and UA skeletons were synthesised and evaluated. Structure–activity relationship (SAR) analysis of these compounds revealed that the acetyl group at the C-3 site of UA (compound 41) was very essential for both PL and hCES1A inhibition, with IC50 of 0.75 μM and 0.014 μM, respectively. In addition, compound 39 with 2-enol and 3-ketal moiety of OA also has strong inhibitory effects against both PL and hCES1A, with IC50 of 2.13 μM and 0.055 μM, respectively. Furthermore, compound 39 and 41 exhibited good selectivity over other human serine hydrolases including hCES2A, butyrylcholinesterase (BChE) and dipeptidyl peptidase IV (DPP-IV). Inhibitory kinetics and molecular docking studies demonstrated that both compounds 39 and 41 were effective mixed inhibitors of PL, while competitive inhibitors of hCES1A. Further investigations demonstrated that both compounds 39 and 41 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. Collectively, we found two triterpenoid derivatives with strong inhibitory ability on both PL and hCES1A, which can be served as promising lead compounds for the development of more potent dual-target inhibitors targeting on PL and hCES1A.
- He, Rong-Jing,Huo, Hong,Li, Yan-Ran,Pan, Qiu-Sha,Qian, Xing-Kai,Sun, Cheng-Gong,Sun, Lei,Wang, Le-Tian,Wang, Ya-Jie,Yang, Ling,Zhang, Jing,Zhou, Xiang-Lu,Zou, Li-Wei
-
p. 629 - 640
(2022/02/09)
-
- Synthesis and biological evaluation of pentacyclic triterpenoid derivatives as potential novel antibacterial agents
-
A series of ursolic acid (UA), oleanolic acid (OA) and 18β-glycyrrhetinic acid (GA) derivatives were synthesized by introducing a range of substituted aromatic side-chains at the C-2 position after the hydroxyl group at C-3 position was oxidized. Their antibacterial activities were evaluated in vitro against a panel of four Staphylococcus spp. The results revealed that the introduction of aromatic side-chains at the C-2 position of GA led to the discovery of potent triterpenoid derivatives for inhibition of both drug sensitive and resistant S. aureus, while the other two series derivatives of UA and OA showed no significant antibacterial activity even at high concentrations. In particular, GA derivative 33 showed good potency against all four Staphylococcus spp. (MIC = 1.25–5 μmol/L) with acceptable pharmacokinetics properties and low cytotoxicity in vitro. Molecular docking was also performed using S. aureus DNA gyrase to rationalize the observed antibacterial activity. This series of GA derivatives has strong potential for the development of a new type of triterpenoid antibacterial agent.
- Wu, Panpan,Tu, Borong,Liang, Jinfeng,Guo, Shengzhu,Cao, Nana,Chen, Silin,Luo, Zhujun,Li, Jiahao,Zheng, Wende,Tang, Xiaowen,Li, Dongli,Xu, Xuetao,Liu, Wenfeng,Zheng, Xi,Sheng, Zhaojun,Roberts, Adam P.,Zhang, Kun,Hong, Weiqian David
-
-
- Synthesis and antileukemic activity of an ursolic acid derivative: A potential co-drug in combination with imatinib
-
Imatinib, a specific Bcr-Abl tyrosine kinase inhibitor, is the most commonly used drug in the treatment of chronic myeloid leukemia. However, optimal response is not achieved in up to 33% of patients. Therefore, development of novel therapeutic strategies for chronic myeloid leukemia is critical. Betulinic (1) and ursolic (2) acids are natural pentacyclic triterpenes that exhibit antileukemic activities. In this study, we evaluated the effects of pharmacomodulations at the C-3 position of the triterpene moiety of betulinic and ursolic acids on their activity against K562 leukemia cells. Six new derivatives (1a-2c) were synthesized and evaluated for pro-apoptotic and anti-proliferative effects in mammalian and leukemic cells. 2c derivative containing an amine group at the C-3 position of ursolic acid was the most active against leukemia cells with an IC50 value of 5.2 μM after 48 h of treatment. 2c did not exhibit cytotoxic effects against VERO and HepG2 cells and human lymphocytes, showing a good selectivity index for cancer over normal cells. Induced cell death by apoptosis via caspases 3 and 8, and also caused cell cycle arrest as evidenced by accumulation of cells in the G1 phase and decreased cell population in the G2 phase. Furthermore, co-treatment of 2c with imatinib, the chemotherapy drug most commonly used to treat leukemia, resulted in a synergistic effect. Our findings provide a strong rationale for further investigation of combination therapy using the 2c derivative and imatinib in pre-clinical studies.
- da Silva, Elenilson F.,de Vargas, Artur S.,Willig, Julia B.,de Oliveira, Cristiane B.,Zimmer, Aline R.,Pilger, Diogo A.,Buffon, Andréia,Gnoatto, Simone C.B.
-
-
- Antibacterial and antitumoral properties of 1,2,3-triazolo fused triterpenes and their mechanism of inhibiting the proliferation of HL-60 cells
-
Antimicrobial resistance and cancer are two important problems affecting human health. Actively developing novel antibiotics and anticancer medicines is a priority. Natural pentacyclic triterpenoids have attracted wide attention due to their significant biological activities. In this study, a series of 1,2,3-triazolo fused triterpenoids (betulin, oleanolic acid and ursolic acid) were functionalized on the A-ring by an in-house developed multi-component triazolization reaction. The compounds were investigated for antitumoral activity in twelve cancer cell lines and were also tested for antibacterial activity against four bacteria. In terms of anticancer effects, compounds 5b-f and 8a-d displayed strong cytotoxic activity in pancreatic adenocarcinoma (Capan-1), chronic myeloid leukemia (Hap-1), acute myeloid leukemia (HL-60), acute lymphoblastic leukemia (Jurkat) and non-Hodgkin lymphoma (Rec-1) cell lines. Among them, compound 5f exhibited the most potent antiproliferative effect on HL-60 cells. Further pharmacological research confirmed that compound 5f caused mitochondrial dysfunction and arrested the cell cycle in the G0/G1 phase to induce apoptosis of HL-60 cells. In addition, compound 5f also induced autophagy to inhibit the proliferation of HL-60 cells. Antibacterial screening revealed that compounds 2a-g and 5a-d showed modest activity against Gram-negative bacteria (Escherichia coli and Salmonella enterica subsp. enterica) with especially compounds 2c and 2d being potent inhibitors of Salmonella enterica subsp. enterica growth. Because of their promising anticancer and antibacterial activity, this series of compounds deserve further study.
- Daelemans, Dirk,De Jonghe, Steven,Dehaen, Wim,Hu, Haibo,Krasniqi, Besir,Li, Yang,Luyten, Walter,Persoons, Leentje,Wang, Rui
-
-
- Synthesis, anticancer evaluation and mechanism studies of novel indolequinone derivatives of ursolic acid
-
A series of novel indolequinone derivatives of ursolic acid bearing ester, hydrazide, or amide moieties were designed, synthesized, and screened for their in vitro antiproliferative activities against three cancer cell lines (MCF-7, HeLa, and HepG2) and a normal gastric mucosal cell line (Ges-1). A number of compounds showed significant activity against tested cancer cell lines. Among them, compound 6t exhibited the most potent activity against three cancer cell lines with IC50 values of 1.66 ± 0.21, 3.16 ± 0.24, and 10.35 ± 1.63 μM, respectively, and considerably lower cytotoxicity to Ges-1 cells. Especially, compound 6t could arrest cell cycle at S phase, suppress the migration of MCF-7 cells, elevate intracellular reactive oxygen species (ROS) level, and decrease mitochondrial membrane potential. Western blot analysis showed that compound 6t upregulated Bax, cleaved caspase-3/9, cleaved PARP levels and downregulated Bcl-2 level of MCF-7 cells. All these results indicated that compound 6t could significantly induce the apoptosis of MCF-7 cells. Meanwhile, compound 6t markedly decreased p-AKT and p-mTOR expression, which revealed that compound 6t probably exerted its cytotoxicity through targeting PI3K/AKT/mTOR signaling pathway. Therefore, compound 6t could be a promising lead for the discovery of novel anticancer agents.
- Wang, Wen-Yan,Wu, Wen-Yi,Li, A-Liang,Liu, Qing-Song,Sun, Yue,Gu, Wen
-
-
- Ursolic acid pyrimidine amide derivative as well as preparation method and application thereof
-
The invention discloses an ursolic acid pyrimidine amide derivative as well as a preparation method and application thereof, and belongs to the technical field of organic synthesis and medicinal chemistry. The structural formula of the ursolic acid pyrimi
- -
-
Paragraph 0039-0041
(2021/06/23)
-
- Design, Synthesis and Biological Activity of C3 Hemisynthetic Triterpenic Esters as Novel Antitrypanosomal Hits
-
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.
- Schioppa, Laura,Beaufay, Claire,Bonneau, Natacha,Sanchez, Marianela,Girardi, Cynthia,Leverrier, Aurélie,Ortiz, Sergio,Palermo, Jorge,Poupaert, Jacques H.,Quetin-Leclercq, Jo?lle
-
p. 896 - 903
(2021/09/28)
-
- Synthesis and α-Glucosidase Inhibitory Activity of Ursolic Acid, Lupeol, and Betulinic Acid Derivatives
-
Seven synthetic derivatives of ursolic acid, lupeol, and betulinic acid (1a–1b, 2a–2b, and 3a–3c) were synthesized to study their α-glucosidase inhibitory activity. Three of them (2b, 3b, and 3c) are new compounds. Among the synthetic derivatives, betulinic acid analogues 3b and 3c exhibited the best activity against α-glucosidase and is superior to the positive agent, with IC50 values of 35.0 ± 3.37 and 34.0 ± 1.24 μM, respectively.
- Nguyen, Ngoc-Hong,Pham, Duc Dung,Le, Thi-Thanh-Van,Nguyen, Thi-Anh-Tuyet,Huynh, Dinh-Long,Duong, Thuc-Huy,Sichaem, Jirapast
-
p. 1038 - 1041
(2021/11/22)
-
- Semisynthesis of ursolic acid-2-(2-thienylidene)-oxadiazole hybrid molecule and an evaluation of its COX inhibition property
-
A new derivative of ursolic acid containing dual functionality was synthesized. Molecular docking studies and in vitro analysis indicated promising COX inhibition potential for the molecule. The synthesis, characterization, in silico and in vitro studies
- Deepthi, Ani,Krishnan, Deepa,Sanju, Anuroopa
-
supporting information
(2020/02/20)
-
- Low-toxicity anti-inflammatory ursolic acid derivative as well as preparation method and application thereof
-
The invention belongs to the technical field of pentacyclic triterpene compounds and application thereof, and particularly relates to a low-toxicity and anti-inflammatory ursolic acid derivative as well as a preparation method and application thereof. Acc
- -
-
Paragraph 0009; 0010; 0018-0020
(2020/09/09)
-
- Ursdic acid isatin amide derivatives as well as preparation method and application thereof
-
The invention discloses ursdic acid isatin amide derivatives as well as a preparation method and application thereof. The invention discloses ursdic acid isatin amide derivatives I-a to I-I with structures as shown in a general formula (I) and pharmaceutically acceptable salts thereof. The ursdic acid isatin amide derivatives and the pharmaceutically acceptable salts thereof disclosed by the invention have remarkable antitumor activity, and proven by pharmacological experiments, the ursdic acid isatin amide derivatives disclosed by the invention have an obvious effect on inhibiting human hepatoma cells HepG2 and SMMC-7721 and have the potential of developing antitumor drugs.
- -
-
Paragraph 0063-0065
(2020/02/17)
-
- Isatin ursolate derivative as well as preparation method and application thereof
-
The invention discloses an isatin ursolate derivative as well as a preparation method and application thereof, and belongs to the technical field of organic synthesis and medicinal chemistry. The structural general formula of the isatin ursolate derivativ
- -
-
Paragraph 0033-0035
(2020/02/10)
-
- Antimicrobial properties of amine- and guanidine-functionalized derivatives of betulinic, ursolic and oleanolic acids: Synthesis and structure/activity evaluation
-
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.
-
-
- With anti-tumor activity of ursolic acid derivative and its preparation method
-
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.
- -
-
Paragraph 0055-0057
(2019/05/08)
-
- Design, synthesis, and anticancer evaluation of novel quinoline derivatives of ursolic acid with hydrazide, oxadiazole, and thiadiazole moieties as potent MEK inhibitors
-
In this article, a series of novel quinoline derivatives of ursolic acid (UA) bearing hydrazide, oxadiazole, or thiadiazole moieties were designed, synthesised, and screened for their in vitro antiproliferative activities against three cancer cell lines (MDA-MB-231, HeLa, and SMMC-7721). A number of compounds showed significant activity against at least one cell line. Among them, compound 4d exhibited the most potent activity against three cancer cell lines with IC50 values of 0.12 ± 0.01, 0.08 ± 0.01, and 0.34 ± 0.03 μM, respectively. In particular, compound 4d could induce the apoptosis of HeLa cells, arrest cell cycle at the G0/G1 phase, elevate intracellular reactive oxygen species level, and decrease mitochondrial membrane potential. In addition, compound 4d could significantly inhibit MEK1 kinase activity and impede Ras/Raf/MEK/ERK transduction pathway. Therefore, compound 4d may be a potential anticancer agent and a promising lead worthy of further investigation.
- Jin, Xiao-Yan,Chen, Hao,Li, Dong-Dong,Li, A-Liang,Wang, Wen-Yan,Gu, Wen
-
p. 955 - 972
(2019/05/21)
-
- 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
-
-
- Synthesis and biological evaluation of ursolic acid derivatives bearing triazole moieties as potential anti-Toxoplasma gondii agents
-
Ursolic acid (UA), a plant-derived compound, has many properties beneficial to health. In the present study, we synthesised three series of novel UA derivatives and evaluated their anti-Toxoplasma gondii activity both in vitro and in vivo. Most derivative
- Luan, Tian,Jin, Chunmei,Jin, Chun-Mei,Quan, Zhe-Shan,Gong, Guo-Hua
-
p. 761 - 772
(2019/03/23)
-
- Synthesis and evaluation of the HIF-1α inhibitory activities of novel ursolic acid tetrazole derivatives
-
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
-
supporting information
p. 1440 - 1445
(2019/04/25)
-
- 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.
-
-
- Semisynthesis, cytotoxicity, antimalarial evaluation and structure-activity relationship of two series of triterpene derivatives
-
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
-
p. 265 - 272
(2018/02/15)
-
- Ursolic acid neutral cholesterol fat hydrolase inhibitors and use thereof (by machine translation)
-
The present invention provides a bearberries acid neutral cholesterol fat hydrolase inhibitors and its application, which belongs to the technical field of biological medicines. The bearberries compounds can be potent to, selectively inhibiting NCEH1 active, thereby improving the carboxylic acid ester exogenous precursor oral bioavailability. Such inhibitors can inhibit clopidogrel metabolism non-active product, as clopidogrel of the synergist. Such inhibitors also can be through inhibiting the NCEH1 involved in fat metabolism, relieve the lipid ectopic deposition-induced insulin resistance development to sugar impaired glucose tolerance. The in vitro activity assay revealed that the compound (3 - suosuo third acyl - ursolic acid) inhibit NCEH1 of IC50 Can reach 12 accepts morocco, and its another human carboxylic acid esterase (hCE2) did not significantly inhibit, selectivity as high as 6919 times. In addition, the compounds also has good safety, simple preparation process, synthetic high yield strengths, prompting the compounds display has good application prospect. (by machine translation)
- -
-
Paragraph 0030-0032; 0035
(2018/04/26)
-
- Design, synthesis and biological evaluation of seco-A-pentacyclic triterpenoids-3,4-lactone as potent non-nucleoside HBV inhibitors
-
A series of seco-A-pentacyclic triterpenoids-3,4-lactone were synthesized and the anti-HBV activities were evaluated in vitro. Several compounds inhibited the secretion of HBV antigen and the replication of HBV DNA in micromolar level. Compounds D7 and D10, seco-A-oleanane-3,4-lactone, suppressed the HBeAg secretion with IC50 values of 0.14 μM and 0.86 μM respectively, and the inhibitory activities were also confirmed by detecting the fluorescence intensity of FITC-labeled monoclonal mouse HBeAg antibody via flow cytometry. Compounds D7 and D10 as well as B4, ring-A cleaved 3,30-dioic acid, also displayed remarkable inhibition on both HBV DNA replication at the concentration of 25 μM and HBV cccDNA (covalently closed circularDNA) replication with IC50 values of 33.5 μM, 32.7 μM and 12.3 μM respectively.
- Li, Zhijian,Min, Qingxi,Huang, Haoji,Liu, Ruixuan,Zhu, Yongyan,Zhu, Quanhong
-
supporting information
p. 1501 - 1506
(2018/04/20)
-
- Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors
-
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
-
p. 2235 - 2243
(2018/10/20)
-
- Ursolic acid derivative, preparation method thereof, and application thereof in preparation of drug for treating MRSA infection
-
The invention discloses an ursolic acid derivative, a preparation method thereof, and an application thereof in the preparation of a drug for treating methicillin-resistant Staphylococcus aureus (MRSA) infection. The preparation method comprises the following steps: oxidizing ursolic acid by a Sarrett reagent to obtain a 3-hydroxy oxidation product of ursolic acid, and carrying out reductive amination on the 3-hydroxy oxidation product of ursolic acid by isopropyl titanate and sodium triacetoxyborohydride in order to prepare the ursolic acid derivative. Anti-MRSA activity test proves that theMIC of the obtained ursolic acid derivative on MRSA test strains is 16-32 [mu]g/mL, the anti-MRSA activity of the ursolic acid derivative is 4-8 times higher than that of the ursolic acid, and the derivative can form a salt together with equimolar hydrochloric acid in order to significantly improve the water solubility. The ursolic acid derivative has a significant anti-MRSA activity and a good development prospect, and can be used to prepare the drug for treating the MRSA infection.
- -
-
Page/Page column 5-8
(2018/11/27)
-
- With anti-inflammatory activity of ursolic acid derivatives and its preparation and use (by machine translation)
-
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)
- -
-
Paragraph 0052
(2017/09/05)
-
- Ursolic acid quinolinyl hydrazide derivative with anti-tumor activity as well as preparation method and application thereof
-
The invention discloses an ursolic acid quinolinyl hydrazide derivative with anti-tumor activity as well as a preparation method and application thereof. The invention provides an ursolic acid quinolinyl hydrazide heterocyclic derivative with a structure shown as a general formula I and pharmaceutically acceptable salt thereof: the formula I is shown in the description, wherein I-a: R1 is equal to H and R2 is equal to CH3; I-b: R1 is equal to OMe and R2 is equal to CH3; I-c: R1 is equal to F and R2 is equal to CH3; I-d: R1 is equal to C1 and R2 is equal to CH3; I-e: R1 is equal to H1 and R2 is equal to n-C4H9; I-f: R1 is equal to OMe and R2 is equal to n-C4H9; I-g: R1 is equal to F and R2 is equal to n-C4H9; I-h: R1 is equal to C1 and R2 is equal to n-C4H9. The ursolic acid quinolinyl hydrazide heterocyclic derivative and the pharmaceutically acceptable salt thereof, provided by the invention, have the remarkable anti-tumor activity; a pharmacology experiment shows that the ursolic acid quinolinyl hydrazide derivative disclosed by the invention has a remarkable inhibition effect on human breast cancer cells MDA-MB-231, human cervical cancer cells HeLa and human hepatoma cells SMMC-7721, has low toxicity on human normal epithelial cells QSG-7701 and has a potential of being used for developing anti-tumor drugs.
- -
-
Paragraph 0128; 0129; 0130
(2018/01/19)
-
- 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
-
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
-
p. 1421 - 1434
(2017/07/25)
-
- Effective synthesis of novel furan-fused pentacyclic triterpenoids via anionic 5-exo dig cyclization of 2-alkynyl-3-oxotriterpene acids
-
An efficient synthetic route to biologically interesting furan-fused pentacyclic triterpenoids with a furan moiety 2,3-annelated to the terpenoid skeleton has been developed. New heterocyclic triterpenoids have been obtained in moderate to good yields by base-promoted 5-exo-dig cyclization of the pent-4-yn-1-one moiety in ring А of the 2-alkynyl-3-oxotriterpene acids of lupane, ursane and oleane type.
- Gubaidullin, Rinat R.,Yarmukhametova, Darina S.,Nedopekina, Darya A.,Khalitova, Rezeda R.,Spivak, Anna Yu.
-
p. 100 - 116
(2017/08/10)
-
- Design, synthesis and in vitro anticancer activity of novel quinoline and oxadiazole derivatives of ursolic acid
-
A series of new quinoline derivatives of ursolic acid were designed and synthesized in an attempt to develop potential anticancer agents. The structures of these compounds were identified by 1H NMR, 13C NMR, IR and ESI-MS spectra analysis. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (MDA-MB-231, Hela and SMMC-7721). From the results, compounds 3a–d displayed significant antitumor activity against three cancer cell lines. Especially, compound 3b was found to be the most potent derivative with IC50 values of 0.61 ± 0.07, 0.36 ± 0.05, 12.49 ± 0.08 μM against MDA-MB-231, HeLa and SMMC-7721 cells, respectively, stronger than positive control etoposide. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound 3b could significantly induce the apoptosis of MDA-MB-231 cells in a dose-dependent manner. The cell cycle analysis also indicated that compound 3b could cause cell cycle arrest of MDA-MB-231 cells at G0/G1 phase.
- Gu, Wen,Jin, Xiao-Yan,Li, Dong-Dong,Wang, Shi-Fa,Tao, Xu-Bing,Chen, Hao
-
p. 4128 - 4132
(2017/08/23)
-
- Urea derivates of ursolic, oleanolic and maslinic acid induce apoptosis and are selective cytotoxic for several human tumor cell lines
-
2,3-Di-O-acetyl-maslinic acid benzylamide (5) has previously been shown to possess high cytotoxicity for a variety of human tumor cell lines while being of low cytotoxicity to non-malignant cells. Structural modifications performed on 5 revealed that the presence of these acetyl groups in 5 and the presence of (2β,3β)-configurated centers seems necessary for obtaining high cytotoxicity combined with best selectivity between malignant cells and non-malignant mouse fibroblasts. Compounds carrying an ursane skeleton showed weaker cytotoxicity than their oleanane derived analogs. In addition, the benzylamide function in compound 5 should be replaced by a phenylurea moiety to gain better cytotoxicity while retaining and improving the selectivity. Thus, maslinic acid derived N-[2β,3β-di-O-acetyl-17β-amino-28-norolean-12-en-17-yl]phenylurea (45) gave best results showing EC50 = 0.9 μM (for A2780 ovarian cancer cells) with EC50 > 120 μM for fibroblasts (NIH 3T3) and triggered apoptosis while caspase-3 was not activated by this compound.
- Sommerwerk, Sven,Heller, Lucie,Kuhfs, Julia,Csuk, René
-
-
- Targeting cancer cells with oleanolic and ursolic acid derived hydroxamates
-
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
-
supporting information
p. 907 - 909
(2016/05/24)
-
- 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
-
-
- A kind of bearberries acid indole derivatives, preparation method and its use
-
The invention relates to the field of organic synthesis and medicinal chemistry, in particular to a preparation method of an ursolic acid indole derivative having the cytotoxic activity of human body tumor cells, pharmaceutical composition containing the
- -
-
Paragraph 0014; 0022; 0023
(2016/10/31)
-
- Effective synthesis of novel C(2)-propargyl derivatives of betulinic and ursolic acids and their conjugation with β-d-glucopyranoside azides via click chemistry
-
A new synthetic approach to the incorporation of an alkynyl group into pentacyclic triterpenoids was developed and utilized to prepare C(2)-propargyl derivatives of lupane- and ursane-type triterpenoic acids. Novel triterpenoid derivatives with a propynyl group at the C(2) atom were successfully used for click chemistry bioconjugation with glucopyranoside azides.
- Spivak, Anna Yu.,Gubaidullin, Rinat R.,Galimshina, Zulfiya R.,Nedopekina, Darya A.,Odinokov, Victor N.
-
p. 1249 - 1256
(2016/02/16)
-