- Synthesis and biological evaluation of T-OA analogues as the cytotoxic agents
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Abstract The lead compound T-OA, 3β-hydroxyolean-12-en-28-oic acid-(3,5,6-trimethylpyrazine-2-yl) methyl ester, which exhibited promising anticancer effects in vitro and in vivo, has previously been reported. According to the structural features, a series of novel T-OA analogues were synthesized via amino condensation reaction. These analogues' cytotoxic activities were evaluated on five cancer cell lines (Bel-7402, HepG-2, HT-29, Hela, BGC-823) and hepatic stellate cell line (HSC-6). Among the candidates, compounds 8 and 16 showed promising effects; 3β-hydroxy-lup-20(29)-ene-28-oic acid-(3,5,6-trimethylpyrazin-2-yl) methyl amine (16) even possessed superior bioactivities to positive drugs (cisplatin and ursolic acid), which was worthy of further study. In addition, structure-activity relationships and Clog P values of T-OA analogues were briefly discussed.
- Xu, Kuo,Xu, Xin,Chu, Fuhao,Wang, Mina,Wang, Penglong,Li, Guoliang,Song, Jixiang,Zhang, Yuzhong,Lei, Haimin
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- Oleanolic acid indole derivatives as novel α-glucosidase inhibitors: Synthesis, biological evaluation, and mechanistic analysis
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Research efforts have been directed to the development of oleanolic acid (OA) based α-glucosidase inhibitors and various OA derivatives showed improved anti-α-glucosidase activity. However, the inhibitory effects of indole infused OA derivatives on α-glucosidase is unknown. Herein, we synthesized a series of indole-OA (2a-2o) and -OA methyl ester (3a-3 l) derivatives with various electron withdrawing groups inducted to indole benzene ring and evaluated their anti-α-glucosidase activity. Indole OA derivatives (2a-2o) exhibited superior α-glucosidase inhibitory effects as compared to OA methyl ester derivatives (3a-3l) and OA (with IC50 values of 4.02 μM-5.30 μM v.s. over 10 μM and 5.52 μM, respectively). In addition, mechanistic studies using biochemical (kinetic assay), biophysical (circular dichroism), and computational (docking) methods revealed that OA-indole derivatives (2a and 2f) are mixed type of α-glucosidase inhibitors and their inhibitory effects were attributed to their capacity of forming the ligand-enzyme complex with α-glucosidase enzyme. Findings from this study support that OA indole derivatives are promising α-glucosidase inhibitors as a potential management of diabetes mellitus.
- Wu, Panpan,He, Hao,Ma, Hang,Tu, Borong,Li, Jiahao,Guo, Shengzhu,Chen, Silin,Cao, Nana,Zheng, Wende,Tang, Xiaowen,Li, Dongli,Xu, Xuetao,Zheng, Xi,Sheng, Zhaojun,David Hong, Weiqian,Zhang, Kun
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- Novel A-ring cleaved analogs of oleanolic and ursolic acids which affect growth regulation in NRP.152 prostate cells
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Syntheses of eight novel A-ring cleaved oleanane and ursane analogs are described. These compounds were assessed for their ability to inhibit cell proliferation in NRP. 152 prostate cells. Four A-ring cleaved derivatives showed significant activity; 5β-(1-methyl-2-ethyl)-10α-(3-aminopropyl)- des-A-urs-12-en-28-oic acid was the most active compound, (IC50, 0.3 μM).
- Finlay, Heather J.,Honda, Tadashi,Gribble, Gordon W.,Danielpour, David,Benoit, Nicole E.,Suh, Nanjoo,Williams, Charlotte,Sporn, Michael B.
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- Methyl 1,2-shift rearrangement on c-ring and decarboxylation at C28 of oleanolic acid derivatives
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A new oleanolic acid derivative with A-ring lactone, C-ring rearrangement and decarboxylation at C28 was synthesized, which was confirmed by HRMS, NMR and X-ray crystal structure. It is the first report about the methyl rearrangement on C-ring of oleanoli
- Hu, Jun,Wu, Jindan,Ju, Yong
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- Synthesis and in vitro activity of oleanolic acid derivatives against Chlamydia trachomatis and Staphylococcus aureus
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A series of nitrogen-containing modificants with amide, arylidene or heterocyclic fragments of oleanolic, oleanonic and 2,3-indolo-oleanolic acids have been synthesized and evaluated for activity against C. trachomatis and key ESKAPE pathogens. Oleanolic acid conjugates with homopyperazine 3, N-hydroxymethyl-homopyperazine 4, and diethylenetriamine 23 demonstrated a high inhibitory activity against C. trachomatis with chemotherapeutic index (CTI) 8 and >8, while 3-amino-3,4-seco-4(23)-en-erythrodiol 22 was found to be a leader compound with significant activity (MIC 3.125 μg/mL). Compounds 3 and 22 showed a moderate activity against MRSA with MICs of 8 and 4 μg/mL. Compounds 2, 3, and 23 exhibited remarkable activities against NCI-60 subpanel (GI50 ranges from 0.18 to 2.21 μM) exceeding the activity of sorafenib with compound 23 as a leader (GI50 0.17 μM for melanoma LOX IMVI). [Figure not available: see fulltext.]
- Kazakova, Oxana,Rubanik, Liudmila,Smirnova, Irina,Poleschuk, Nikolay,Petrova, Anastasia,Kapustsina, Yuliya,Baikova, Irina,Tret’yakova, Elena,Khusnutdinova, Elmira
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- Pentacyclic triterpene derivatives possessing polyhydroxyl ring A inhibit Gram-positive bacteria growth by regulating metabolism and virulence genes expression
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The hydroxyl group in ring A of pentacyclic triterpene is essential for antibacterial activity. Pentacyclic triterpenes bearing three hydroxyl groups in ring A were mainly found in plants and displayed significant antibacterial activity. However, no study
- Huang, Lirong,Luo, Heng,Li, Qiji,Wang, Daoping,Zhang, Jianxin,Hao, Xiaojiang,Yang, Xiaosheng
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- Microbial hydroxylation and glycosylation of pentacyclic triterpenes as inhibitors on tissue factor procoagulant activity
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To discover new inhibitors on tissue factor procoagulant activity, 20 pentacyclic triterpenes were semi-synthetized through microbial transformation and assayed on the model of human THP-1 cells stimulated by lipopolysaccharide. In the biotransformation two types of reactions were observed, regio-selective hydroxylation and glycosylation. The bioassay results showed that most of tested compounds were significant effective on this model and two of the biotransformation products 23-hydroxy-28-O-β-D-glucopyranosyl betulinic acid (3d) and 28-O-β-D-glucopyranosyl oleanic acid (1a) exhibited most potential activities with the IC50 values of 0.028, 0.035 nM respectively. The preliminary structure and activity relationship analysis revealed that the aglycones with single free hydroxyl group on the skeleton (1, 1j) were less effective than that with more free hydroxyl groups (1d, 1f, 2), mono-glycosylation can significantly enhance their inhibitory effects. Our findings also provide some potential leading compounds for tissue factor-related diseases, such as cancer and cardiovascular diseases.
- Wang, Wei-Wei,Xu, Shao-Hua,Zhao, Ya-Zheng,Zhang, Chao,Zhang, Yuan-Yuan,Yu, Bo-Yang,Zhang, Jian
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- Ring-A cleavage of 3-oxo-olean-12-en-28-oic acid by the fungus Chaetomium longirostre
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3-Oxo-olean-12-en-28-oic acid was transformed by the filamentous fungus Chaetomium longirostre into 3,4-seco-olean-12-en-4-ol-3,28-dioic acid and the 21β-hydroxylated compound. A cell-free preparation derived from the fungus converted 3-oxo-olean 12-en-28-oic acid into 3,4-seco-olean-12-en-4-ol-3,28- dioic acid. The ring-A cleavage activity was detected in the soluble fraction of the cell-free preparation and showed a requirement for NADPH.
- Shirane, Noboru,Hashimoto, Yutaka,Ueda, Kazuo,Takenaka, Hideyuki,Katoh, Kenji
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- 2-Cyano-3,10-dioxooleana-1,9(11)-dien-28-oic acid anhydride. A novel and highly potent anti-inflammatory and cytoprotective agent
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2-Cyano-3,10-dioxooleana-1,9(11)-dien-28-oic acid anhydride (CDDO anhydride) has been synthesized, which is the first example of an oleanane triterpenoid anhydride. CDDO anhydride shows potency similar to or higher than the corresponding acid (CDDO) in various in vitro and in vivo assays related to inflammation and carcinogenesis. Notably, preliminary phamacokinetics studies show that CDDO anhydride levels are higher than CDDO levels in mouse tissues and blood. Further evaluation of CDDO anhydride is in progress.
- Honda, Tadashi,Padegimas, Eric M.,David, Emilie,Sundararajan, Chitra,Liby, Karen T.,Williams, Charlotte,Sporn, Michael B.,Visnick, Melean
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- Triterpenoids as novel natural inhibitors of human cathepsin L
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Cathepsins L (catL) and B play an important role in tumor progression and have been considered promising therapeutic targets in the development of novel anticancer agents. Using a bioactivity-guided fractionation, a series of triterpenoids was identified as a new class of competitive inhibitors towards cathepsin L with affinity values in micromolar range. Among the 14 compounds evaluated, the most promising were 3-epiursolic acid (3), 3-(hydroxyimino)oleanolic acid (9), and 3-(hydroxyimino)masticadienoic acid (13) with IC50 values of 6.5, 2.4, and 2.6 μM on catL, respectively. Most of the evaluated triterpenoids do not inhibit cathepsin B. Thus, the evaluated compounds exhibit a great potential to help in the design of new inhibitors with enhanced potency and affinity towards catL. Docking studies were performed in order to gain insight on the binding mode and SAR of these compounds.
- Ramalho, Suelem D.,De Sousa, Lorena R. F.,Nebo, Liliane,Maganhi, Stella H.,Caracelli, Ignez,Zukerman-Schpector, Julio,Lima, Maria Inês S.,Alves, Marcio F. M.,Da Silva, M. Fátima Das G. F.,Fernandes, Jo?o B.,Vieira, Paulo C.
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- Practical application of oxidation using a novel Na2WO 4-H2O2 system under neutral conditions for scale-up manufacturing of 12α-Hydroxy-3-oxooleanano-28,13-lactone: Key intermediate of endothelin a receptor antagonist S-0139
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Novel alcohol oxidation using a Na2WO4-H 2O2 system was applied to manufacture 12α-hydroxy-3- oxooleanano-28,13- lactone which is a key intermediate of S-0139. Oxidation of the hydroxyl group of oleanolic acid was optimized based on the design of experiment (DoE) approach. Statistical analysis was used to maximize the yield of the corresponding ketone and minimize the generation of byproducts. The safety evaluation of this oxidation was also conducted in detail, and pilot manufacturing was achieved.
- Hida, Takemasa,Fukui, Yuuki,Kawata, Kyozo,Kabaki, Mikio,Masui, Toshiaki,Fumoto, Masataka,Nogusa, Hideo
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- Strong inhibitory activity and action modes of synthetic maslinic acid derivative on highly pathogenic coronaviruses: Covid-19 drug candidate
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In late December 2019, a novel coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), escaped the animal–human interface and emerged as an ongoing global pandemic with severe flu-like illness, commonly known as coronavirus disea
- Al-Karmalawy, Ahmed A.,Alasiri, Ahlam,Ali, Mohamed A.,Choua?b, Karim,Chrouda, Amani,Dhahri, Abdelwaheb,Gharbi, Jawhar,Jannet, Hichem Ben,Kutkat, Omnia,Mostafa, Ahmed,Pashameah, Rami Adel,Shehata, Mahmoud,Soltane, Raya
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- Synthesis and biological evaluations of oleanolic acid indole derivatives as hyaluronidase inhibitors with enhanced skin permeability
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Oleanolic acid (OA) is a natural cosmeceutical compound with various skin beneficial activities including inhibitory effect on hyaluronidase but the anti-hyaluronidase activity and mechanisms of action of its synthetic analogues remain unclear. Herein, a series of OA derivatives were synthesised and evaluated for their inhibitory effects on hyaluronidase. Compared to OA, an induction of fluorinated (6c) and chlorinated (6g) indole moieties led to enhanced anti-hyaluronidase activity (IC50 = 80.3 vs. 9.97 and 9.57 μg/mL, respectively). Furthermore, spectroscopic and computational studies revealed that 6c and 6g can bind to hyaluronidase protein and alter its secondary structure leading to reduced enzyme activity. In addition, OA indole derivatives showed feasible skin permeability in a slightly acidic environment (pH = 6.5) and 6c exerted skin protective effect by reducing cellular reactive oxygen species in human skin keratinocytes. Findings from the current study support that OA indole derivatives are potential cosmeceuticals with anti-hyaluronidase activity.
- He, Hao,Li, Huifang,Akanji, Toyosi,Niu, Shengli,Luo, Zhujun,Li, Dongli,Seeram, Navindra P.,Wu, Panpan,Ma, Hang
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- A Series of Oleanolic Acid Derivatives as Anti-Hepatitis B Virus Agents: Design, Synthesis, and in Vitro and in Vivo Biological Evaluation
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A series of oleanolic acid derivatives were synthesized by diverse reactions, including the introduction of conjugated alkadiene and epoxy ring moieties formed by means of photosensitized oxidation. Eosin Y was used as photosensitizer during this process. Next the cytotoxicity of the products was evaluated on HepG2.2.15 cells to determine the appropriate treatment concentration for the subsequent experiments. Most of the OA derivatives exhibited anti-HBV antigens secretion activity in HepG2.2.15 cells. Among the tested compounds, OA-4 (3.13 μg/mL) showed significant activity against the secretion of HBsAg, HBeAg, and HBV DNA replication with inhibitory ratios of 90.52% ± 1.78%, 31.55% ± 3.65%, and 94.57% ± 3.11% after 6 days, respectively. Besides, OA-4 was further investigated in a duck model with DHBV infection. When OA-4 was administered at a dosage of 500 mg/kg, the results revealed a significant inhibitory effects of DHBV at 19.94% ± 2.87%, 28.80% ± 3.62% and 29.25% ± 2.65% at days 5, 10, and 3 after the cessation of OA-4 treatment, respectively. It's worth noting that OA-4 is superior to lamivudine in the inhibition of rebound of viral replication rate. The structure-activity relationships of OA derivatives had been preliminary discussed, which should be useful to explore further novel anti-HBV agents.
- Yan, Wenqiang,Zhang, Chenze,Li, Bi,Xu, Xin,Liang, Miao,Gu, Shun,Chu, Fuhao,Xu, Bing,Ren, Jian,Wang, Penglong,Lei, Haimin
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- Synthesis of new betulonic and oleanonic acid amides
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Amides of betulonic and oleanonic acids with diethylenetriamine, triethylenetetramine, and spermidine were synthesized. Antitumor activity in vitro was not found for the conjugate of betulonic acid with diethylenetriamine.
- Giniyatullina,Kazakova,Salimova,Tolstikov
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- Synthesis and antitumor activity evaluation of novel oleanolic acid derivatives
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Ten novel oleanolic acid (OA) derivatives were synthesized through modifications at positions of A ring and C-28. Inhibitory activities of the oleanolic acid derivatives against SGC7901 and A549 cell lines were evaluated and confirmed by the tetrazolium b
- Meng, Yan-Qiu,Zhao, Yu-Wei,Kuai, Zhen-Yu,Liu, Li-Wei,Li, Wei
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- Anti-AIDS agents, 30. Anti-HIV activity of oleanolic acid, pomolic acid, and structurally related triterpenoids
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Oleanolic acid (1) was identified as an anti-HIV principle from several plants, including Rosa woodsii (leaves), Prosopis glandulosa (leaves and twigs), Phoradendron juniperinum (whole plant), Syzygium clavifiorum (leaves), Hyptis capitata (whole plant), and Ternstromia gymnanthera (aerial part). It inhibited HIV-1 replication in acutely infected H9 cells with an EC50 value of 1.7 μg/mL, and inhibited H9 cell growth with an IC50 value of 21.8 μg/mL [therapeutic index (T. I.) 12.8]. Pomolic acid, isolated from R. woodsii and H. capitata, was also identified as an anti-HIV agent (EC50 1.4 μg/mL, T. I. 16.6). Although ursolic acid did show anti-HIV activity (EC50 2.0 μg/mL), it was slightly toxic (IC50 6.5 μg/mL, T. I. 3.3). A new triterpene (11) was also isolated from the CHCl3-soluble fraction of R. woodsii, though it showed no anti-HIV activity. The structure of 11 was determined to be 1β-hydroxy-2-oxopomolic acid by spectral examination. Based on these results, we examined the anti-HIV activity of oleanolic acid- or pomolic acid-related triterpenes isolated from several plants. In addition, we previously demonstrated that derivatives of betulinic acid, isolated from the leaves of S. claviflorum as an anti-HIV principle, exhibited extremely potent anti-HIV activity. Accordingly, we prepared derivatives of oleanolic acid and evaluated their anti-HIV activity. Among the oleanolic acid derivatives, 18 demonstrated most potent anti-HIV activity, with an EC50 value of 0.0005 μg/mL and a T. I. value of 22 400.
- Kashiwada, Yoshiki,Wang, Hui-Kang,Nagao, Tsuneatsu,Kitanaka, Susumu,Yasuda, Ichiro,Fujioka, Toshihiro,Yamagishi, Takashi,Cosentino, L. Mark,Kozuka, Mutsuo,Okabe, Hikaru,Ikeshiro, Yasumasa,Hu, Chang-Qi,Yeh, Eric,Lee, Kuo-Hsiung
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- An efficient semi-synthesis of 1-hydroxyl oleanolic acid analogs
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An efficient route for the semi-synthesis of either 1α- or 1β-OH epimers of 1-hydroxy-3-deoxyolean-12-en-28-oic acid (1), 6–8 steps from oleanolic acid is reported. The synthesis involves stereoselective formation of α,β-unsaturated epoxy ketone and subsequent Wharton reaction as key steps, offering a new access to the 1-O-substituted oleanolic acid-type pentacyclic triterpenoids.
- Zhang, Da-Hui,Fang, Wei-Shuo,Wang, Shao-Rong
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- Anticancer effect of SZC015 on lung cancer cells through ROS-dependent apoptosis and autophagy induction mechanisms in vitro
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Oleanolic acid (OA) and its several derivatives possess various pharmacological activities, such as antitumor and anti-inflammation. In present study, anticancer effect of SZC015, an OA derivative, and its underlying mechanisms were investigated. We demonstrated that cell viability was significantly decreased in SZC015-treated lung cancer cells, but has less cytotoxicity in human bronchial epithelial cell line. Further investigation verified that apoptosis and autophagy induction and G0/G1 phase arrest were observed in SZC015-treated H322 cells. Mechanically, the level of Akt, p-Akt, p-IκBα, and total p65, the p-p65 in the cytoplasm and nucleus were suppressed by SZC015 in H322 cells, respectively. Inhibition of p65 nuclear translocation was also confirmed by immunofluorescence staining. In addition, co-treatment with chloroquine, an autophagy inhibitor, significantly inhibited SZC015-induced autophagy and enhanced SZC015-induced apoptotic cell death. Intracellular ROS was increased in a concentration-dependent manner, which could be prevented by N-Acetyl L-Cysteine, an ROS scavenger. Moreover, the level of Akt and procaspase-3 were increased, while the ratio of LC3 II/I was decreased. Taken together, our study demonstrates that the inhibitory effect of SZC015 against H322 cells is mediated by excessive ROS generation that could suppress Akt/NF-κB signaling pathway, which thereby leads to apoptotic and autophagic cell death.
- Sun, Bin,Gao, Lei,Ahsan, Anil,Chu, Peng,Song, Yanlin,Li, Hailong,Zhang, Zonghui,Lin, Yuan,Peng, Jinyong,Song, Zhicheng,Wang, Shisheng,Tang, Zeyao
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- Fluorescent probes for subcellular localization during osteclast formation
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Labeling of a small bioactive molecule with fluorescent probe has been becoming an essential tool in cell biology to reveal the subcellular distribution and the location of a molecular target. QOA-8a is a novel molecule with potent antiosteoporotic effect in vivo. To investigate the molecular mechanism of QOA-8a, novel fluorescence-tagged chemical probes as bioactive as their parent molecule were designed and synthesized. The fluorescent compound 12 showed a more potent inhibitory activity on RANKL-induced osteoclastogenesis at 2 μM compared with that of QOA-8a. Microscopy experiments revealed that almost all of probe 12 accumulated in the fusing region, with little in the osteoclast precursors or the mature osteoclasts during osteoclast formation. The result suggests the location of the binding target of QOA-8a, which might greatly narrow down the search field of the target protein(s).
- Wu, Jing,Shen, Qi,Wang, Yue,Zhao, Dan,Peng, Chen,Li, Jian-Xin
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- Design, synthesis, and antitumor activity of oleanolic acid derivatives
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Using the techniques of computer-aided drug design, the docking of survivin and known active small molecules was simulated and then the key amino acid residue fragments of the target protein were analyzed. It led to the discovery of active groups capable
- Meng, Yan-Qiu,Kuai, Zhen-Yu,Zhan, Shen-Wen,Li, Chun-Lin,Chen, Hong-Rong
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- Antibacterial and antitumoral properties of 1,2,3-triazolo fused triterpenes and their mechanism of inhibiting the proliferation of HL-60 cells
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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
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- Synthesis and bioactivities evaluation of oleanolic acid oxime ester derivatives as α-glucosidase and α-amylase inhibitors
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Different oleanolic acid (OA) oxime ester derivatives (3a-3t) were designed and synthesised to develop inhibitors against α-glucosidase and α-amylase. All the synthesised OA derivatives were evaluated against α-glucosidase and α-amylase in?vitro. Among them, compound 3a showed the highest α-glucosidase inhibition with an IC50 of 0.35 μM, which was ～1900 times stronger than that of acarbose, meanwhile compound 3f exhibited the highest α-amylase inhibitory with an IC50 of 3.80 μM that was ～26 times higher than that of acarbose. The inhibition kinetic studies showed that the inhibitory mechanism of compounds 3a and 3f were reversible and mixed types towards α-glucosidase and α-amylase, respectively. Molecular docking studies analysed the interaction between compound and two enzymes, respectively. Furthermore, cytotoxicity evaluation assay demonstrated a high level of safety profile of compounds 3a and 3f against 3T3-L1 and HepG2 cells.Highlights Oleanolic acid oxime ester derivatives (3a–3t) were synthesised and screened against α-glucosidase and α-amylase. Compound 3a showed the highest α-glucosidase inhibitory with IC50 of 0.35 μM. Compound 3f presented the highest α-amylase inhibitory with IC50 of 3.80 μM. Kinetic studies and in silico studies analysed the binding between compounds and α-glucosidase or α-amylase.
- Deng, Xu-Yang,Ke, Jun-Jie,Li, Dong-Li,Wu, Jing-Ying,Wu, Pan-Pan,Xiong, Zhuang,Xu, Xue-Tao,Zhang, Kun,Zheng, Xi,Zheng, Ying-Ying
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p. 451 - 461
(2022/01/20)
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- Discovery of triterpenoids as potent dual inhibitors of pancreatic lipase and human carboxylesterase 1
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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
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p. 629 - 640
(2022/02/09)
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- Synthesis and biological evaluation of pentacyclic triterpenoid derivatives as potential novel antibacterial agents
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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
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- Design, synthesis, molecular modelling, and biological evaluation of oleanolic acid-arylidene derivatives as potential anti-inflammatory agents
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Introduction: Oleanolic acid, a pentacyclic triterpenic acid, is widely distributed in medicinal plants and is the most commonly studied triterpene for various biological activities, including anti-allergic, anti-cancer, and anti-inflammatory. Methods: The present study was carried out to synthesize arylidene derivatives of oleanolic acid at the C-2 position by Claisen Schmidt condensation to develop more effective anti-inflammatory agents. The derivatives were screened for anti-inflammatory activity by scrutinizing NO production inhibition in RAW 264.7 cells induced by LPS and their cytotoxicity. The potential candidates were further screened for inhibition of LPS-induced interleukin (IL-6) and tumour necrosis factor-alpha (TNF-α) production in RAW 264.7 cells. Results: The results of in vitro studies revealed that derivatives 3d, 3e, 3L, and 3o are comparable to that of the oleanolic acid on the inhibition of TNF-α and IL-6 release. However, derivative 3L was identified as the most potent inhibitor of IL-6 (77.2%) and TNF-α (75.4%) when compared to parent compound, and compounds 3a (77.18%), 3d (71.5%), and 3e (68.8%) showed potent inhibition of NO than oleanolic acid (65.22%) at 10μM. Besides, from docking score and Cyscore analysis analogs (3e, 3L, 3n) showed greater affinity towards TNF-α and IL-1β than dexamethasone. Conclusion: Herein, we report a series of 15 new arylidene derivatives of oleanolic acid by Claisen Schmidt condensation reaction. All the compounds synthesized were screened for their anti-inflammatory activity against NO, TNF-α and IL-6. From the data, it was evident that most of the compounds exhibited better anti-inflammatory activity.
- Mir, Reyaz Hassan,Godavari, Goutami,Siddiqui, Nasir Ali,Ahmad, Bilal,Mothana, Ramzi A.,Ullah, Riaz,Almarfadi, Omer M.,Jachak, Sanjay M.,Masoodi, Mubashir Hussain
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p. 385 - 397
(2021/05/06)
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- Synthesis and antitumor activity of α,β-unsaturated carbonyl moiety- containing oleanolic acid derivatives targeting PI3K/AKT/mTOR signaling pathway
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Oleanolic acid (OA) and its semi-synthetic derivatives have been reported to have a wide range of biological activities. The introduction of electrophilic Michael acceptor group can increase the reactivity of OA to cellular targets and thus improve the an
- Wang, Shi-Sheng,Zhang, Qiao-Li,Chu, Peng,Kong, Ling-Qi,Li, Guang-Zhe,Li, Yue-Qing,Yang, Li,Zhao, Wei-Jie,Guo, Xiu-Han,Tang, Ze-Yao
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- Cytotoxicity of oleanolic and ursolic acid derivatives toward hepatocellular carcinoma and evaluation of NF-κB involvement
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Oleanolic and ursolic acids are two ubiquitous isomeric triterpene phytochemicals known for their anticancer activity. A set of derivatives of the two compounds with a modified oxidation state and lipophylicity at C-3 and C-28 positions, were prepared and tested as anticancer agents versus the lines HepG2, Hep3B and HA22T/VGH of hepatocarcinoma, a strongly aggressive tumor that is not responsive toward the standard therapies. New derivatives containing a three carbons side chain on the C-3 position were synthetized in both stereoisomeric forms by the Barbier-Grignard procedure and three of them were found to be active toward all of the three targets. The implication of the transcriptional nuclear factor NF?κB in the mechanism of action was assessed for the more active compounds in the set, as hepatocellular carcinoma (HCC) cyto-types are known to overexpress NF?κB.
- Fontana, Gianfranco,Bruno, Maurizio,Notarbartolo, Monica,Labbozzetta, Manuela,Poma, Paola,Spinella, Alberto,Rosselli, Sergio
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- Oleanolic acid oxime derivatives and their conjugates with aspirin modulate the NF-κB-mediated transcription in HepG2 hepatoma cells
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The aim of this study was to evaluate the effect of new oleanolic acid oxime (OAO) derivatives and their conjugates with aspirin (ASP) on the expression and activation of NF-κB in human hepatoma HepG2 cells. OAO derivatives showed a stronger cytotoxic effect against HepG2 cells compared with their conjugates with aspirin. Moreover, conjugation of OAO with ASP led to enhanced downregulation of NF-κB expression and activation. Among the hybrids with ASP, compounds: 19, 3-(2-acetoxy)benzoyloxyiminoolean-12-en-28-oic acid morpholide and 13, 3-(2-acetoxy)benzoyloxyiminoolean-12-en-28-oic acid methyl ester, differing, respectively, in morpholide and methyl ester groups at the C-17 position of oleanolic acid (OA) molecule were the most efficient. COX-2 transcript and protein levels were also diminished after treatment with these compounds. The results of this study indicate that the new derivatives of OAO and particularly their conjugates with ASP, downregulate the expression of COX-2 in HepG2 cells by modulating the NF-κB signaling pathway and suggest their potential application in the prevention of liver inflammation and cancer.
- Krajka-Ku?niak, Violetta,Bednarczyk-Cwynar, Barbara,Paluszczak, Jaros?aw,Szaefer, Hanna,Naro?na, Maria,Zaprutko, Lucjusz,Baer-Dubowska, Wanda
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- Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors
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Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular end-points with low to moderate affinity. To explore the biological space associated with PCTTAs, we have investigated the carboxylate-to-hydroxamate transformation, discovering that it de-emphasizes affinity for the transcription factors targeted by the natural compounds (NF-κB, STAT3, Nrf2, TGR5) and selectively induces inhibitory activity on HIF prolyl hydrolases (PHDs). Activity was reversible, isoform-selective, dependent on the hydroxamate location, and negligible when this group was replaced by other chelating elements or O-alkylated. The hydroxamate of betulinic acid (5b) was selected for further studies, and evaluation of its effect on HIF-1α expression under normal and hypoxic conditions qualified it as a promising lead structure for the discovery of new candidates in the realm of neuroprotection.
- Minassi, Alberto,Rogati, Federica,Cruz, Cristina,Prados, M. Eugenia,Galera, Nuria,Jinénez, Carla,Appendino, Giovanni,Bellido, M. Luz,Calzado, Marco A,Caprioglio, Diego,Mu?oz, Eduardo
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p. 2235 - 2243
(2018/10/20)
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- Carboxylesterase 1 inhibitor for oleanolic acid compounds and application of carboxylesterase 1 inhibitor
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The invention relates to a carboxylesterase 1 strong-effect inhibitor for oleanolic acid compounds and application of the inhibitor, belonging to the technical field of biological medicine. The compounds have a oleanolic acid skeleton structure, so that the activity of a human carboxylesterase subtype 1 can be strongly and selectively inhibited, and the oral bioavailability of carboxylic ester type exogenous pro-drugs can be increased. The inhibitor is capable of inhibiting clopidogrel non-activity metabolite and is taken as a synergist for clopidogrel. The inhibitor is capable of relieving the development of insulin resistance induced by ectopic deposition of lipids to impaired glucose tolerance through inhibiting the participation of carboxylesterase 1 in fat metabolism. An in-vitro activity testing experiment shows that the IC50 of human carboxylesterase 1 inhibited by the inhibitor can reach 17 nano-moles, and the IC50 of human carboxylesterase 2 inhibited by the inhibitor can reach 3296 times of that of human carboxylesterase 1 inhibited by the inhibitor; and the compounds have the advantages that the safety is high, a preparation process is simple, the synthesis yield is high, and the like, namely that the compounds have good application prospects.
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Paragraph 0029; 0030; 0031
(2018/04/26)
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- Design, synthesis and biological evaluation of seco-A-pentacyclic triterpenoids-3,4-lactone as potent non-nucleoside HBV inhibitors
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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
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supporting information
p. 1501 - 1506
(2018/04/20)
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- COMPOSITIONS COMPRISING ACIDIC EXTRACTS OF MASTIC GUM AND USES THEREOF FOR TREATING OPTIC NEUROPATHY
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The invention relates to compositions and formulations comprising isolated acidic fraction of mastic gum and uses thereof for treating optic neuropathy conditions.
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- COMPOSITIONS COMPRISING TRITERPENOIDS AND USES THEREOF FOR TREATING OPTIC NEUROPATHY
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The invention relates to compositions and formulations comprising at least one triterpenoic acid and at least one neutral triterpenoid and uses thereof for treating optic neuropathy conditions.
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- Design and synthesis of novel oleanolic acid based chromenes as anti-proliferative and anti-inflammatory agents
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A practical and novel approach has been developed for the synthesis of oleanolic acid based chromene analogues. Different α,β-unsaturated carbonyl and chromene derivatives of oleanolic acid were synthesized and evaluated for their anticancer activity. Compounds 6e, 6k, 7e and 7g showed significant anticancer activity within the IC50 range of 12.23-39.04 μg mL-1. The promising derivatives 7e and 7g were further analyzed for their effects on the cell cycle and apoptosis in A-549 and MDA-MB-231 cells, and it was depicted that 7e and 7g triggered apoptosis in A-549 and MDA-MB-231 cells and arrested the cell population in the G2/M phase. The anticancer activity of the most active analogue 7g occurred through microtubule destabilization (IC50: ～3.6 μg mL-1), and it was found to be non-toxic against human erythrocytes. The compounds 7e and 7g significantly inhibited the proinflammatory cytokines TNF-α and IL-6.
- Raghuvanshi, Dushyant Singh,Verma, Narsingh,Singh, Shilpi,Luqman, Suaib,Chand Gupta, Amit,Bawankule, Dnyaneshwar U.,Tandon, Sudeep,Nagar, Abhishek,Kumar, Yogesh,Khan, Feroz
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p. 16782 - 16794
(2018/10/23)
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- Oleanolic acid derivative taking ethene diamine as connecting arm, and applications thereof
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The invention discloses an oleanolic acid derivative taking ethene diamine as a connecting arm, and applications thereof, and relates to an oleanolic acid derivative in pharmaceutical chemistry, and applications thereof. According to the oleanolic acid de
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Paragraph 0039
(2017/07/20)
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- Effective synthesis of novel furan-fused pentacyclic triterpenoids via anionic 5-exo dig cyclization of 2-alkynyl-3-oxotriterpene acids
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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.
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p. 100 - 116
(2017/08/10)
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- COMPOSITIONS COMPRISING TRITERPENOIDS
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The invention relates to compositions and formulations comprising at least one triterpenoic acid and at least one neutral triterpenoid and uses thereof for treating for use in treating a condition selected from Alzheimer's disease (AD), Parkinson's Diseases (PD) and vascular dementia (VD).
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- Hybrids of oleanolic acid with norbornene-2,3-dicarboximide-n-carboxylic acids as potential anticancer agents
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The synthesis and cytotoxic activity of new oleanolic acid derivatives (8anc and 9anc) are presented. The obtained compounds are hybrids of oleanolic acid oximes and carboxylic acids containing short alkyl chains linked with nitrogen atom of norbornene-2,3-dicarboximide moieties via the nitrogen atom. The structures of the obtained new compounds (8anc and 9anc) were confirmed by spectral data. The derivatives 8anc and 9anc were subjected to the MTT assay in order to evaluate their cytotoxic activity towards HeLa, KB, MCF-7, HepG2 and HDF cell lines in comparison to mother compound (oleanolic acid, 1). Among the tested oximes acylated with carboxylic acids containing norbornene-imide moieties, the derivative 8b, with a propionoxyimino linker, exhibited the most advantageous level of cytotoxicity, with IC50 values from 2.75 μM (for MCF-7 cells) to 4.36 μM (for HDF cells).
- Bednarczyk-Cwynar, Barbara,Ruszkowski, Piotr,Atamanyuk, Dmytro,Lesyk, Roman,Zaprutko, Lucjusz
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p. 827 - 835
(2017/06/05)
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- Synthesis and cytotoxic activity of triterpenoid thiazoles derived from allobetulin, methyl betulonate, methyl oleanonate, and oleanonic acid
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A total of 41 new triterpenoids were prepared from allobetulone, methyl betulonate, methyl oleanonate, and oleanonic acid to study their influence on cancer cells. Each 3-oxotriterpene was brominated at C2 and substituted with thiocyanate; subsequent cyclization with the appropriate ammonium salts gave N-substituted thiazoles. All compounds were tested for their in vitro cytotoxic activity on eight cancer cell lines and two non-cancer fibroblasts. 2-Bromoallobetulone (2b) methyl 2-bromobetulonate (3b), 2-bromooleanonic acid (5b), and 2- thiocyanooleanonic acid (5c) were best, with IC50 values less than 10 mm against CCRF-CEM cells (e.g., 3b: IC50=2.9 μm) as well as 2'-(diethylamino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 f, IC50=9.7 μm) and 2'-(N-methylpiperazino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5k, IC50=11.4 μm). Compound 5c leads to the accumulation of cells in the G2 phase of the cell cycle and inhibits RNA and DNA synthesis significantly at 1xIC50. The G2/M cell-cycle arrest probably corresponds to the inhibition of DNA/RNA synthesis, similar to the mechanism of action of actinomycin D. Compound 5c is new, active, and nontoxic; it is therefore the most promising compound in this series for future drug development. Methyl 2-bromobetulonate (3b) and methyl 2-thiocyanometulonate (3c) were found to inhibit nucleic acid synthesis only at 5xIC50. We assume that in 3b and 3c (unlike in 5c), DNA/RNA inhibition is a nonspecific event, and an unknown primary cytotoxic target is activated at 1xIC50 or lower concentration.
- Borkova, Lucie,Adamek, Richard,Kalina, Petr,Dra?ar, Pavel,Dzubak, Petr,Gurska, Sona,Rehulka, Jiri,Hajduch, Marian,Urban, Milan,Sarek, Jan
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supporting information
p. 390 - 398
(2017/12/07)
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- Synthesis and biological evaluations of cytotoxic and antiangiogenic triterpenoids-jacaranone conjugates
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Background: The development of antiangiogenic agents arises as a more effective and selective therapeutic approach for the treatment of cancer. In addition to reduced acute toxicity, the efficacy of chemotherapy could be improved when administered in combination specific antiangiogenic with cytotoxic agents. The conjugation or hybridization of bifunctional molecules is one of the alternative rational design strategies for co-administration of anticancer drugs. Objective and Methods: The goal of this work is to prepare the conjugates of an antiangiogenic triterpene, 3-oxo oleanolic acid, and structurally related triterpenoids with a cytotoxic semibenzoquinone, jacaranone. The cytotoxic, antiproliferative and antiangiogenic activities of segments and conjugates were determined. The possible targets of conjugates 6a-6h were predicted using Similarity Ensemble Approach (SEA). Results: The results showed that these conjugates are more potent in both cytotoxic and antiangiogenic assays than their corresponding parent molecules, and are also selectively more active against melanoma cells B16 and metastatic B16BL6 than the two other cancer cell lines (A549 and MCF-7) tested. The predicted antiangiogenesis related targets could involve glycogen phosphorylase, neuraminidase, interferon gamma, and tubulin beta chain. Conclusion: The bifunctional conjugates could be useful as dual acting antitumor/antigiogenic agents.
- Sun, Hua,Yue, Partick Y.K.,Wang, Shao-Rong,Huo, Lihong,Zhao, Ying,Xie, Songbo,Kringelum, Jens V.,Lund, Ole,Taboureau, Olivier,Zhou, Jun,Wong, Ricky N. S.,Fang, Wei-Shuo
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p. 775 - 785
(2016/11/29)
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- Novel heterocyclic ring-fused oleanolic acid derivatives as osteoclast inhibitors for osteoporosis
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Osteoporosis is a major public health problem in our aging society. In the present study, a series of novel oleanolic acid (OA) derivatives were synthesized via modifications in the A-ring and C-28 position of OA, and their anti-bone resorption activities
- Wu, Jing,Bao, Bei-Hua,Shen, Qi,Zhang, Yu-Chao,Jiang, Qing,Li, Jian-Xin
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supporting information
p. 371 - 377
(2016/03/01)
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- Targeting cancer cells with oleanolic and ursolic acid derived hydroxamates
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Oleanolic and ursolic acid derived hydroxamates were easily obtained from their parent compounds; they were screened for their cytotoxicity applying SRB assays employing several human tumor cell lines. Low EC50values were determined for compounds in which the nitrogen as well as the oxygen in the hydroxamic acid part still holds acidic hydrogens. Thus, ursolic acid derived compounds having at least an OH and/or NH moiety in the hydroxamate part of the molecule showed good cytotoxicity but they are significantly less selective for the tumor cells than oleanolic acid derived compounds. Good results were determined for oleanolic acid derived 7 for tumor cell lines 518A2 (melanoma, EC50= 3.3 μM), A2780 (ovarian carcinoma, EC50= 3.4 μM) and HT29 (colon adenocarcinoma, EC50= 5.6 μM) while being significantly less cytotoxic for fibroblasts (EC50= 20.4 μM).
- Wiemann, Jana,Heller, Lucie,Csuk, René
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supporting information
p. 907 - 909
(2016/05/24)
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- Hybrid compounds strategy in the synthesis of oleanolic acid skeleton-NSAID derivatives
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The current study focuses on the synthesis of several hybrid individuals combining a natural oleanolic acid skeleton and synthetic nonsteroidal anti-inflammatory drug moieties (NSAIDs). It studied structural modifications of the oleanolic acid structure by use of the direct reactivity of hydroxyl or hydroxyimino groups at position C-3 of the triterpenoid skeleton with the carboxylic function of anti-inflammatory drugs leading to new perspective compounds with high potential pharmacological activities. Novel ester- and iminoester-type derivatives of oleanolic unit with the different NSAIDs, such as ibuprofen, aspirin, naproxen, and ketoprofen, were obtained and characterized. Moreover, preliminary research of compounds obtaining structure stability under acidic conditions was examined and the PASS method of prediction of activity spectra for substances was used to estimate the potential biological activity of these compounds.
- Pawe?czyk, Anna,Olender, Dorota,Sowa-Kasprzak, Katarzyna,Zaprutko, Lucjusz
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- With anti-malignant tumor effect of the oleanolic acid derivatives and process for their preparation and use
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The invention belongs to the technical field of medicines for resisting malignant tumors and discloses an oleanolic acid derivative with a structure shown as formula I, wherein R1 stands for a hydrogen; C1-C4 stands for a straight-chain or a branch-chain alkyl; R2 is an ethyl which is substituted by a halogen, a hydroxyl, a C1-C4 straight-chain or a branch-chain alkyl or a C1-C4 straight-chain or a branch-chain alkoxy. Furthermore, the invention relates to a method for preparing the compound, as well as pharmaceutical compositions taking the compound as an active and effective ingredient and applications of the pharmaceutical compositions as medicines for resisting the malignant tumors.
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Paragraph 0063-0065
(2017/02/02)
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- Straightforward partial synthesis of four diastereomeric 2,3-dihydroxy-olean-12-en-28-oic acids from oleanolic acid
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The four diastereomeric 2,3-dihydroxy-olean-12-en-28-oic acids (maslinic, augustic, bredemolic and 3-epi-maslinic acid) were easily accessed from one single starting material, oleanolic acid. The procedures allow the medium-to-large scale preparation of these valuable starting materials. Except for maslinic acid, the triterpenoic acids showed only a low cytotoxicity towards several human tumor cell lines.
- Sommerwerk, Sven,Heller, Lucie,Serbian, Immo,Csuk, René
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p. 8528 - 8534
(2016/02/03)
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- Discovery, optimization, and pharmacophore modeling of oleanolic acid and analogues as breast cancer cell migration and invasion inhibitors through targeting Brk/Paxillin/Rac1 axis
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Bioassay-guided fractionation of Terminalia bentzoe L. leaves methanol extract identified the known triterpene oleanolic acid (1) as its major breast cancer cell migration inhibitor. Further chemical optimization afforded five new (9-12 and 15) and seven
- Elsayed, Heba E.,Akl, Mohamed R.,Ebrahim, Hassan Y.,Sallam, Asmaa A.,Haggag, Eman G.,Kamal, Amel M.,El Sayed, Khalid A.
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p. 231 - 243
(2015/01/30)
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- Application of positive mode atmospheric chemical ionisation to distinguish epimeric oleanolic and ursolic acids
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A new and more reliable method is reported for distinguishing the equatorial and axial epimers of oleanolic and ursolic acids and related triterpenoids based primarily on the relative abundance of the [M + H]+ and [M + H - H2O]+ signals in their positive mode atmospheric pressure chemical ionisation mass spectra. The rate of elimination of water, which is the principal primary fragmentation of protonated oleanolic and ursolic acids, depends systematically on the stereochemistry of the hydroxyl group in the 3 position. For the b-epimer, in which the 3-hydroxyl substituent is in an equatorial position, [M + H - H2O]+ is the base peak. In contrast, for the a-epimer, where the 3-hydroxyl group is axial, [M + H]+ is the base peak. This trend, which is general for a range of derivatives of oleanolic and ursolic acids, including the corresponding methyl esters, allows epimeric triterpenoids in these series to be securely differentiated. Confrmatory information is available from the collision-induced dissociation of the [M + H - H2O]+ primary fragment ions, which follow different pathways for the species derived from axial and equatorial epimers of oleanolic and ursolic acids. These two pieces of independent spectral information permit the stereochemistry of epimeric oleanolic and ursolic acids (and selected derivatives) to be assigned with confdence without relying either on chromatographic retention times or referring to the spectra or other properties of authentic samples of these triterpenoids.
- Townley, Chloe,Brettell, Rhea C.,Bowen, Richard D.,Gallagher, Richard T.,Martin, William H.C.
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p. 433 - 442
(2016/04/05)
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- Novel inhibitors of bacterial biofilms and related methods
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Multi-cyclic compounds of chemical structure represented by formula given below and compositions thereof are useful for reducing or inhibiting the growth of bacterial biofilms and for controlling bacterial biofilm infections. Such compounds and compositions are also useful in methods for reducing or inhibiting the growth of biofilms and for controlling bacterial biofilm infections involving biofilms.
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Paragraph 0040
(2014/05/06)
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- Convenient and chromatography-free partial syntheses of maslinic acid and augustic acid
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A convenient and chromatography-free 4-step synthesis of analytically pure maslinic acid (1, 41.2%) from oleanolic acid has been developed. Slight variations in the final steps gave an excellent yield of isomeric augustic acid (7, 71.9%).
- Sommerwerk, Sven,Csuk, René
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p. 5156 - 5158
(2014/12/11)
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- Synthesis and biological evaluation of oleanolic acid derivative-chalcone conjugates as α-glucosidase inhibitors
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α-Glucosidase is a promising target for the treatment of obesity and diabetes mellitus. A series of oleanolic acid derivative-chalcone conjugates were designed and synthesized as α-glucosidase inhibitors. Their structures were determined by spectroscopic analysis and their α-glucosidase inhibitory activities were investigated in vitro. Most conjugates exhibited moderate inhibitory activity against α-glucosidase; among them, conjugate 1b (IC50 = 3.2 ± 0.2 μM) possessed the strongest α-glucosidase inhibitory activity, and the preliminary structure-activity relationship showed that the furan or thiophene rings in the chalcone units of the conjugates had a tendency to enhance the activity. Lineweaver-Burk plot analysis demonstrated competitive inhibition of α-glucosidase activity by 1b, 6b, 5c and 4d; their inhibition constant (Ki) values were 16.6, 29.3, 14.6 and 20.6 μM, respectively. The interaction forces between the conjugates and α-glucosidase were hydrogen bonding and van der Waals.
- Tang, Chu,Zhu, Linhui,Chen, Yu,Qin, Rui,Mei, Zhinan,Xu, Jing,Yang, Guangzhong
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p. 10862 - 10874
(2014/03/21)
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- 2-SUBSTITUTED OLEANOLIC ACID DERIVATIVE, METHOD PREPARING FOR SAME, AND APPLICATION THEREOF
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The present invention belongs to the field of natural medicine and pharmaceutical chemistry, and specifically relates to novel 2-substituted oleanolic acid derivatives of formula (I) or a pharmaceutically acceptable salt thereof, to a process for the preparation of these compounds, compositions containing such compounds and their use in preparing antineoplastic medicaments.
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Paragraph 0071-0072
(2014/10/16)
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- 2-SUBSTITUTED OLEANOLIC ACID DERIVATIVE, METHOD PREPARING FOR SAME, AND APPLICATION THEREOF
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The present invention belongs to the field of natural medicine and pharmaceutical chemistry, and specifically relates to novel 2-substituted oleanolic acid derivatives of formula (I) or a pharmaceutically acceptable salt thereof, to a process for the preparation of these compounds, compositions containing such compounds and their use in preparing antineoplastic medicaments.
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Paragraph 0072; 0073
(2014/12/09)
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- Oleanolic acid analogs as NO, TNF-α and IL-1β inhibitors: Synthesis, biological evaluation and docking studies
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A series of oleanolic acid analogs, characterized by structural modifications at position C-3 and C-28 of oleanane skeleton were synthesized and assessed for antiinflammatory potential towards lipopolysaccharide (LPS) induced nitric oxide (NO) production
- Bhandari, Pamita,Patel, Neeraj Kumar,Gangwal, Rahul P.,Sangamwar, Abhay T.,Bhutani, Kamlesh Kumar
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supporting information
p. 4114 - 4119
(2014/10/15)
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- Synthesis of novel heterocyclic oleanolic acid derivatives with improved antiproliferative activity in solid tumor cells
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A series of new oleanane imidazole carbamates, N-acylimidazoles or N-alkylimidazoles were synthesized, characterized and evaluated for their antiproliferative activity in AsPC-1 pancreatic cancer cells. Structure-activity relationship analysis revealed that the N-alkylimidazole 27 was the most active compound with apoptosis induction abilities correlated with upregulation of NOXA and downregulation of Bcl-xL. The antiproliferative activity of compound 27 was further tested in more solid tumor cell lines with IC50 values lower than 1 μM.
- Leal, Ana S.,Wang, Rui,Salvador, Jorge A. R.,Jing, Yongkui
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p. 1726 - 1738
(2013/03/29)
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- AMOORANIN COMPOUNDS AND ANALOGS THEREOF AND RELATED METHODS OF USE
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Methods for synthesizing amooranin (25-hydroxy-3-oxoolean-12-en-28-oic acid (AMR) and/or amooranin analogs, including amooranin methyl ester (AMR-Me), by using oleanolic acid in an oxidation process, and therapeutic uses thereof are described.
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Paragraph 0049; 0050
(2013/07/19)
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