- Synthesis and anti-tumor activity evaluation of salinomycin C20-O-alkyl/benzyl oxime derivatives
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Seventeen C20-O-alkyl/benzyl oxime derivatives were synthesized by a concise and effective method. Most of these derivatives showed tens to several hundred nanomolar IC50 values against HT-29 colorectal, HGC-27 gastric and MDA-MB-231 breast cancer cells, whose antiproliferative activity is 15-240 fold better than that of salinomycin. The C20-oxime etherified derivatives can coordinate potassium ions, and further adjust the cytosolic Ca2+ concentrations in HT-29 cells. The significant improvement of the potency should be attributed to the better ion binding and transport ability of the modified derivatives. In addition, the C20-O-alkyl/benzyl oxime derivatives showed much better selectivity indexes (SI) than salinomycin, indicating that they present lower neurotoxic risk.
- Duan, Wenfang,Hao, Jie,Hu, Yuhua,Li, Bo,Li, Tianlei,Li, Zhongwen,Lian, Xu,Qin, Tong,Tang, Lei,Wu, Jun,Wu, Song,Zhang, Chi,Zhang, Jihong,Zhang, Wenxuan,Zhao, Xintong
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p. 870 - 876
(2022/02/03)
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- Structure-activity relationships of pyrimidine nucleotides containing a 5′-α,β-methylene diphosphonate at the P2Y6 receptor
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The Gq-coupled P2Y6 receptor (P2Y6R) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the native P2Y6R agonist and P2Y14R partial agonist, is subject to hydrolysis by ectonucleotidases. Therefore, we have synthesized UDP/CDP analogues containing a stabilizing α,β-methylene bridge as P2Y6R agonists and identified compatible affinity-enhancing pyrimidine modifications. A distal binding region on the receptor was explored with 4-benzyloxyimino cytidine 5′-diphosphate analogues and their potency determined in a calcium mobilization assay. A 4-trifluoromethyl-benzyloxyimino substituent in 25 provided the highest human P2Y6R potency (MRS4554, 0.57 μM), and a 5-fluoro substitution of the cytosine ring in 28 similarly enhanced potency, with >175- and 39-fold selectivity over human P2Y14R, respectively. However, 3-alkyl (31–33, 37, 38), β-D-arabinofuranose (39) and 6-aza (40) substitution prevented P2Y6R activation. Thus, we have identified new α,β-methylene bridged N4-extended CDP analogues as P2Y6R agonists that are highly selective over the P2Y14R.
- Dobelmann, Clemens,Gopinatth, Varun,Jacobson, Kenneth A.,Jain, Shanu,Junker, Anna,Oliva, Paola,Phung, Ngan B.,Scortichini, Mirko,Toti, Kiran S.
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supporting information
(2021/06/15)
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- Synthesis and antibacterial evaluation of (E)-1-(1H-indol-3-yl) ethanone O-benzyl oxime derivatives against MRSA and VRSA strains
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Infections caused due to multidrug resistant organisms have emerged as a constant menace to human health. Even though numerous antibiotics are currently available for treating infectious diseases, a great number of bacterial strains have acquired resistance to many of them. Among these, infections caused due to Staphylococcus aureus are predominant in adult and paediatric population. Indole is a prominent chemical scaffold found in many pharmacologically active natural products and synthetic drugs. A number of oxime ether containing compounds have attracted attention of researchers owing to their interesting biological properties. Current work details the synthesis of indole containing oxime ether derivatives and their evaluation for antimicrobial activity against a panel of bacterial and mycobacterial strains. Synthesized compounds demonstrated good to moderate activity against drug-resistant S. aureus including resistant to vancomycin. Among all, compound 5h was found to possess potent activity against susceptible as well as MRSA and VRSA strains of S. aureus with MIC of 1 μg/mL and 2–4 μg/mL respectively. In addition, compound 5h was found to be non-toxic to Vero cells and exhibited good selectivity index of >40. Further, 5h, E-9a and E-9b possessed good biofilm inhibition against S. aureus. With these assuring biological properties, synthesized compounds could be potential prospective antimicrobial agents.
- Akunuri, Ravikumar,Veerareddy, Vaishnavi,Kaul, Grace,Akhir, Abdul,Unnissa, Tanveer,Parupalli, Ramulu,Madhavi,Chopra, Sidharth,Nanduri, Srinivas
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supporting information
(2021/08/27)
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- Multifunctional small molecules as potential anti-alzheimer’s disease agents
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Alzheimer’s disease (AD) is a severe multifactorial neurodegenerative disorder characterized by a progressive loss of neurons in the brain. Despite research efforts, the pathogenesis and mechanism of AD progression are not yet completely understood. There are only a few symptomatic drugs approved for the treatment of AD. The multifactorial character of AD suggests that it is important to develop molecules able to target the numerous pathological mechanisms associated with the disease. Thus, in the context of the worldwide recognized interest of multifunctional ligand therapy, we report herein the synthesis, characterization, physicochemical and biological evaluation of a set of five (1a–e) new ferulic acid-based hybrid compounds, namely feroyl-benzyloxyamidic derivatives enclosing different substituent groups, as potential anti-Alzheimer’s disease agents. These hybrids can keep both the radical scavenging activity and metal chelation capacity of the naturally occurring ferulic acid scaffold, presenting also good/mild capacity for inhibition of self-Aβ aggregation and fairly good inhibition of Cu-induced Aβ aggregation. The predicted pharmacokinetic properties point towards good absorption, comparable to known oral drugs.
- Bargagna, Beatrice,Camodeca, Caterina,Chaves, Sílvia,Ciccone, Lidia,Nencetti, Susanna,Orlandini, Elisabetta,Santos, M. Amélia
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- Design, synthesis and evaluation of wound healing activity for β-sitosterols derivatives as potent Na+/K+-ATPase inhibitors
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β-Sitosterols, is a common steroid that can be identified in a variety of plants and their efficacy in promoting wound healing has been demonstrated. Na+/K+-ATPase, more than a pump, its signal transduction function for involvement in cell growth regulation attracts widespread concern. The Na+/K+-ATPase/Src receptor complex can serve as a receptor involved in multiple signaling pathways including promoting wound healing pathways. To finding potent accelerating wound healing small molecular, we choose the high inhibitory activity of Na+/K+-ATPase and non-cardiotoxic natural compound, β-sitosterol as the substrate. A series of β-sitosterol derivatives were designed, synthesized and evaluated as potential Na+/K+-ATPase inhibitors. Among them, compounds 31, 47, 49, showed improved inhibitory activity on Na+/K+-ATPase, with IC50 value of 3.0 μM, 3.4 μM, 2.2 μM, which are more potent than β-sitosterol with IC50 7.6 μM. Especially, compound 49 can induce cell proliferation, migration and soluble collagen production in L929 fibroblasts. Compared to model, compound 49 can accelerate wound healing in SD rats. Further studies indicated that 49 can activate the sarcoma (Src), uptake the protein kinase B (Akt), extracellular signal-regulated kinase (ERK) proteins expression in a concentration dependent manner. Finally, binding mode of compound 49 with Na+/K+-ATPase was studied, which provides insights into the determinants of potency and selectivity. These results proved β-stitosterol derivative 49 can serve as an effective inhibitor of Na+/K+-ATPase and potential candidate for accelerating wound healing agents.
- Cui, Shaoyu,Jiang, Hongli,Chen, Lei,Xu, Jian,Sun, Wenzhuo,Sun, Haopeng,Xie, Zijian,Xu, Yunhui,Yang, Fubai,Liu, Wenyuan,Feng, Feng,Qu, Wei
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- Sterol derivatives and its preparation method and application
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The invention discloses a sterol derivative of beta-sitosterol, beta-stigmasterol and cholesterol, and is shown as a formula VI. The invention also discloses a preparation method of the sterol derivative. The invention also discloses application of the sterol derivative to the aspect of preparation of wound healing promoting medicine. By starting from easily obtained natural products, the beta-sitosterol, the beta-stigmasterol and the cholesterol are used as starting raw materials; the synthetic method is simple; better operability and reaction yield are realized. The prepared sterol derivative has the obvious wound healing promoting activity; the multiplication, migration and collagen synthesis capability on L929 mechanocytes is obviously higher than that of the raw material and positive control medicine recombinant human bFGF (basic fibroblast growth factor). Compared with protide type medicine (such as bFGF), the prepared sterol derivative has more diversified dosage forms and medication modes; the reference is provided for the application in the field of wound healing promoting. The formula VI is shown as the accompanying diagram.
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Paragraph 0182-0184
(2019/05/19)
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- PRODRUG INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE 1 (IDO1)
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Indoleamine 2,3-dioxygenase-1 prodrugs and methods of use thereof are disclosed.
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Page/Page column 15-16
(2019/04/09)
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- O-benzyl-N-(9-acridinyl)hydroxylamines
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A series of O-benzyl-N-(9-acridinyl)hydroxylamines was prepared, isolated, and evaluated for biological activity using both thermal denaturation and MTT assays. Changes in the thermal denaturation temperature of genomic calf-thymus DNA ranged from +6.6 °C to +20.2 °C. MTT assays on SNB-19 glioblastoma cells provided biological activity that ranged from 17.4 μM to 33.2 μM. Both evaluation methods of biological activity indicate that substitution of the benzyl group by either electron-withdrawing or electron-donating groups provides a measureable benefit in these assays. The two assays agreed on the magnitude of the interaction for each substitution pattern.
- Johnson, Alyssa L.,Duncan, Nathan,Mosher, Michael D.
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p. 139 - 148
(2018/06/27)
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- Direct cycle between co-product and reactant: An approach to improve the atom economy and its application in the synthesis and protection of primary amines
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Two important goals of green chemistry are to maximize the efficiency of reactants and to minimize the production of waste. In this study, a novel approach to improve the atom economy of a chemical process was developed by incorporating a direct cycle between a co-product and a reactant of the same reaction. To demonstrate this concept, recoverable 3,4-diphenylmaleic anhydride (1) was designed and used for the atom-economical synthesis of aliphatic primary amines from aqueous ammonia. In each individual cycle, only ammonia and alkyl halide were consumed, and 1 was recovered in nearly a quantitative yield. In this approach for developing atom-economical protecting agents, 1 showed good performance as a recoverable protecting agent for primary amines. The broad substrate scope, good tolerance to various reaction conditions, and high reaction and recovery rates make 1 a valuable complement to conventional primary amine protecting agents.
- Guan, Qi,Jiang, Mingyang,Wu, Junhui,Zhai, Yanpeng,Wu, Yue,Bao, Kai,Zhang, Weige
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supporting information
p. 5794 - 5799
(2016/11/06)
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- O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1
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Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1's catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a potent sub-micromolar inhibitor of IDO1. Structure-activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications.
- Malachowski, William P.,Winters, Maria,DuHadaway, James B.,Lewis-Ballester, Ariel,Badir, Shorouk,Wai, Jenny,Rahman, Maisha,Sheikh, Eesha,LaLonde, Judith M.,Yeh, Syun-Ru,Prendergast, George C.,Muller, Alexander J.
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p. 564 - 576
(2016/01/09)
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- NOVEL VASCULAR LEAKAGEAGE INHIBITOR
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The present disclosure relates to a novel vascular leakage inhibitor. The novel vascular leakage inhibitor of the present invention inhibits the apoptosis of vascular endothelial cells, inhibits the formation of actin stress fibers induced by VEGF, and enhances the cortical actin ring structure, thereby inhibiting vascular leakage. Accordingly, the vascular leakage inhibitor of the present invention can prevent or treat various diseases caused by vascular leakage. Since the vascular leakage inhibitor of the present invention is synthesized from commercially available or easily synthesizable pregnenolones, it has remarkably superior feasibility of commercial synthesis.
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Paragraph 0130
(2015/01/07)
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- Synthesis and in vitro cytotoxic activity of N-2-(2-furyl)-2- (chlorobenzyloxyimino) ethyl ciprofloxacin derivatives
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Quinolone are a class of potent broad-spectrum antibacterial drugs that target the bacterial type II DNA topoisomerases (DNA gyrase) and topoisomerase IV. In the present study, the synthesis and evaluation of cytotoxicity activity of a new series of N-pipearzinyl quinolones containing N-2-(furyl-2-yl)-2- (chlorobenzyloxyimino) ethyl moiety (6a-c) have been studied. Preliminary screening showed that one of the new compounds, namely 7-(4-(2-(3- chlorobenzyloxyimino)-2-(furan-2-yl) ethyl) piperazin-1-yl)-1-cyclopropyl-6- fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (6b) showed significant cytotoxic activity against human breast tumor cell lines.
- Alipour, Eskandar,Mohammadhosseini, Negar,Panah, Fatemeh,Ardestani, Sussan K.,Safavi, Maliheh,Shafiee, Abbas,Foroumadi, Alireza
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scheme or table
p. 1226 - 1231
(2012/06/30)
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