- AIE-Active Chiral [3]Rotaxanes with Switchable Circularly Polarized Luminescence
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The construction of circularly polarized luminescence (CPL) switches with multiple switchable emission states and high dissymmetry factors (glum) has attracted increasing attention due to their broad applications in diverse fields such as the development of smart devices and sensors. Herein, a new family of AIE-active chiral [3]rotaxanes were designed and synthesized, from which a novel CPL switching system was successfully constructed. The switching process was realized through the controlled motions of the chiral pillar[5]arene macrocycles along the axle through the addition or removal of the acetate anions, which not only modulated the chirality information transfer but also tuned the aggregations of the integrated [3]rotaxanes, thus resulting in reversible transformations between two emission states with both high photoluminescence quantum yields (PLQYs) and high dissymmetry factors (glum) values.
- Li, Wei-Jian,Gu, Qingyi,Wang, Xu-Qing,Zhang, Dan-Yang,Wang, Yu-Te,He, Xiao,Wang, Wei,Yang, Hai-Bo
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Read Online
- Bivalent carbamates as novel control agents of the malaria mosquito, Anopheles gambiae
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Widespread pyrethroid resistance has caused an urgent need to develop new insecticides for control of the malaria mosquito, Anopheles gambiae. Insecticide discovery efforts were directed towards the construction of bivalent inhibitors that occupy both the peripheral and catalytic sites of the mosquito acetylcholinesterase (AChE). It was hypothesized that this approach would yield a selective, high potency inhibitor that would also circumvent known catalytic site mutations (e.g. G119S) causing target site resistance. Accordingly, a series of bivalent phthalimide-pyrazole carbamates were prepared having an alkyl chain linker of varying length, along with other modifications. The most active compound was (1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-4-yl methylcarbamate, 8a), which has a chain length of three carbons, good mosquito anticholinesterase activity, and ca. 5-fold selectivity compared to human AChE. Moreover, this compound was toxic to mosquitoes by topical application (LD50 = 63 ng/female) with only 6-fold cross resistance in the Akron strain of Anopheles gambiae that showed 50- to 60-fold resistance to conventional carbamate insecticides. However, contact lethality in the WHO paper assay was disappointing. The implications of these results for design of new mosquitocides are discussed.
- Mutunga, James M.,Chen, Qiao-Hong,Wong, Dawn M.,Lam, Polo C.-H.,Li, Jianyong,Totrov, Maxim M.,Gross, Aaron D.,Carlier, Paul R.,Bloomquist, Jeffrey R.
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- Synthesis and photopolymerizations of first monomers with phosphonate and bisphosphonate or phosphonic and bisphosphonic acid functionalities for potential dental applications
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The first monomers containing both phosphonate and bisphosphonate (M1) or phosphonic and bisphosphonic acid (M2) functionalities are synthesized, aiming to improve binding abilities of self-etching adhesive systems and composites: An amine having both phosphonate and bisphosphonate functionalities is prepared via Michael addition reaction between diethyl (6-aminohexyl)phosphonate and tetraethyl vinylidene bisphosphonate, its reaction with 2-isocyanatoethyl methacrylate gives M1 which is converted to M2 by selective dealkylation of the phosphonate/bisphosphonate ester groups. Their copolymerization with commercial dental monomers (bisphenol A glycidyl methacrylate, triethylene glycol dimethacrylate, and 2-hydroxyethyl methacrylate) investigated by photo-differential scanning calorimetry shows adequate photopolymerization rate and conversion. X-ray diffraction, Fourier transform infrared, and X-ray photoelectron spectroscopy analyses of M2-treated hydroxyapatite particles show formation of stable M2-calcium salts. These monomers are assessed to be not toxic according to MTT standards by in vitro cytotoxicity studies with NIH 3T3, U2OS, and Saos-2 cells. All these properties make these monomers potential candidates as biocompatible components for dental adhesives and composites.
- Gencoglu, Turkan,Duman, Fatma Demir,Olcay, Keziban,Acar, Havva Yagci,Avci, Duygu
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- Sequence-Specific Osmium Reagents for Polynucleotides. 2. A Method for Thymine-Cytosine Pairs
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We have modified the dinucleoside monophosphate, deoxythymidylyldeoxycytidine (d-TpC), by replacement of the exocyclic amino group of cytosine with a series of ligands, H2N(CH2)nN(CH3)CH2CH2N(CH3)2, where n = 2, 4, and 6.The kinetics of the reactions of these modified dinucleoside monophosphates with osmium tetroxide were measured.The modified nucleotides react with osmium tetroxide 4200, 7900, and 1200 times faster than the unmodified species for n = 6, 4, and 2, respectively.The products of the reactions are macrocyclic oxoosmium (VI) esters for which 360-MHz proton NMR spectra are reported.
- Ford, H.,Chang, C.-H.,Behrman, E.J.
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- Chemical puzzles in the search for new, flexible derivatives of lurasidone as antipsychotic drugs
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In the pharmacotherapy of schizophrenia, there is a lack of effective drugs, and currently used agents cause a large number of side effects. The D2, 5-HT1A, 5-HT2A receptors are among the most important receptor targets in the treatment of schizophrenia, but antagonism at 5-HT6 and 5-HT7 receptors may bring about additional improvement of cognitive functions. However, doubt exists regarding the importance of 5-HT7R in the pharmacotherapy. In 2010, lurasidone (with high affinity for D2, D3, 5-HT1A, 5-HT2A, 5-HT7 receptors) was approved for the treatment of schizophrenia. Due to the efficacy of the mentioned drug and doubts related to the role of 5-HT7R, we decided to obtain compounds with an activity profile similar to that of lurasidone, but with the reduced affinity for 5-HT7R and increased affinity for 5-HT6R. For this purpose, we chose a flexible hexyl derivative of lurasidone (2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 1a) as a hit structure. After molecular modeling, we modified it, in the area of the arylpiperazine and imide group, using the moieties found in other known CNS drugs. We received the compounds in accordance with the previously developed method of ecological synthesis in the microwave radiation field. Among the obtained compounds, N-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)naphthalene-sulfonamides 1v and 1w were distinguished as multifunctional ligands showing increased affinity for 5-HT6R, and 2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 1i – a multifunctional ligand showing moderate affinity for 5-HT6R and threefold lower for 5-HT7R. In the paper, we discuss some of the observed dependencies regarding 5-HT6/5-HT7R affinity using molecular docking methods.
- Drabczyk, Anna K.,Ja?kowska, Jolanta,Sata?a, Grzegorz,Zar?ba, Przemys?aw
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- Preparation of a DNA Complex with Lipoglutamide Having Tetraethylene Glycol Tails, and Its Application to DNA Delivery into Tumor Cells1
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We newly prepared a polyion complex of DNA with lipoglutamide, N,N′-bis(18-hydroxy-7,10,13,16-tetraoxaoctadecyl)-L-glutamide hydrochloride (abbreviated to 2EO4C6N+). Formation and characterization of the DNA/2EO4C6N+ complex were investigated by elemental analysis, melting temperature, and light-scattering measurements. Compaction of DNA by binding with the cationic 2EO4C6N+ was seen by multi-angle light scattering. Aggregation of the DNA/2EO4C6N+ complex was significantly depressed compared with the DNA complex without tetraethylene glycol. The DNA/2EO4C6N+ complex had low cytotoxicity and efficient internalization into tumor cells compared with native DNA.
- Sato, Toshinori,Akino, Hiroyuki,Okahata, Yoshio
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- Design and synthesis of new potent 5-HT7 receptor ligands as a candidate for the treatment of central nervous system diseases
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Owing to their multifunctional pharmacological profiles (including dual 5-HT1A/5-HT7 action), arylpiperazine derivatives are widely used for treating central nervous system diseases including the depression or neuropathic pain. Herein we describe the design, synthesis and evaluation of biological activity of novel 5-HT7 ligands derived of 2,4,6-triamino-1,3,5-triazine. The studied compounds showed affinity and high selectively towards 5-HT7 receptor with the two most active compounds 34 (Ki = 61 nM), 22 (Ki = 109 nM) showing good metabolic stability and moderate affinity to CYP3A4 isoenzyme. Compound 22 had high hepatotoxicity at a concentration below 50 μM, while compound 34 showed low hepatotoxicity even at a concentration above 50 μM.
- Drabczyk, Anna K.,Latacz, Gniewomir,Ja?kowska, Jolanta,Ku?aga, Damian,Pla?uk, Damian,Rózga, Karolina,Sata?a, Grzegorz
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supporting information
(2021/10/29)
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- Discovery of EGFR-Targeted Environment-Sensitive fluorescent probes for cell imaging and efficient tumor detection
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Overexpression of human epidermal growth factor receptor (EGFR) plays an important role in several signaling pathways inside and outside the cell, especially in the processes of cell proliferation, differentiation, and death in various cancers. Due to the complexity of the structure and function of EGFR, research on the fluorescence visualization of EGFR protein visualization has proved challenging. One possible strategy for designing a receptor-targeting fluorescent probe with a switching mechanism is to introduce an environment-sensitive fluorophore into the drug ligand. Based on this strategic molecular design, we introduced two environment-sensitive small molecular fluorophores, dansyl chloride (DNS) and nitrobenzoxadiazole (NBD), to replace the morpholine group of gefitinib, achieving a series of fluorescent molecular probes bearing a switching mechanism. The GN probes exhibited prominent environment sensitivity, suggesting good performance as turn-on EGFR-targeting fluorescent ligands. The representative probe GN3 specifically responded to tumor cells overexpressing EGFR, which was validated with live-cell fluorescence imaging and in vivo xenograft tumor imaging. Ligand-induced EGFR phosphorylation in A431 cells was considerably inhibited by probe GN3, demonstrating that this probe still functions as an EGFR inhibitor. Owing to the turn-on response of GN3 to EGFR in tumor cells, and the competitive replacement behavior to the EGFR inhibitor gefitinib, these probes have the potential to be used for fluorescence imaging of cells overexpressing EGFR.
- Sheng, Jun,Sun, Xiu-Li,Wang, Li-Xia,Wang, Xuan-Jun,Wang, Ze-Hao,Zi, Cheng-Ting
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supporting information
(2022/02/21)
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- Strategic engineering of alkyl spacer length for a pH-tolerant lysosome marker and dual organelle localization
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Long-term visualization of lysosomal properties is extremely crucial to evaluate diseases related to their dysfunction. However, many of the reported lysotrackers are less conducive to imaging lysosomes precisely because they suffer from fluorescence quenching and other inherent drawbacks such as pH-sensitivity, polarity insensitivity, water insolubility, slow diffusibility, and poor photostability. To overcome these limitations, we have utilized an alkyl chain length engineering strategy and synthesized a series of lysosome targeting fluorescent derivatives namelyNIMCsby attaching a morpholine moiety at theperiposition of the 1,8-naphthalimide (NI) ring through varying alkyl spacers between morpholine and 1,8-naphthalimide. The structural and optical properties of the synthesizedNIMCswere explored by1H-NMR, single-crystal X-ray diffraction, UV-Vis, and fluorescence spectroscopy. Afterward, optical spectroscopic measurements were carefully performed to identify a pH-tolerant, polarity sensitive, and highly photostable fluoroprobes for further live-cell imaging applications.NIMC6displayed excellent pH-tolerant and polarity-sensitive properties. Consequently, allNIMCswere employed in kidney fibroblast cells (BHK-21) to investigate their applicability for lysosome targeting and probing lysosomal micropolarity. Interestingly, a switching of localization from lysosomes to the endoplasmic reticulum (ER) was also achieved by controlling the linker length and this phenomenon was subsequently applied in determining ER micropolarity. Additionally, the selected probeNIMC6was also employed in BHK-21 cells for 3-D spheroid imaging and inCaenorhabditis elegans(C. elegans) forin vivoimaging, to evaluate its efficacy for imaging animal models.
- Bhowal, Rohit,Biswas, Suprakash,Chopra, Deepak,Dutta, Tanoy,Koner, Apurba L.,Silswal, Akshay
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p. 9630 - 9644
(2021/07/28)
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- COUNTERCURRENT RARE EARTH SEPARATION PROCESS
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A method for extracting a rare earth metal from a mixture of one or more rare earth metals, said method comprising countercurrently contacting an acidic solution of the rare earth metal with a composition which comprises an ionic liquid to form an aqueous phase and a non-aqueous phase into which the rare earth metal has been selectively extracted.
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Paragraph 0178; 0183
(2021/09/17)
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- Tuning DNA Supramolecular Polymers by the Addition of Small, Functionalized Nucleobase Mimics
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Nucleobase mimicking small molecules able to reconfigure DNA are a recently discovered strategy that promises to extend the structural and functional diversity of nucleic acids. However, only simple, unfunctionalized molecules such as cyanuric acid and melamine have so far been used in this approach. In this work, we show that the addition of substituted cyanuric acid molecules can successfully program polyadenine strands to assemble into supramolecular fibers. Unlike conventional DNA nanostructure functionalization, which typically end-labels DNA strands, our approach incorporates functional groups into DNA with high density using small molecules and results in new DNA triple helices coated with alkylamine or alcohol units that grow into micrometer-long fibers. We find that small changes in the small molecule functional group can result in large structural and energetic variation in the overall assembly. A combination of circular dichroism, atomic force microscopy, molecular dynamics simulations, and a new thermodynamic method, transient equilibrium mapping, elucidated the molecular factors behind these large changes. In particular, we identify substantial DNA sugar and phosphate group deformations to accommodate a hydrogen bond between the phosphate and the small-molecule functional groups, as well as a critical chain length of the functional group which switches this interaction from intra- to interfiber. These parameters allow the controlled formation of hierarchical, hybrid DNA assemblies simply through the addition and variation of small, functionalized molecules.
- Lachance-Brais, Christophe,Hennecker, Christopher D.,Alenaizan, Asem,Luo, Xin,Toader, Violeta,Taing, Monica,Sherrill, C. David,Mittermaier, Anthony K.,Sleiman, Hanadi F.
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supporting information
p. 19824 - 19833
(2021/11/30)
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- Repurposing Antiviral Drugs for Orthogonal RNA-Catalyzed Labeling of RNA
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In vitro selected ribozymes are promising tools for site-specific labeling of RNA. Previously known nucleic acid catalysts attached fluorescently labeled adenosine or guanosine derivatives through 2′,5′-branched phosphodiester bonds to the RNA of interest. Herein, we report new ribozymes that use orthogonal substrates, derived from the antiviral drug tenofovir, and attach bioorthogonal functional groups, as well as affinity handles and fluorescent reporter units through a hydrolytically more stable phosphonate ester linkage. The tenofovir transferase ribozymes were identified by in vitro selection and are orthogonal to nucleotide transferase ribozymes. As genetically encodable functional RNAs, these ribozymes may be developed for potential cellular applications. The orthogonal ribozymes addressed desired target sites in large RNAs in vitro, as shown by fluorescent labeling of E. coli 16S and 23S rRNAs in total cellular RNA.
- Dey, Surjendu,Ghaem Maghami, Mohammad,H?bartner, Claudia,Lenz, Ann-Kathrin
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supporting information
p. 9335 - 9339
(2020/04/17)
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- Synthesis of hydroxyethyl methyl morpholinium azide (HEM Morph)N3: A highly efficient new task specific azide-based ionic liquid and its dual application as an azide source and media for synthesis of some novel aromatic O-oxime ethers-1,2,3-triazole conjugates as a potential antihistaminic agents
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The synthesis, characterization and application of hydroxyethyl methyl morpholinium azide (HEM Morph)N3 as a new azide-based ionic liquid (ABIL) has been described. (HEM Morph)N3 is used as a source of azide and reaction media for three components ‘Click’ Huisgen cycloaddition reaction between O-propargyl oxime ether and alkyl bromide to acquire novel aromatic O-oxime ethers-1,2,3-triazole conjugates as potential antihistaminic agents in good yields. The influence of parameters like temperature, amount of IL, type of azide-based ionic liquids and its reusability is investigated. The (HEM Morph)N3 is proved to be an efficient, thermally stable, inexpensive and recyclable azide-based ionic liquid which can be easily synthesized and used as both azide's source and reaction media for ‘Click’ Huisgen cycloaddition reaction.
- Rad, Mohammad Navid Soltani,Behrouz, Somayeh,Saremi, Hossein,Mohammadtaghi-Nezhad, Javad
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- Novel CDKs inhibitors for the treatment of solid tumour by simultaneously regulating the cell cycle and transcription control
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A novel series of cyclin-dependent kinases (CDKs) inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription, were synthesised. A systematic study of enzymatic and cellular assays led to the identification of compound X22 with a nanomolar potency against CDK4 and CDK9 and potent antiproliferative activities against a panel of tumour cell lines. X22 could induce cell cycle arrest and cell apoptosis in cancer cell lines. X22 dose-dependently inhibits signalling pathways downstream of CDKs in cancer cells. In vivo antitumor activity assays, oral administration of X22 led to significant tumour regression in mouse model without obvious toxicity. Superior anti-cancer efficacy in vitro and in vivo of X22 demonstrated combined depletion of cell cycle and transcriptional CDK all contributed to antitumor activity. Taken together, concomitant inhibition of cell cycle and transcriptional CDK activities provided valuable guide for further structural optimisation.
- Deng, Kaiyuan,Fan, Yan,Huang, Zhi,Li, Yao,Ma, Yakun,Shi, Yi,Sun, Peiqing,Wang, Cheng,Wang, Tianqi,Wang, Xin,Xiang, Rong,Yang, Shengyong
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p. 414 - 423
(2020/01/08)
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- Development of phthalimide-donepezil hybrids as potent multitargetdirected ligands for the treatment of alzheimer’s disease
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Background: Due to the complex etiology of AD, multi-target-directed ligands (MTDLs), combining two or more distinct pharmacological moieties, have been developed in both symptomatic and disease-modifying efficiencies and are considered as an effective way for the treatment of AD. Methods: To test their biological activities, including AChE/BChE inhibitory activity and MAOA/MAO-B inhibitory activity. In addition, molecular modeling studies were performed to afford insight into the binding mode. Results and Discussions: The results displayed that compound 4c showed the best AChE inhibitory activity with an IC50 value of 4.2 μM, which was supported by the kinetic study and docking study. Compound 4c was also a selective MAO-B inhibitor (IC50 = 8.2 μM). Moreover, compound 4c could cross the blood-brain barrier in vitro. Conclusion: Compound 4c deserved to further study as a potential multifunctional agent for the treatment of Alzheimer’s disease.
- Yu, Lintao,Shi, Jian,Cheng, Xinfeng,Wang, Keren,Liu, Shuang,Liu, Wenmin,Sang, Zhipei
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p. 1155 - 1163
(2020/09/15)
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- Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents
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The multifaceted nature of Alzheimer's disease (AD) demands treatment with multitarget-directed ligands (MTDLs) to confront the key pathological aberrations. A novel series of triazinoindole derivatives were designed and synthesized. In vitro studies revealed that all the compounds showed moderate to good anticholinesterase activity; the most active compound 23e showed an IC50 value of 0.56 ± 0.02 μM for AChE and an IC50 value of 1.17 ± 0.09 μM for BuChE. These derivatives are also endowed with potent antioxidant activity. To understand the plausible binding mode of the compound 23e, molecular docking studies and molecular dynamics simulation studies were performed, and the results indicated significant interactions of 23e within the active sites of AChE as well as BuChE. Compound 23e successfully diminished H2O2-induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2 as well as Aβ-induced toxicity in SH-SY5Y cells in a concentration dependent manner. Furthermore, it did not show any significant toxicity in neuronal SH-SY5Y cells in the cytotoxicity assay. Compound 23e did not show any acute toxicity in rats at doses up to 2000 mg/kg, and it significantly reversed scopolamine-induced memory deficit in mice model. Additionally, compound 23e showed notable in silico ADMET properties. Taken collectively, these findings project compound 23e as a potential balanced MTDL in the evolution process of novel anti-AD drugs.
- Patel, Dushyant V.,Patel, Nirav R.,Kanhed, Ashish M.,Patel, Sagar P.,Sinha, Anshuman,Kansara, Deep D.,Mecwan, Annie R.,Patel, Sarvangee B.,Upadhyay, Pragnesh N.,Patel, Kishan B.,Shah, Dharti B.,Prajapati, Navnit K.,Murumkar, Prashant R.,Patel, Kirti V.,Yadav, Mange Ram
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p. 3635 - 3661
(2019/08/20)
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- Novel salicylamide derivatives as potent multifunctional agents for the treatment of Alzheimer's disease: Design, synthesis and biological evaluation
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A series of salicylamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors. They showed good inhibitory activities of self- and Cu2+-induced Aβ1–42 aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward RatAChE and EeAChE with IC50 value of 10.4 μM and 15.2 μM, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu2+-induced Aβ1–42 aggregation inhibitory potency (42.5% and 31.4% at 25.0 μM, respectively) and moderate disaggregation ability to self- and Cu2+-induced Aβ1–42 aggregation fibrils (23.4% and 27.0% at 25 μM, respectively). Furthermore, 15b also showed biometal chelating abilities, anti-neuroinflammatory ability and BBB permeability. These multifunctional properties indicated compound 15b was worthy of being chosen for further pharmacokinetics, toxicity and behavioral researches to test its potential for AD treatment.
- Song, Qing,Li, Yan,Cao, Zhongcheng,Qiang, Xiaoming,Tan, Zhenghuai,Deng, Yong
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p. 137 - 149
(2018/11/30)
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- Preparation method of supramolecular polymer network based on tetraphenylethylene
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The invention discloses a synthesis method of a ureido pyrimidone substituted tetraphenylethylene derivative. The synthesis method relates to synthesis of a tetraphenylethylene compound, specifically,a compound B is synthesized through a synthesis reactio
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Paragraph 0030; 0034; 0038; 0042; 0046; 0050
(2019/07/01)
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- ENHANCED SEPARATION OF RARE EARTH METALS
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A method for extracting a rare earth metal from a mixture of one or more rare earth metals, said method comprising contacting an acidic solution of the rare earth metal with a composition which comprises an ionic liquid to form an aqueous phase and a non-aqueous phase into which the rare earth metal has been selectively extracted, wherein the ionic liquid has the formula [Cat+][X'], where [Χ'] represents a phosphinate anion.
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Page/Page column 28
(2020/01/08)
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- IONIC LIQUID PREPARATION
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A process for preparing a cationic species [Cat + ] for an ionic liquid, said process comprising reacting a reagent (1) H 2 N-L -[Z] with a reagent (2) LG-L 2 -EDG, to form a cationic species EDG-L 2 -[Z + ]-L -N(L 2 -EDG) 2, wherein the process is carried out in a sealed reactor at a temperature of at least 100 °C.
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Page/Page column 30; 32
(2020/01/08)
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- Highly Selective Butyrylcholinesterase Inhibitors with Tunable Duration of Action by Chemical Modification of Transferable Carbamate Units Exhibit Pronounced Neuroprotective Effect in an Alzheimer's Disease Mouse Model
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In this study, the carbamate structure of pseudo-irreversible butyrylcholinesterase (BChE) inhibitors was optimized with regard to a longer binding to the enzyme. A set of compounds bearing different heterocycles (e.g., morpholine, tetrahydroisoquinoline, benzimidazole, piperidine) and alkylene spacers (2 to 10 methylene groups between carbamate and heterocycle) in the carbamate residue was synthesized and characterized in vitro for their binding affinity, binding kinetics, and carbamate hydrolysis. These novel BChE inhibitors are highly selective for hBChE over human acetycholinesterase (hAChE), yielding short-, medium-, and long-acting nanomolar hBChE inhibitors (with a half-life of the carbamoylated enzyme ranging from 1 to 28 h). The inhibitors show neuroprotective properties in a murine hippocampal cell line and a pharmacological mouse model of Alzheimer's disease (AD), suggesting a significant benefit of BChE inhibition for a disease-modifying treatment of AD.
- Hoffmann, Matthias,Stiller, Carina,Endres, Erik,Scheiner, Matthias,Gunesch, Sandra,Sotriffer, Christoph,Maurice, Tangui,Decker, Michael
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p. 9116 - 9140
(2019/11/03)
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- Synthesis and Pharmacological Properties of 1-(6-Aminohexylamino)-1-Phenylcyclohexyl Dihydrochloride (IEM-2062) as Compared with Memantine
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1-(6-Aminohexylamino)-1-phenylcyclohexyl dihydrochloride (IEM-2062) had significantly greater antihypoxic, anticonvulsant, antidepressant, and analgesic activity than memantine and similar antiparkinsonism activity as memantine; it had low toxicity and was safer for use. IEM-2062 produced significant pharmacological effects in the dose range 0.3 – 3 mg/kg.
- Gmiro,Serdyuk,Veselkina
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- Design, synthesis and insecticide activity of novel acetylcholinesterase inhibitors: Triazolinone and phthalimide heterodimers
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Based on the “cluster effect” and the structure characters of acetylcholinesterase (AChE; EC 3.1.1.7), a new series of 1,2,4-triazolin-3-one and phthalimide heterodimers were designed, synthesized, and evaluated as potent dual acetylcholinesterase inhibitors (AChEIs). Most of the synthesized compounds showed good in vitro inhibitory activities towards both Drosophila melanogaster acetylcholinesterase (DmAChE) and Musca domestica acetylcholinesterase (MdAChE). Among them, 5g was found to be the most potent anti-AChE de-rivate (5g, IC50=8.07μM to DmAChE, IC50=32.24μM to MdAChE). It was 2.31- and 1.35-fold more active than the positive control ethion (CP, IC50=18.62μM to DmAChE, IC50=43.56μM to MdAChE). The docking model study revealed that 5g possessed the fitted spatial structure and bound to the central pocket and peripheral site of DmAChE. Moreover, most compounds demonstrated high insecticidal activity to Lipaphis erysimi and Tetranychus cinnabarinus at the concentration of 300mg/L.
- Xie, Ruliang,Mei, Xiangdong,Ning, Jun
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p. 345 - 350
(2019/05/07)
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- NITROGEN RING LINKED DEOXYURIDINE TRIPHOSPHATASE INHIBITORS
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Provided herein are dUTPase inhibitors, compositions comprising such compounds and methods of using such compounds and compositions.
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Paragraph 0626
(2018/06/12)
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- 6-MEMBERED URACIL ISOSTERES
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Provided herein are dUTPase inhibitors, compositions comprising such compounds and methods of using such compounds and compositions.
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Paragraph 0715
(2018/06/12)
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- HYDANTOIN CONTAINING DEOXYURIDINE TRIPHOSPHATASE INHIBITORS
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Provided herein are dUTPase inhibitors, compositions comprising such compounds and methods of using such compounds and compositions.
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Paragraph 0731
(2018/06/12)
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- HYDANTOIN CONTAINING DEOXYURIDINE TRIPHOSPHATASE INHIBITORS
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Provided herein are dUTPase inhibitors, compositions comprising such compounds and methods of using such compounds and compositions.
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Paragraph 0724
(2018/06/12)
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- URACIL CONTAINING COMPOUNDS
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Provided herein are dUTPase inhibitors, compositions comprising such compounds and methods of using such compounds and compositions.
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Paragraph 0690
(2018/07/31)
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- Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease
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A series of scutellarein-O-acetamidoalkylbenzylamines derivatives were designed based on a multitarget-directed ligands strategy for the treatment of Alzheimer's disease. Among these compounds, compound T-22 demonstrated excellent acetylcholinesterase inhibitory, moderate inhibitory effects on self-induced Aβ1-42 aggregation, Cu2+-induced Aβ1-42 aggregation, human AChE-induced Aβ1-40 aggregation and disassembled Cu2+-induced aggregation of the well-structured Aβ1-42 fibrils, and also acted as potential antioxidant and biometals chelator. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that T-22 interacted with both the catalytic active site and peripheral anionic site of AChE. Moreover, compound T-22 showed a good neuroprotective effect against H2O2-induced PC12?cell injury and low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated T-22 significantly reversed scopolamine-induced memory deficit in mice. Taken together, the data showed that T-22 was an interesting multifunctional lead compound worthy of further study for AD.
- Sang, Zhipei,Qiang, Xiaoming,Li, Yan,Xu, Rui,Cao, Zhongcheng,Song, Qing,Wang, Ting,Zhang, Xiaoyu,Liu, Hongyan,Tan, Zhenghuai,Deng, Yong
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p. 307 - 323
(2017/05/01)
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- Pyrrolo pyrrole diketone (DPP) quaternary ammonium salt compound and its preparation and use
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The invention provides diketopyrrolopyrrole (DPP) quaternary ammonium salt compounds, which are disclosed as the structural formula in the specification, wherein N-R2 is disclosed in the specification, and R1 is Cl, Br, F, I, CF3, CN, tBu, CH3, H, 2,6-F2,
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Paragraph 0046-0048
(2017/07/08)
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- HYDANTOIN CONTAINING DEOXYURIDINE TRIPHOSPHATASE INHIBITORS
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Provided herein are dUTPase inhibitors, compositions comprising such compounds and methods of using such compounds and compositions.
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Paragraph 0642
(2017/01/26)
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- Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer's disease
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A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer's disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC50 values of 1.2 μM, 3.8 μM and 2.6 μM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM-9 abided by Lipinski's rule of five. Furthermore, our investigation proved that TM-9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro. The results suggest that compound TM-9, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.
- Sang, Zhipei,Wang, Keren,Wang, Huifang,Yu, Lintao,Wang, Huijuan,Ma, Qianwen,Ye, Mengyao,Han, Xue,Liu, Wenmin
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supporting information
p. 5053 - 5059
(2017/10/18)
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- Threading of an Inherently Directional Calixarene Wheel with Oriented Ammonium Axles
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The threading of monostoppered alkylbenzylammonium axles 7+ and 8+ with the calix[6]-wheel 3 can occur by both routes of entering the macrocycle 3 in the cone conformation: passage through the upper rim and the through the lower rim. Thus, under thermodynamic conditions, with both the axles 7+ and 8+, the two possible orientations of calix[2]pseudorotaxane, namely, endo-benzyl and endo-alkyl, are formed by a stereoselectivity controlled by the endo-alkyl rule. Interestingly, by 1H NMR monitoring of the threading process between 8+ and 3, we revealed two calix[2]pseudorotaxane isomers in which the calix-wheel adopts 1,2,3-alternate and cone conformations, which represent the kinetic and thermodynamic species, respectively. Finally, the synthesis of ammonium-based oriented calix[2]rotaxane is here described.
- La Manna, Pellegrino,Talotta, Carmen,Gaeta, Carmine,Soriente, Annunziata,De Rosa, Margherita,Neri, Placido
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supporting information
p. 8973 - 8983
(2017/09/11)
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- Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer's disease
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A series of pterostilbene-O-acetamidoalkylbenzylamines were designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Aβ1-42 aggregation and HuAChE-induced Aβ1-40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d exhibited the best AChE inhibitory activity (IC50 = 0.06 μM) and good inhibition of BuChE (IC50 = 28.04 μM). Both the inhibition kinetic analysis and molecular modeling study revealed that these compounds showed mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activity. However, the inhibitory activities against self-induced and HuAChE-induced Aβ aggregation of these new derivatives were unsatisfied. Taking into account the results of the biological evaluation, further modifications will be designed in order to increase the potency on the different targets. The results displayed in this Letter can be a new starting point for further development of multifunctional agents for Alzheimer's disease.
- Li, Yuxing,Qiang, Xiaoming,Li, Yan,Yang, Xia,Luo, Li,Xiao, Ganyuan,Cao, Zhongcheng,Tan, Zhenghuai,Deng, Yong
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supporting information
p. 2035 - 2039
(2016/04/05)
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- Triphenylene-perylene monoimide diformate binary compound, preparation method and applications thereof
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The present invention provides a triphenylene-perylene monoimide diformate binary compound, which has a structure represented by a general formula I. The present invention further provides a preparation method of the triphenylene-perylene monoimide diformate binary compound, and applications of the triphenylene-perylene monoimide diformate binary compound as an organic solar cell active layer. Compared to the compound in the prior art, the compound of the present invention has advantages of easy adjustment of liquid crystal phase change temperature and temperature range, such that the compound has optical, electronic and electro-optical uses, and especially has uses as the organic solar cell active layer. The general formula (I) is defined in the specification.
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- Design, synthesis and evaluation of novel ferulic acid-memoquin hybrids as potential multifunctional agents for the treatment of Alzheimer's disease
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A novel series of ferulic acid-memoquin hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro studies showed that most of the compounds exhibited a significant ability to inhibit acetylcholinesterase (AChE) (IC50 of 3.2-34.7 μM) and self-induced β-amyloid (Aβ1-42) aggregation (30.8-39.1%, 25 μM), to act as potential antioxidants (ORAC-FL value of 0.9-1.3). In particular, compound 17d had the greatest ability to inhibit AChE (IC50 = 3.2 μM), and Aβ1-42 aggregation (30.8%) was also an excellent antioxidant and neuroprotectant. Moreover, it is capable of disaggregating self-induced Aβ aggregation. Furthermore, 17d could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 17d is a potential multifunctional agent for the treatment of AD.
- Pan, Wanli,Hu, Ke,Bai, Ping,Yu, Lintao,Ma, Qinge,Li, Tao,Zhang, Xu,Chen, Changzhong,Peng, Kelin,Liu, Wenmin,Sang, Zhipei
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supporting information
p. 2539 - 2543
(2016/07/07)
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- Design, synthesis and bioactivity of novel phthalimide derivatives as acetylcholinesterase inhibitors
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A series of novel phthalimide derivatives related to benzylpiperazine were synthesized and evaluated as cholinesterase inhibitors. The results showed that all compounds were able to inhibit acetylcholinesterase (AChE), with two of them dramatically inhibiting butyrylcholinesterase (BuChE). Most compounds exhibited potent anti-AChE activity in the range of nM concentrations. In particular, compounds 7aIII and 10a showed the most potent activity with the IC50 values of 18.44 nM and 13.58 nM, respectively. To understand the excellent activity of these compounds, the structure-activity relationship was further examined. The protein-ligand docking study demonstrated that the target compounds have special binding modes and these results are in agreement with the kinetic study.
- Si, Weijie,Zhang, Tao,Zhang, Lanxiang,Mei, Xiangdong,Dong, Mengya,Zhang, Kaixin,Ning, Jun
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supporting information
p. 2380 - 2382
(2016/04/20)
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- Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents
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A new series of 4-dimethylamine flavonoid derivatives were designed and synthesized as potential multifunctional anti-Alzheimer agents. The inhibition of cholinesterase activity, self-induced β-amyloid (Aβ) aggregation, and antioxidant activity by these derivatives was investigated. Most of the compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. A Lineweaver-Burk plot and molecular modeling study showed that these compounds targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. The derivatives showed potent self-induced Aβ aggregation inhibition and peroxyl radical absorbance activity. Moreover, compound 6d significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Thus, these compounds could become multifunctional agents for further development for the treatment of AD.
- Luo, Wen,Wang, Ting,Hong, Chen,Yang, Ya-Chen,Chen, Ying,Cen, Juan,Xie, Song-Qiang,Wang, Chao-Jie
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supporting information
p. 17 - 26
(2016/07/06)
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- 15 the position escapes acetylprotoaescigenin 13 bit linear amino sulfonic acid substituted hypocrellin derivative and its preparation method and application
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The invention discloses a site-15 deacetylation and site-13 straight-chain sulfamic acid substituted hypocrellin derivative, a preparation method and application thereof. The structural general formula of the derivative is shown as the formula I (disclosed in the specification). The derivative is a novel hypocrellin derivative designed specially aiming at photodynamic medical treatment of micrangium diseases such as related retina macular degeneration, and the like. The maximum light absorption wavelength of the derivative is 58 nm, and the light tissue penetration depth in the wavelength range conforms to the focus depth of the micrangium diseases, meanwhile, the absorption spectrum of visual pigment is kept away as far as possible; and in addition, the derivative has optimized dual affiliation to fat and water and can be directly dissolved into normal saline to prepare intravenous injection solutions without complicated preparation technologies.
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Paragraph 0035; 0036
(2016/10/08)
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- Microorganism detection and analysis using carbohydrate and lectin recognition
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Methods of binding and detecting a microorganism on a solid substrate. The microorganism is bound on a solid substrate covalently bound to a capture agent having a saccharide moiety. A lectin capable of binding to the microorganism and the saccharide moiety of the capture agent is added to the sample to bind the microorganism on the solid substrate. Further provided are biosensor devices, such as a quartz crystal microbalance (QCM) device or a surface plasmon resonance (SPR) device, that incorporate the solid substrate for the detection of microorganisms.
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Sheet 23 of 24
(2016/09/26)
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- Metal-free C-N cross-coupling of electrophilic compounds and N-haloimides
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When DBU is added, the cross-coupling reaction between alkyl halides (halogen = Cl, Br and I) and N-haloimides (halogen = Cl, Br) occurs, resulting in the formation of aminated products. A halogen bond activated nucleophilic substitution mechanism was proposed. The methodology represents an elegant example of applying the halogen bond activation strategy in an organic transformation.
- Zhang, Luyan,Li, Yanru,Jin, Long-Yi,Liang, Fushun
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p. 65600 - 65603
(2015/08/18)
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- Forward and reverse (Retro) Iron(III) or gallium(III) desferrioxamine e and ring-expanded analogues prepared using metal-templated synthesis from endo -hydroxamic acid monomers
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A metal-templated synthesis (MTS) approach was used to preorganize the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoic acid (for-PBH) about iron(III) in a 1:3 metal/ligand ratio to furnish the iron(III) siderophore for-[Fe(DFOE)] (ferrioxamine E) following peptide coupling. Substitution of for-PBH with the reverse (retro) hydroxamic acid analogue 3-(6-amino-N-hydroxyhexanamido)propanoic acid (ret-PBH) furnished ret-[Fe(DFOE)] (ret-ferrioxamine E). As isomers, for-[Fe(DFOE)] and ret-[Fe(DFOE)] gave identical mass spectrometry signals ([M + H+]+, m/zcalc 654.3, m/zobs 654.3), yet for-[Fe(DFOE)] eluted in a more polar window (tR = 23.44 min) than ret-[Fe(DFOE)] (tR = 28.13 min) on a C18 reverse-phase high-performance liquid chromatography (RP-HPLC) column. for-[Ga(DFOE)] (tR = 22.99 min) and ret-[Ga(DFOE)] (tR = 28.11 min) were prepared using gallium(III) as the metal-ion template and showed the same trend for the retention time. Ring-expanded analogues of for-[Fe(DFOE)] and ret-[Fe(DFOE)] were prepared from endo-hydroxamic acid monomers with one additional methylene unit in the amine-containing region, 4-[(6-aminohexyl)(hydroxy)amino]-4-oxobutanoic acid (for-HBH) or 3-(7-amino-N-hydroxyheptanamido)propanoic acid (ret-HBH), to give the corresponding tris(homoferrioxamine E) macrocycles, for-[Fe(HHDFOE)] or ret-[Fe(HHDFOE)] ([M + H+]+, m/zcalc 696.3, m/zobs 696.4). The MTS reaction using a constitutional isomer of for-HBH that transposed the methylene unit to the carboxylic acid containing region, 5-[(5-aminopentyl)(hydroxy)amino]-5-oxopentanoic acid (for-PPH), gave the macrocycle for-[Fe(HPDFOE)] in a yield significantly less than that for for-[Fe(HHDFOE)], with the gallium(III) analogue for-[Ga(HPDFOE)] unable to be detected. The work demonstrates the utility and limits of MTS for the assembly of macrocyclic siderophores from endo-hydroxamic acid monomers. Indirect measures (RP-HPLC order of elution, c log P values, molecular mechanics, and density functional theory calculations) of the relative water solubility of the ligands, the iron(III) macrocycles, and the apomacrocycles were consistent in identifying for-DFOE as the most water-soluble macrocycle from for-DFOE, ret-DFOE, for-HHDFOE, ret-HHDFOE, and for-HPDFOE. From this group, only for-DFOE is known in nature, which could suggest that water solubility is an important trait in its natural selection.
- Lifa, Tulip,Tieu, William,Hocking, Rosalie K.,Codd, Rachel
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supporting information
p. 3573 - 3583
(2015/04/14)
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- Isoindoline-1,3-dione derivatives targeting cholinesterases: Design, synthesis and biological evaluation of potential anti-Alzheimer's agents
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Alzheimer's disease is a fatal neurodegenerative disorder with a complex etiology. Because the available therapy brings limited benefits, the effective treatment for Alzheimer's disease remains the unmet challenge. Our aim was to develop a new series of donepezil-based compounds endowed with inhibitory properties against cholinesterases and β-amyloid aggregation. We designed the target compounds as dual binding site acetylcholinesterase inhibitors with N-benzylamine moiety interacting with the catalytic site of the enzyme and an isoindoline-1,3-dione fragment interacting with the peripheral anionic site of the enzyme. The results of pharmacological evaluation lead us to identify a compound 3b as the most potent and selective human acetylcholinesterase inhibitor (hAChE IC50 = 0.361 μM). Kinetic studies revealed that 3b inhibited acetylcholinesterase in non-competitive mode. The result of the parallel artificial membrane permeability assay for the blood-brain barrier indicated that the compound 3b would be able to cross the blood-brain barrier and reach its biological targets in the central nervous system. The selected compound 3b represents a potential lead structure for further development of anti-Alzheimer's agents.
- Guzior, Natalia,Bajda, Marek,Rakoczy, Jurand,Brus, Boris,Gobec, Stanislav,Malawska, Barbara
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p. 1629 - 1637
(2015/03/30)
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- Multiple Ligands Targeting Cholinesterases and β-Amyloid: Synthesis, Biological Evaluation of Heterodimeric Compounds with Benzylamine Pharmacophore
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Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti-AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitors, where the N-benzylamine pharmacophore is responsible for interactions with the catalytic anionic site of the enzyme. The heteroaromatic fragment responsible for interactions with the peripheral anionic site was modified and three different heterocycles were introduced: isoindoline, isoindolin-1-one, and saccharine. Based on the results of the pharmacological evaluation, we identified compound 8b with a saccharine moiety as the most potent and selective human acetylcholinesterase inhibitor (IC50=33 nM) and beta amyloid aggregation inhibitor. It acts as a non-competitive acetylcholinesterase inhibitor and is able to cross the blood-brain barrier in vitro. We believe that compound 8b represents an important lead compound for further development as potential anti-AD agent.
- Szalaj, Natalia,Bajda, Marek,Dudek, Katarzyna,Brus, Boris,Gobec, Stanislav,Malawska, Barbara
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p. 556 - 563
(2015/08/11)
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- Encapsulation of a catalytic imidazolium salt into avidin: Towards the development of a biohybrid catalyst active in ionic liquids
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Herein, we report the development of biohybrid catalysts that are capable of catalyzing the aldol reaction. The use of biotinylated imidazolium salts in combination with racemic or enantiomerically pure catalytic anions allowed us to study the adaptive and cooperative positioning of the anionic catalyst inside the protein. Supramolecular encapsulation of the biotinylated catalyst into avidin resulted in good selectivity for the aldol reaction performed in ionic liquid/water mixtures. Biohybrid catalysts capable of catalyzing the aldol reaction are prepared from avidin and biotinylated imidazolium salts with either racemic or enantiomerically pure catalytic anions. Supramolecular encapsulation (see figure) of the biotinylated catalyst in avidin resulted in good selectivities for the aldol reaction when performed in ionic liquid/water mixtures and the adaptive and cooperative positioning of the anionic catalyst inside the avidin protein is discussed. Copyright
- Gauchot, Vincent,Branca, Mathieu,Schmitzer, Andreea
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supporting information
p. 1530 - 1538
(2014/03/21)
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- MACROCYCLIC COMPOUNDS AS IRAK4 INHIBITORS FOR THE TREATMENT OF INFLAMMATORY DISEASES
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Provided are compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein i.a. Ring A is phenylene or 5- to 6-membered heteroarylene; Ring B is phenylene, 5- to 6-membered heterocycloalkylene or 5- to 6-membered heteroarylen; R4/s
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Paragraph 0281
(2014/09/29)
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- Synthesis, in vitro cytotoxicity and radiosensitizing activity of novel 3-[(2,4-dinitrophenylamino)alkyl] derivatives of 5-fluorouracil
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Previously, it was reported that 3[3-(2,4-dinitrophenylamino)-propyl]-5- fluorouracil 8c unlike its components 5-fluorouracil (5-FU) 6 and 2,4-dinitroaniline 2 in HT-29 cells under aerobic conditions had no cytotoxicity but showed radiosensitizing activity. In this study several analogues of 8c differing in the number of linking methylene groups were prepared and tested for in vitro cytotoxicity and radiosensitizing activity under both aerobic and hypoxic conditions. Tethered compound 8a was prepared in one pot by the reaction of 5-FU 6 with paraformaldehyde and 2,4-dinitroaniline 2 in the presence of the concentrated hydrochloric acid, and compounds 8b-f were prepared by the reaction of N-(bromoalkyl) - 2,4-dinitrobenzeneamines 5b-f with 1-(t-butoxycarbonyl)-5-fluorouracil 7 followed by hydrolysis of the protecting group. The cytotoxicity of the tested compounds were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and propidium iodide (PI)-digitonin assays and values of sensitization enhancement ratio (SER) as a measure of the radiosensitizing activity were measured from radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively. Results showed that tethered compounds 8a-f induced time- and concentration-dependent cytotoxicity under hypoxia but had no significant effect under aerobic conditions. These compounds also showed selective and concentration-dependent radiocytotoxicity under hypoxic conditions. Several novel 3[3-(2,4-dinitro-phenylamino)-alkyl]-5-fluorouracil resulting from linkage of 2,4-dinitrophenylamine through 1-6 methylene units with 5-fluorouracil were prepared and tested for in vitro cytotoxicity in HT-29 cell line under aerobic and hypoxic conditions with and without radiation. These compounds induced time- and concentration-dependent cytotoxicity which were higher under hypoxic than aerobic conditions, and showed selective radiosensitizing activities under hypoxic conditions.
- Khalaj, Ali,Abdi, Khosrou,Ostad, Seyed Nasser,Khoshayand, Mohammad Reza,Lamei, Navid,Nedaie, Hasan Ali
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p. 183 - 190
(2014/02/14)
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- New arylpiperazines with flexible versus partly constrained linker as serotonin 5-HT1A/5-HT7 receptor ligands
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A series of new long-chain arylpiperazine (LCAP) derivatives with flexible and partly constrained alkyl linker were synthesized and investigated in vitro as potential serotonin 5-HT1A and 5-HT7 receptor ligands. The compounds were prepared by a two-step procedure using naphthalimide and 2H-1,3-benzoxazine-2,4(3H)-dione as imides, and 1-(2-methoxyphenyl)piperazine (o-OMe-PhP) and 1,2,3,4-tetrahydroisoquinoline (THIQ) as amine pharmacophores. Modifications of the spacer structure included introduction of flexible penta- and hexamethylene chains as well as partly constrained m- and p-xylyl moieties. In general, the new compounds were more active at the 5-HT1A than at the 5-HT7 receptor, and the o-OMe-PhP derivatives displayed higher affinities than their respective THIQ analogs. The spacer modifications had little effect on the observed in vitro activities. Within the o-OMe-PhP series, except for a small binding reduction for ligands containing the m-xylyl moiety, there was no substantial change in the compounds' potency at both receptors, while for the THIQ derivatives a clear structure-activity relationship was visible only for the interaction of the compounds with the 5-HT7 receptor, which strongly favored flexible analogs. New LCAP derivatives with flexible and partly constrained alkyl linker were tested as potential serotonin 5-HT1A and 5-HT7 receptor ligands. The spacer structure was modified by introduction of flexible penta- and hexamethylene chains and partly constrained m- and p-xylyl moieties. The new compounds were more active at the 5-HT1A than at the 5-HT7 receptor. o-OMe-PhP derivatives displayed higher affinities than their respective THIQ analogs. The spacer modifications had little effect on the observed in vitro activities. Copyright
- Kowalski, Piotr,Mitka, Katarzyna,Jaskowska, Jolanta,Duszynska, Beata,Bojarski, Andrzej J.
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p. 339 - 348
(2013/07/19)
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- Design and synthesis of protoporphyrin IX/vitamin B12 molecular hybrids via CuAAC reaction
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The design and synthesis of new molecular hybrids composed of protoporphyrin IX (PPIX) and vitamin B12 via copper catalyzed alkyne azide cycloaddition reaction is described. New, clickable aminoazide and aminoalkyne linkers were prepared and subsequently attached to PPIX (via vinyl group) and to vitamin B12 giving desired building blocks. Preliminary results showed that respective water soluble hybrids were formed under CuAAC reaction. Gratifyingly, Cu incorporation into the PPIX core was avoided, which was important for further biological studies. Copyright
- Loska, Rafa?,Janiga, Anita,Gryko, Dorota
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p. 104 - 117
(2013/04/23)
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- Hybrids consisting of the pharmacophores of salmeterol and roflumilast or phthalazinone: Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of COPD
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A novel class of dual pharmacology bronchodilators targeting both β2-adrenoceptor and PDE4 was designed and synthesised by combining the pharmacophores of salmeterol and roflumilast or phthalazinone. All the compounds exhibited better β2-adrenoceptor agonist activities (pEC50 = 8.47-9.20) than the reference compound salmeterol (pEC50 = 8.3) and good inhibitory activity on PDE4B2 (IC 50 = 0.235-1.093 μM).
- Liu, Anqiu,Huang, Ling,Wang, Zhiren,Luo, Zonghua,Mao, Fei,Shan, Wenjun,Xie, Jiaxing,Lai, Kefang,Li, Xingshu
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p. 1548 - 1552
(2013/03/28)
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- AMIDOALKYLPIPERAZINYL DERIVATIVES FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISEASES
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The invention relates to novel amidoalkylpiperazinyl derivatives of tricyclic heterocyclic systems of general formula (I), wherein Z represents -NH- and X represents -S-, or Z represents -S- and X represents >C=C1 represents H or -CH3, R6 and R7 both represent H, n is an integer from 0 to 4 inclusive, G represents a cyclic amide or imide moiety, and optical isomers, geometric isomers, and pharmaceutically acceptable salts thereof. The compounds may be useful for the treatment and/or prevention of the central nervous system disorders.
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Page/Page column 31; 32; 33
(2013/03/26)
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- Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship
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Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm3), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
- Christensen, Mette K.,Erichsen, Kamille D.,Olesen, Uffe H.,Tj?rnelund, Jette,Fristrup, Peter,Thougaard, Annemette,Nielsen, S?ren Jensby,Sehested, Maxwell,Jensen, Peter B.,Loza, Einars,Kalvinsh, Ivars,Garten, Antje,Kiess, Wieland,Bj?rkling, Fredrik
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supporting information
p. 9071 - 9088
(2014/01/06)
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