- Cancer Targeted Enzymatic Theranostic Prodrug: Precise Diagnosis and Chemotherapy
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The development of targeted and effective theranostic (therapeutic and diagnostic) chemotherapeutic agents is highly desirable for precise diagnosis and treatment of cancer. To realize this goal, we developed a cancer-targeting and enzyme-triggered theranostic prodrug 1, containing 7-ethyl-10-hydroxycamptothecin (SN-38), a well-known anticancer drug, which inhibits topoisomerase I in the cell nucleus; hydroquinone as an enzyme-triggered moiety; and biotin as a cancer targeting unit. Enzyme-triggered theranostic prodrug 1 selectively targets cancer cells and is subsequently activated in the presence of NAD(P)H: quinone oxidoreductase-1 (NQO1), a cytosolic flavoprotein that catalyzes the two-electron reduction of quinone moieties with the concomitant consumption of NADH or NADPH as electron donors. High levels of NQO1 were found in a variety of cancer cell lines compared to healthy cells, and therefore, it is an excellent target for the development of cancer targeted drug delivery systems. Upon preferential cancer cell delivery and uptake, aided by biotin, the enzyme-triggered theranostic prodrug 1 is cleaved by NQO1, with the subsequent release of SN-38, inhibiting topoisomerase I, leading to apoptosis. The drug release and induced apoptosis of cancer cells expressing both biotin receptors and high levels of NQO1 was simultaneously monitored via the innate fluorescence of the released SN-38 by confocal microscopy. In vitro and in vivo studies showed an effective inhibition of cancer growth by the enzyme-triggered theranostic prodrug 1. Thus, this type of enzyme-triggered targeted prodrug therapy is an interesting and promising approach for future cancer treatment.
- Shin, Weon Sup,Han, Jiyou,Verwilst, Peter,Kumar, Rajesh,Kim, Jong-Hoon,Kim, Jong Seung
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- Hydrophilic 2,9-bis-triazolyl-1,10-phenanthroline ligands enable selective Am(III) separation: A step further towards sustainable nuclear energy
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The first hydrophilic, 1,10-phenanthroline derived ligands consisting of only C, H, O and N atoms for the selective extraction of Am(iii) from spent nuclear fuel are reported herein. One of these 2,9-bis-triazolyl-1,10-phenanthroline (BTrzPhen) ligands combined with a non-selective extracting agent, was found to exhibit process-suitable selectivity for Am(iii) over Eu(iii) and Cm(iii), providing a clear step forward.
- Edwards, Alyn C.,Mocilac, Pavle,Geist, Andreas,Harwood, Laurence M.,Sharrad, Clint A.,Burton, Neil A.,Whitehead, Roger C.,Denecke, Melissa A.
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- Safe and efficient membrane permeabilizing polymers based on PLLA for antibacterial applications
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Poly(N,N-dimethylaminoethyl methacrylate)-block-poly(l-lactic acid)-block-poly(N,N-dimethylaminoethyl methacrylate) conjugated with poly(ethylene glycol) (D-PLLA-D@PEG) copolymers were synthesized. These non-aggregating polymers showed low MIC values agai
- Li, Zibiao,Chee, Pei Lin,Owh, Cally,Lakshminarayanan, Rajamani,Loh, Xian Jun
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- A new signal-on photoelectrochemical biosensor based on a graphene/quantum-dot nanocomposite amplified by the dual-quenched effect of bipyridinium relay and AuNPs
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A new photoelectrochemical (PEC) biosensor was developed by using carboxyl-functionalized graphene and CdSe nanoparticles. This sensitive interface was then successfully applied to detection of thrombin based on the dual-quenched effect of PEC nanoparticle, which relied on the electron transfer of a bipyridinium relay and energy transfer of AuNPs. After recognition with an aptamer, the PEC nanoparticle was removed and a signal-on PEC biosensor was obtained. Moreover, the bio-barcode technique used in the preparation of PEC nanoparticle could avoid cross-reaction and enhances the sensitivity. Taking advantages of the various methods mentioned above, the sensitivity could be easily enhanced. In addition, in this work we also investigated graphene that was modified with different functional groups and AuNPs of different particle sizes. Under optimal conditions, a detection limit of 5.9×10-15 M was achieved. With its simplicity, selectivity, and sensitivity, this strategy shows great promise for the fabrication of highly efficient PEC biosensors. PECking order! A new photoelectrochemical (PEC) biosensor was developed by using carboxyl-functionalized graphene and CdSe nanoparticles (NPs). This sensitive interface was successfully applied to detection of thrombin based on the dual-quenched effect of a PEC nanoparticle, which relied on the electron transfer of a bipyridinium relay and energy transfer of AuNPs (see figure). After recognition with an aptamer, the PEC nanoparticle was removed and a signal-on PEC biosensor was obtained. (TEOA=triethanolamine.).
- Zhang, Xiaoru,Xu, Yunpeng,Yang, Yanqiang,Jin, Xia,Ye, Sujuan,Zhang, Shusheng,Jiang, Lilin
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- Targeted combinational therapy inducing mitochondrial dysfunction
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We report on a mitochondria-specific combinational theranostic agent, 1. This system contains a chlorambucil prodrug and an aggregation induced emission dye. In addition, compound 1 bears both an intracellular thiol-triggered moiety and a mitochondria targeting unit (triphenylphosphonium). Glutathione (GSH) is the most abundant thiol and its concentrations are significantly higher in a great number of cancer cell lines, compared to normal cells. The GSH-induced prodrug 1 upon activation releases chlorambucil and exhibits mitochondria targeted aggregation induced emission (AIE) fluorescence, resulting in cell apoptosis via the caspase pathway due to mitochondrial dysfunction.
- Shin, Weon Sup,Park, Soon Ki,Verwilst, Peter,Koo, Seyoung,Lee, Joung Hae,Chi, Sung-Gil,Kim, Jong Seung
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- Synthesis of racemic ethanolamine plasmalogen
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Racemic C12-ethanolamine plasmalogen 5b was prepared in high yield. The amino group was generated by selective reaction of azide 4b with polymeric triphenylphosphine followed by mild hydrolysis of the intermediate phosphine imine. A novel universal phosphorylation reagent 2-azidoethyl dichlorophosphate (7) was used.
- Pfaendler, Hans Rudolf,Weimar, Volker
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- A study of the thermal decomposition of 2-azidoethanol and 2-azidoethyl acetate by ultraviolet photoelectron spectroscopy and matrix isolation infrared spectroscopy
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The thermal decomposition of 2-azidoethanol and 2-azidoethyl acetate were studied by matrix isolation IR spectroscopy and real-time UV photoelectron spectroscopy. The products detected in a flow system at different temperatures (CH2NH, H2CO, N2, CO, and HCN from N3CH2CH2OH and C2H4, CH2NH, HCN, CO2, and N2 from N3CH2COOCH2CH3) allowed mechanisms for decomposition to be proposed. Ab initio calculations were performed for these azides, and application of Koopmans' theorem to the computed orbital energies yielded vertical ionization energies that agreed with experimental values. Two main mechanisms of decomposition of organic azides of the type considered began to emerge. 2-Azidoacetic acid and 2-azidoehtyl acetate decomposed via a concerted process through a cyclic transition state to give the products, while 2-azidoethanol and azidoacetone decomposed via a stepwise mechanism through imine intermediates, which decomposed to give the products via two possible pathways.
- Dyke,Dias,Barros,Hooper,Costa,Beeching,Barros,Cabral,Morris,Cabral,Moutinho,Ogden,Moutinho
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- Facile formation of hydrogels by using functional precursor polymers and the chemoselective Staudinger coupling
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Hydrogel formation based on chemoselective crosslinking methods has become an important topic in biomedicine. Although the Staudinger ligation has been utilized in protein modification for many years only one example based on polysaccharides has been published to apply this reaction also for hydrogel formation. Therefore, methacrylate monomers with azide Az-MA or triphenylphosphine TPP-MA functional groups were synthesized and used to prepare two water-soluble precursor copolymers P1 (with Az-MA) and P2 (with TPP-MA) by free radical polymerization. The molecular weight and the composition of the copolymers were analyzed by SEC, 1H NMR, FTIR and UV/Vis spectroscopy. Mixing of the water-soluble copolymers P1 and P2 in aqueous media led to the irreversible and easy formation of covalently crosslinked polymers. The kinetics of gelation, swelling and mechanical properties of the hydrogels in aqueous PBS buffer can be tuned by the total polymer concentration and the stoichiometric ratio of the complementary functional groups.
- Sallouh, Omar,Weberskirch, Ralf
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- Light-Induced Self-Escape of Spherical Nucleic Acid from Endo/Lysosome for Efficient Non-Cationic Gene Delivery
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Developing non-cationic gene carriers and achieving efficient endo/lysosome escape of functional nucleic acids in cytosol are two major challenges faced by the field of gene delivery. Herein, we demonstrate the concept of self-escape spherical nucleic aci
- Duan, Yukun,Hou, Lidan,Liu, Bin,Meng, Xiangjun,Shi, Leilei,Wu, Wenbo,Xu, Li,Xu, Yingying,Zhu, Xinyuan
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- RAFT polymerization of bio-based 1-vinyl-4-dianhydrohexitol-1,2,3-triazole stereoisomers obtained via click chemistry
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Four 1-vinyl-4-dianhydrohexitol-1,2,3-triazole stereoisomers are prepared from isomannide, isoidide, and isosorbide using an alkylation/CuAAC-ligation/ elimination three-step strategy. After characterization of the monomers by NMR, differential scanning calorimetry (DSC), and high-resolution mass spectrometry (HRMS), the corresponding stereocontrolled poly(1-vinyl-4-dianhydrohexitol-1,2, 3-triazole)s are obtained by RAFT polymerization using a xanthate chain transfer agent. A systematic investigation of the structure-properties relationship of both the monomers and polymers highlights the significant impact of the dianhydrohexitols stereochemistry on their physical properties (1H and 13C NMR chemical shifts, physical state, Tg, thermal stability and solubility). A particularly original and unexpected behavior is highlighted since the two different isosorbide-based poly(1-vinyl-4- dianhydrohexitol-1,2,3-triazole) stereoisomers exhibit contrasting solubility in water.
- Beghdadi, Samir,Abdelhedi Miladi, Imen,Ben Romdhane, Hatem,Bernard, Julien,Drockenmuller, Eric
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- Phenyltriazole-functionalized sulfamate inhibitors targeting tyrosyl- or isoleucyl-tRNA synthetase
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Antimicrobial resistance is considered as one of the major threats for the near future as the lack of effective treatments for various infections would cause more deaths than cancer by 2050. The development of new antibacterial drugs is considered as one of the cornerstones to tackle this problem. Aminoacyl-tRNA synthetases (aaRSs) are regarded as good targets to establish new therapies. Apart from being essential for cell viability, they are clinically validated. Indeed, mupirocin, an isoleucyl-tRNA synthetase (IleRS) inhibitor, is already commercially available as a topical treatment for MRSA infections. Unfortunately, resistance developed soon after its introduction on the market, hampering its clinical use. Therefore, there is an urgent need for new cellular targets or improved therapies. Follow-up research by Cubist Pharmaceuticals led to a series of selective and in vivo active aminoacyl-sulfamoyl aryltetrazole inhibitors targeting IleRS (e.g. CB 168). Here, we describe the synthesis of new IleRS and TyrRS inhibitors based on the Cubist Pharmaceuticals compounds, whereby the central ribose was substituted for a tetrahydropyran ring. Various linkers were evaluated connecting the six-membered ring with the base-mimicking part of the synthesized analogues. Out of eight novel molecules, a three-atom spacer to the phenyltriazole moiety, which was established using azide-alkyne click chemistry, appeared to be the optimized linker to inhibit IleRS. However, 11 (Ki,app = 88 ± 5.3 nM) and 36a (Ki,app = 114 ± 13.5 nM) did not reach the same level of inhibitory activity as for the known high-affinity natural adenylate-intermediate analogue isoleucyl-sulfamoyl adenosine (IleSA, CB 138; Ki,app = 1.9 ± 4.0 nM) and CB 168, which exhibit a comparable inhibitory activity as the native ligand. Therefore, 11 was docked into the active site of IleRS using a known crystal structure of T. thermophilus in complex with mupirocin. Here, we observed the loss of the crucial 3′- and 4′- hydroxyl group interactions with the target enzyme compared to CB 168 and mupirocin, which we suggest to be the reason for the limited decrease in enzyme affinity. Despite the lack of antibacterial activity, we believe that structurally optimizing these novel analogues via a structure-based approach could ultimately result in aaRS inhibitors which would help to tackle the antibiotic resistance problem.
- De Graef, Steff,De Ruysscher, Dries,Lescrinier, Eveline,Mattelaer, Charles-Alexandre,Nautiyal, Manesh,Pang, Luping,Rozenski, Jef,Strelkov, Sergei V.,Van Aerschot, Arthur,Weeks, Stephen D.
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- Ultrathin Covalently Bound Organic Layers on Mica: Formation of Atomically Flat Biofunctionalizable Surfaces
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Mica is the substrate of choice for microscopic visualization of a wide variety of intricate nanostructures. Unfortunately, the lack of a facile strategy for its modification has prevented the on-mica assembly of nanostructures. Herein, we disclose a convenient catechol-based linker that enables various surface-bound metal-free click reactions, and an easy modification of mica with DNA nanostructures and a horseradish peroxidase mimicking hemin/G-quadruplex DNAzyme.
- Sen, Rickdeb,Gahtory, Digvijay,Carvalho, Rui Rijo,Albada, Bauke,van Delft, Floris L.,Zuilhof, Han
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- Neoglycopolymers based on 4-vinyl-1,2,3-triazole monomers prepared by click chemistry
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The synthesis of a new glycomonomer based on mannose, prepared via CuAAC, is reported. The resulting 1,2,3-triazole linkage between mannose and the polymer backbone ensures the formation of highly stable glycopolymers, which will not undergo hydrolysis. The monomer 2′-(4-vinyl-[1,2,3]-triazol-1-yl) ethyl-O-α-D-mannopyranoside was polymerized in the presence of a RAFT agent - 3-benzylsulfanylthiocarbonylsulfanyl propionic acid - to yield well-defined polymers with molecular weights up to 51 500 g mol-1 and a PDI of 1.16. The resulting polymer was employed as a macroRAFT agent in the polymerization of NIPAAm in order to generate thermo-responsive block copolymers, which undergo reversible micelle formation at elevated temperatures. The rapid interaction between the polymers prepared and ConA confirms the high affinity of these structures to proteins. While the linear glycopolymers already undergo a fast complexation with ConA, the reported rates have found to be exceeded by the micellar glycopolymer structure presented in the current contribution.
- Hetzer, Martin,Chen, Gaojian,Barner-Kowollik, Christopher,Stenzel, Martina H.
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- Iterative Convergent Synthesis of Large Cyclic Polymers and Block Copolymers with Discrete Molecular Weights
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We report here the synthesis of cyclic polymers and block copolymers consisting of discrete numbers of repeating units without linear contaminants. The synthesis utilizes the intramolecular cyclization of end-functionalized poly(rac-lactide) (PLA) and its block copolymers with as many as 512 lactic acid units (37 kDa), synthesized by the iterative linear convergence of orthogonally protected building blocks. By exploiting the change in hydrodynamic volume upon cyclization of the linear polymers, macrocyclic polymers were isolated without linear precursors by preparative size-exclusion chromatography as a purification method. Our procedure also allowed the synthesis of a monodisperse cyclic block copolymer in a desired block ratio as a single compound (14 kDa).
- Koo, Mo Beom,Lee, Seul Woo,Lee, Jung Min,Kim, Kyoung Taek
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- Reversible lysine modification on proteins by using functionalized boronic acids
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Iminoboronates have been utilized to successfully install azide and alkyne bioorthogonal functions on proteins, which may then be further reacted with their bioorthogonal counterparts. These constructs were also used to add polyethylene glycol (PEG) to insulin, a modification which has been shown to be reversible in the presence of fructose. Finally, iminoboronates were used to assemble a folic acid/paclitaxel small-molecule/drug conjugate in situ with an IC50 value of 20.7 nM against NCI-H460 cancer cells and negligible cytotoxicity against the CRL-1502 noncancer cells. Easy installation: The use of iminoboronates is a successful strategy to install diverse functions on proteins (see picture; GSH=glutathione, PEG=polyethylene glycol) and to assemble a folic acid/paclitaxel small-molecule/drug conjugate in situ.
- Cal, Pedro M. S. D.,Frade, Raquel F. M.,Cordeiro, Carlos,Gois, Pedro M. P.
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- Quantitative and Orthogonal Formation and Reactivity of SuFEx Platforms
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The constraints of minute reactant amounts and the impossibility to remove any undesired surface-bound products during monolayer functionalization of a surface necessitate the selection of efficient, modular and orthogonal reactions that lead to quantitative conversions. Herein, we explore the character of sulfur–fluoride exchange (SuFEx) reactions on a surface, and explore the applicability for quantitative and orthogonal surface functionalization. To this end, we demonstrate the use of ethenesulfonyl fluoride (ESF) as an efficient SuFEx linker for creating “SuFEx-able” monolayer surfaces, enabling three distinct approaches to utilize SuFEx chemistry on a surface. The first approach relies on a di-SuFEx loading allowing dual functionalization with a nucleophile, while the two latter approaches focus on dual (CuAAC–SuFEx/SPOCQ–SuFEx) click platforms. The resultant strategies allow facile attachment of two different substrates sequentially on the same platform. Along the way we also demonstrate the Michael addition of ethenesulfonyl fluoride to be a quantitative surface-bound reaction, indicating significant promise in materials science for this reaction.
- Gahtory, Digvijay,Sen, Rickdeb,Pujari, Sidharam,Li, Suhua,Zheng, Qinheng,Moses, John E.,Sharpless, K. Barry,Zuilhof, Han
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- Autocatalytic Cycles in a Copper-Catalyzed Azide-Alkyne Cycloaddition Reaction
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This work describes the autocatalytic copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between tripropargylamine and 2-azidoethanol in the presence of Cu(II) salts. The product of this reaction, tris-(hydroxyethyltriazolylmethyl)amine (N(Csub
- Semenov, Sergey N.,Belding, Lee,Cafferty, Brian J.,Mousavi, Maral P.S.,Finogenova, Anastasiia M.,Cruz, Ricardo S.,Skorb, Ekaterina V.,Whitesides, George M.
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- High-Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging αvβ3 Integrin
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Nonpeptidic Arg-Gly-Asp (RGD)-mimic ligands were designed and synthesized by click chemistry between an arginine–azide mimic and an aspartic acid–alkyne mimic. Some of these molecules combine excellent in vitro properties (high αvβ3 affinity, selectivity, drug-like logD, high metabolic stability) with a variety of radiolabeling options (e.g., tritium and fluorine-18, plus compatibility with radio-iodination), not requiring the use of chelators or prosthetic groups. The binding mode of the resulting triazole RGD mimics to αvβ3 or αIIbβ3 receptors was investigated by molecular modeling simulations. Lead compound 12 was successfully radiofluorinated and used for in vivo positron emission tomography/computed tomography (PET/CT) studies in U87 tumor models, which showed only modest tumor uptake and retention, owing to rapid excretion. These results demonstrate that the novel click RGD mimics are excellent radiolabeled probes for in vitro and cell-based studies on αvβ3 integrin, whereas further optimization of their pharmacokinetic and dynamic profiles is necessary for successful use in in vivo imaging.
- Piras, Monica,Testa, Andrea,Fleming, Ian N.,Dall'Angelo, Sergio,Andriu, Alexandra,Menta, Sergio,Mori, Mattia,Brown, Gavin D.,Forster, Duncan,Williams, Kaye J.,Zanda, Matteo
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- Ultrasound responsive block copolymer micelle of poly(ethylene glycol)-poly(propylene glycol) obtained through click reaction
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The well-defined amphiphilic poly(ethylene glycol)-block-poly(propylene glycol) copolymer containing 1, 2, 3-triazole moiety and multiple ester bonds (PEG-click-PPG) was prepared by click reaction strategy. The PEG-click-PPG copolymer can self-assemble in
- Li, Fayong,Xie, Chuan,Cheng, Zhengang,Xia, Hesheng
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- Novel multifunctional hybrid diallyl ether monomer via azide alkyne click reaction as crosslinking agent in protective coatings
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Functionalized hybrid monomers with crosslinking ability can provide advantages over the other monomers due to the flexibility of using it with any vinylic family of monomers. Azide alkyne click reaction is a convenient way of introducing triazole moieties into a molecule and opens up the possibility to add more functionality by suitable design of azide and alkyne compounds. In the present study, we report synthesis and use of new azide click linker containing allyl ether functionality, (3-(2-azidoethoxy) prop-1-ene) as a first example in the click reaction with a siloxane functionalized dialkyne to make a novel triazole, siloxane functionalized diallyl ether (TSDE) monomer. Chemical structure of the as synthesized TSDE, azide click linker and other compounds were characterized by FT-IR, 1H NMR, 13C NMR, and ESI-MS techniques. Hybrid coatings of TSDE with methyl methacrylate (MMA) were evaluated for chemical structure, morphology, wettability, tensile and thermal properties by FTIR, XRD, SEM, UTM, WCA, DSC & TGA. Experimental results from EPS and fog tests indicate significant enhancements in the anticorrosion and antibacterial performance of the as synthesized new Poly (MMA-co-TSDE) hybrid coatings in comparison to PMMA.
- Sykam, Kesavarao,Donempudi, Shailaja
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- Synthesis, antimicrobial evaluation, and in silico studies of quinoline—1H-1,2,3-triazole molecular hybrids
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Abstract: Antimicrobial resistance has become a significant threat to global public health, thus precipitating an exigent need for new drugs with improved therapeutic efficacy. In this regard, molecular hybridization is deemed as a viable strategy to afford multi-target-based drug candidates. Herein, we report a library of quinoline—1H-1,2,3-triazole molecular hybrids synthesized via copper(I)-catalyzed azide-alkyne [3 + 2] dipolar cycloaddition reaction (CuAAC). Antimicrobial evaluation identified compound 16 as the most active hybrid in the library with a broad-spectrum antibacterial activity at an MIC80 value of 75.39?μM against methicillin-resistant S. aureus, E. coli, A. baumannii, and multidrug-resistant K. pneumoniae. The compound also showed interesting antifungal profile against C. albicans and C. neoformans at an MIC80 value of 37.69 and 2.36?μM, respectively, superior to fluconazole. In vitro toxicity profiling revealed non-hemolytic activity against human red blood cells (hRBC) but partial cytotoxicity to human embryonic kidney cells (HEK293). Additionally, in silico studies predicted excellent drug-like properties and the importance of triazole ring in stabilizing the complexation with target proteins. Overall, these results present compound 16 as a promising scaffold on which other molecules can be modeled to deliver new antimicrobial agents with improved potency. Graphic abstract: [Figure not available: see fulltext.].
- Awolade, Paul,Cele, Nosipho,Kerru, Nagaraju,Singh, Parvesh
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p. 2201 - 2218
(2020/06/17)
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- Design, synthesis and evaluation of cholinesterase hybrid inhibitors using a natural steroidal alkaloid as precursor
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To date, Alzheimer's disease is the most alarming neurodegenerative disorder worldwide. This illness is multifactorial in nature and cholinesterase inhibitors have been the ones used in clinical treatments. In this context, many of these drugs selectively inhibit the acetylcholinesterase enzyme interacting in both the active site and the peripheric anionic site. Besides, some agents have exhibited extensive benefits being able to co-inhibit butyrylcholinesterase. In this contribution, a strategy previously explored by numerous authors is reported; the synthesis of hybrid cholinesterase inhibitors. This strategy uses a molecule of recognized high inhibitory activity (tacrine) together with a steroidal alkaloid of natural origin using different connectors. The biological assays demonstrated the improvement in the inhibitory activity compared to the alkaloidal precursor, together with the reinforcement of the interactions in multiple sites of the enzymatic cavity. This strategy should be explored and exploited in this area. Docking and molecular dynamic studies were performed to explain enzyme-ligand interactions, assisting a structure–activity relationship analysis.
- Borioni, José L.,Cavallaro, Valeria,Murray, Ana P.,Pe?é?ory, Alicia B.,Puiatti, Marcelo,García, Manuela E.
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- Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis
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We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.
- Fu, Chih-Wei,Tsai, Han-En,Chen, Wei-Sheng,Chang, Tzu-Ting,Chen, Chia-Ling,Hsiao, Pei-Wen,Li, Wen-Shan
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supporting information
p. 527 - 542
(2021/01/13)
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- Novel 1,2,3-triazole-tethered Pam3CAG conjugates as potential TLR-2 agonistic vaccine adjuvants
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A focused library of water soluble 1,2,3-triazole tethered glycopeptide conjugates derived from variety of azido-monosaccharides and aliphatic azido-alcohols were synthesized through manipulation at the C-terminus of Pam3CAG and screened for their potential as TLR2 agonistic adjuvants against HBsAg antigen. In vitro ligand induced TLR2 signal activation was observed with all the analogues upon treatment with HEK blue TLR2 cell lines. Conjugate derived from ribose (6e), which exhibited pronounced HBsAg specific antibody (IgG) titer also shown enhanced CD8+ population indicating superior cell mediated immunity compared to standard adjuvant Pam3CSK4. Further, docking studies revealed ligand induced heterodimerization between TLR1 and 2. Overall, the result indicates the usefulness of novel conjugates as potential vaccine adjuvant.
- Mhamane, Tukaram B.,Sambyal, Shainy,Vemireddy, Sravanthi,Khan, Imran A.,Shafi, Syed,Halmuthur M., Sampath Kumar
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supporting information
(2021/04/12)
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- A novel18F-labeled clickable substrate for targeted imaging of SNAP-tag expressing cells by PETin vivo
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Bioorthogonal covalent labeling with self-labeling enzymes like SNAP-tag bears a high potential for specific targeting of cells for imagingin vitroand alsoin vivo. To this end, fluorescent SNAP substrates have been established and used in microscopy and fluorescence imaging while radioactive substrates for the highly sensitive and whole-body positron emission tomography (PET) have been lacking. Here, we show for the first time successful and high-contrast PET imaging of subcutaneous SNAP-tag expressing tumor xenografts by bioorthogonal covalent targeting with a novel18F-based radioligandin vivo.
- Depke, Dominic Alexej,Hermann, Sven,Konken, Christian Paul,Rentmeister, Andrea,R?sner, Lukas,Sch?fers, Michael
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supporting information
p. 9850 - 9853
(2021/10/08)
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- GalNAc/CpG liposome vaccine with anti-tumor activity as well as preparation method and application of GalNAc/CpG liposome vaccine
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The invention discloses a GalNAc/CpG liposome vaccine with anti-tumor activity as well as a preparation method and application of the GalNAc/CpG liposome vaccine. The vaccine comprises a Tn antigen GalNAc, cholesterol and a nucleic acid adjuvant CpG ODN. According to the invention, a Chol-GalNAc compound is constructed through a Click reaction, the components of the vaccine can be clearly represented, and the vaccine has the characteristic of biodegradability. The liposome vaccine entrapped with the adjuvant CpG ODN is constructed through a film-ultrasonic method, the purpose of antitumor activity of body fluid and cellular immunity can be achieved, and the liposome vaccine plays a role as a main active component in preparation of drugs for resisting breast cancer and the like. Experiments prove that the GalNAc/CpG liposome vaccine has a good particle size, can well induce maturation of bone marrow derived BMDCs and spleen B cells of mice and induce the mice to generate specific antibodies, and can effectively activate cellular immunity of the mice to realize an anti-tumor effect.
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Paragraph 0043
(2021/10/16)
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- Synthesis, Biological Activity, and Molecular Modeling Studies of Pyrazole and Triazole Derivatives as Selective COX-2 Inhibitors
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Series of diaryl-based pyrazole and triazole derivatives were designed and synthesized in a facile synthetic approach in order to produce selective COX-2 inhibitor. These series of derivatives were synthesized by different reactions like Vilsmeier-Haack reaction and click reaction. In vitro COX-1 and COX-2 inhibition studies showed that five compounds were potent and selective inhibitors of the COX-2 isozyme with IC50 values in 0.551-0.002 μM range. In the diarylpyrazole derivatives, compound 4b showed the best inhibitory activity against COX-2 with IC50 = 0.017 μM as one of the N-aromatic rings was substituted with sulfonamide and the other aromatic ring was unsubstituted. However, when the N-aromatic ring was substituted with sulfonamide and the other aromatic ring was substituted with sulfone (compound 4d), best COX-2 selectivity was achieved (IC50 = 0.098 μM, SI = 54.847). In the diaryltriazole derivatives, compound 15a showed the best inhibitory activity in comparison to all synthesized compounds including the reference celecoxib with IC50 = 0.002 μM and SI = 162.5 as it could better fit the extra hydrophobic pocket which is present in the COX-2 enzyme. Moreover, the docking study supports the obtained SAR data and binding similarities and differences on both isozymes.
- Assali, Mohyeddin,Abualhasan, Murad,Sawaftah, Hadeel,Hawash, Mohammed,Mousa, Ahmed
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- Discovery of a new class of PROTAC BRD4 degraders based on a dihydroquinazolinone derivative and lenalidomide/pomalidomide
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BRD4 has emerged as an attractive target for anticancer therapy. However, BRD4 inhibitors treatment leads to BRD4 protein accumulation, together with the reversible nature of inhibitors binding to BRD4, which may limit the efficacy of BRD4 inhibitors. To address these problems, a protein degradation strategy based on the proteolysis targeting chimera (PROTAC) technology has been developed to target BRD4 recently. Herein, we present our design, synthesis and biological evaluation of a new class of PROTAC BRD4 degraders, which were based on a potent dihydroquinazolinone-based BRD4 inhibitor compound 6 and lenalidomide/pomalidomide as ligand for E3 ligase cereblon. Gratifyingly, several compounds showed excellent inhibitory activity against BRD4, and high anti-proliferative potency against human monocyte lymphoma cell line THP-1. Especially, compound 21 (BRD4 BD1, IC50 = 41.8 nM) achieved a submicromolar IC50 value of 0.81 μM in inhibiting the growth of THP-1 cell line, and was 4 times more potent than compound 6. Moreover, the mechanism study established that 21 could effectively induce the degradation of BRD4 protein and suppression of c-Myc. All of these results suggested that 21 was an efficacious BRD4 degrader for further investigation.
- Zhang, Fangqing,Wu, Zhenwei,Chen, Pan,Zhang, Jian,Wang, Tao,Zhou, Jinpei,Zhang, Huibin
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- Development of small-molecule BRD4 degraders based on pyrrolopyridone derivative
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Bromodomain-containing protein 4 (BRD4) plays a crucial role in the epigenetic regulation of gene transcription and some BRD4 inhibitors have been advanced to clinical trials. Nevertheless, the clinical application of BRD4 inhibitors could be limited by drug resistance. As an alternative strategy, the emerging Proteolysis Targeting Chimeras (PROTACs) technology has the potential to overcome the drug resistance of traditional small-molecule drugs. Based on PROTACs approaches, several BRD4 degraders were developed and have been proved to degrade BRD4 protein and inhibit tumor growth. Herein, we present the design, synthesis, and biological evaluation of pyrrolopyridone derivative-based BRD4 degraders. Four synthesized compounds displayed comparative potence against BRD4 BD1 with IC50 at low nanomolar concentrations. Anti-proliferative activity of 32a against BxPC3 cell line (IC50 = 0.165 μM) was improved by about 7-fold as compared to the BRD4 inhibitor ABBV-075. Furthermore, degrader 32a potently induced the degradation of BRD4 and inhibited the expression of c-Myc in BxPC3 cell line in a time-dependent manner. The exploration of intracellular antitumor mechanism showed 32a induced cell cycle arrest and apoptosis effectively. All the results demonstrated that compound 32a could be considered as a potential BRD4 degrader for further investigation.
- Chen, Pan,Wang, Lixun,Wang, Tao,Xu, Changliang,Zhang, Huibin,Zhang, Jian,Zheng, Peiyuan,Zhou, Jinpei,Zhu, Peiyu
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-
- Anionic Polymerization of Azidoalkyl Glycidyl Ethers and Post-Polymerization Modification
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Polyethers like poly(ethylene glycol) have been widely used for a variety of valuable applications, although their functionalization still poses challenges due to the absence of functional handles along the polymer backbone. Herein, a series of novel azide-functionalized glycidyl ether monomers are presented as a universal approach to synthesize functional polyethers by post-polymerization modification. Three azide-functionalized glycidyl ether monomers possessing different alkyl spacers (ethyl, butyl, and hexyl) were designed and synthesized by a simple two-step substitution reaction. Organic superbase-catalyzed anionic ring-opening polymerization can proceed under mild conditions compatible with an azide pendant group, affording well-controlled azide-functionalized polyethers with low dispersity (? 1.2). The azide pendant groups on the resulting polymers were readily modified to a variety of functional groups via copper-catalyzed azide-alkyne cycloaddition reactions and Staudinger reduction. Furthermore, copolymerization of azidohexyl glycidyl ether with allyl glycidyl ether was demonstrated to provide an additional orthogonal functional handle. We anticipate that this work provides a new platform for the preparation of diverse functional polyethers.
- Lee, Joonhee,Han, Sohee,Kim, Minseong,Kim, Byeong-Su
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p. 355 - 366
(2019/12/30)
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- A Dual Threat: Redox-Activity and Electronic Structures of Well-Defined Donor–Acceptor Fulleretic Covalent-Organic Materials
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The effect of donor (D)–acceptor (A) alignment on the materials electronic structure was probed for the first time using novel purely organic porous crystalline materials with covalently bound two- and three-dimensional acceptors. The first studies towards estimation of charge transfer rates as a function of acceptor stacking are in line with the experimentally observed drastic, eight-fold conductivity enhancement. The first evaluation of redox behavior of buckyball- or tetracyanoquinodimethane-integrated crystalline was conducted. In parallel with tailoring the D-A alignment responsible for “static” changes in materials properties, an external stimulus was applied for “dynamic” control of the electronic profiles. Overall, the presented D–A strategic design, with stimuli-controlled electronic behavior, redox activity, and modularity could be used as a blueprint for the development of electroactive and conductive multidimensional and multifunctional crystalline porous materials.
- Berseneva, Anna A.,Brandt, Amy J.,Buck, Charles N.,Chen, Donna A.,Chusov, Denis,Garashchuk, Sophya,Lamm, Benjamin W.,Leith, Gabrielle A.,Ly, Richard T.,Pellechia, Perry J.,Rice, Allison M.,Shustova, Natalia B.,Smith, Mark D.,Stefik, Morgan,Stephenson, Kenneth S.,Vannucci, Aaron K.,Yarbrough, Brandon J.
-
supporting information
p. 6000 - 6006
(2020/02/20)
-
- Design and synthesis of a peptide derivative of ametantrone targeting the major groove of the d(GGCGCC)2 palindromic sequence
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In oncology, some DNA intercalating agents have been used in chemotherapy for years to eradicate cancer cells, but these drugs generally suffer from a lack of selectivity for malignant tissues and consequently induce major side-effects. We report herein the design and synthesis of an antitumor intercalating agent ametantrone complemented with two identical peptide arms including a central Lys residue in order to selectively target palindromic sequences of DNA of malignant cells. The peptide arms are linked to the ametantrone core through 1,2,3-triazole. According to our docking prediction, this compound should be double-stranded β-sheet structured, and it has been designed to interact with two guanine residues upstream from a central d(CpG)2 intercalation site on each DNA strand, owing to the H-bonds involving the Lys terminal side chain ammonium group of the peptide arms. This new ametantrone derivative has been obtained thanks to a convergent synthetic pathway, whose key steps were double nucleophilic substitution performed on the ametantrone core, followed by "double-site" 1,3-dipolar cycloaddition affording the 1,4-disubstituted triazole linker almost quantitatively. Preliminary binding assays performed by mass spectrometry proved its accuracy for DNA palindromic sequences. The cytotoxicity of this compound was evaluated on three cancer cell lines and one healthy cell line, and compared to that of mitoxantone, a dihydroxylated analog of ametantrone. Such a peptide derivative was about ten-fold less cytotoxic than mitoxantrone on these cancer cell lines, but about fifty times less cytotoxic on healthy cells. This study could open new avenues towards the design of targeted intercalating agents.
- Braud, Emmanuelle,De Franco, Michele,Demange, Luc,Ethève-Quelquejeu, Mélanie,Garbay, Christiane,Gresh, Nohad,Ongaro, Alberto,Ribaudo, Giovanni,Zagotto, Giuseppe
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p. 3624 - 3631
(2020/03/17)
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- Visible-Light-Mediated Click Chemistry for Highly Regioselective Azide–Alkyne Cycloaddition by a Photoredox Electron-Transfer Strategy
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Click chemistry focuses on the development of highly selective reactions using simple precursors for the exquisite synthesis of molecules. Undisputedly, the CuI-catalyzed azide–alkyne cycloaddition (CuAAC) is one of the most valuable examples of click chemistry, but it suffers from some limitations as it requires additional reducing agents and ligands as well as cytotoxic copper. Here, we demonstrate a novel strategy for the azide–alkyne cycloaddition reaction that involves a photoredox electron-transfer radical mechanism instead of the traditional metal-catalyzed coordination process. This newly developed photocatalyzed azide–alkyne cycloaddition reaction can be performed under mild conditions at room temperature in the presence of air and visible light and shows good functional group tolerance, excellent atom economy, high yields of up to 99 %, and absolute regioselectivity, affording a variety of 1,4-disubstituted 1,2,3-triazole derivatives, including bioactive molecules and pharmaceuticals. The use of a recyclable photocatalyst, solar energy, and water as solvent makes this photocatalytic system sustainable and environmentally friendly. Moreover, the azide–alkyne cycloaddition reaction could be photocatalyzed in the presence of a metal-free catalyst with excellent regioselectivity, which represents an important development for click chemistry and should find versatile applications in organic synthesis, chemical biology, and materials science.
- Wu, Zheng-Guang,Liao, Xiang-Ji,Yuan, Li,Wang, Yi,Zheng, You-Xuan,Zuo, Jing-Lin,Pan, Yi
-
supporting information
p. 5694 - 5700
(2020/04/24)
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- Quercetin dimer derivative as well as preparation method and application thereof
-
The invention discloses quercetin dipolymer derivative or pharmaceutically acceptable aquo-complex thereof. The quercetin dipolymer derivative is prepared from stereisomer or tautomer. The quercetin dipolymer derivative is prepared by the steps: preparing 7-propynyl oxy quercetin (II) from quercetin and propargyl bromide under the alkali action; reacting bromhydrin with sodium azide to prepare alcohol azide (III); reacting the (III) with phosphoryl dichloro compound to prepare (IV); preparing a formula (I) from the (II) and the (IV) under the action of CuSO4.5H2O/sodium ascorbate. The quercetin dipolymer derivative disclosed by the invention has the anticancer, antioxidant, inflammation diminishing and antimutation effects.
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Paragraph 0017; 0020
(2020/06/09)
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- Production process of 4-methylbenzenesulfonic acid-2-azido ethyl ester
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The invention discloses a production process of 4-methylbenzenesulfonic acid-2-azido ethyl ester, which comprises the following steps: by using 2-bromoethane and sodium azide as initial raw materials,carrying out a substitution reaction on the 2-bromoethane and sodium azide to prepare an intermediate 3; and carrying out the substitution reaction on the intermediate 3 and p-toluenesulfonyl chloride to obtain a target product 2. By establishing strict internal control standards for initial raw materials and intermediates and strictly controlling key process step parameters, qualified products can be stably prepared in multiple batches.
- -
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Paragraph 0016-0020
(2020/07/21)
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- Targeting interleukin-4 to the arthritic joint
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Anti-inflammatory cytokines are a promising class of therapeutics for treatment of rheumatoid arthritis (RA), but their use is currently limited by a rapid clearance and systemic toxicity. Interleukin-4 is a small cytokine with potential for RA therapy. To increase its pharmacokinetic features, we engineered a murine IL4 conjugate by incorporating an unnatural amino acid through genetic code expansion to which PEG-folate, as a targeting moiety and PEG alone as control, were site-specifically bound. Both IL4 conjugates retained bioactivity and induced primary murine macrophage polarization into an alternatively activated (M2) related phenotype. The PEGylated conjugates had a terminal half-life of about four hours in healthy mice compared to unPEGylated IL4 (0.76 h). We showed that both conjugates successfully accumulated into arthritic joints in an antigen-induced arthritis (AIA) mouse model, as assessed by non-invasive fluorescence imaging. The modular nature of the IL4 conjugate chemistry presented herein facilitates easy adaption of PEG chain length and targeting moieties for further improvement of half-life and targeting function for future efficacy studies.
- Dawson, Janet,Ebersbach, Hilmar,Lühmann, Tessa,Littlewood-Evans, Amanda,Ludwig, Marie-Gabrielle,Müller, Thomas D.,Meinel, Lorenz,Raschig, Martina,Safina, Caterina,Seuwen, Klaus,Spieler, Valerie,Tigani, Bruno,ter Mors, Bj?rn
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p. 172 - 180
(2020/07/23)
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- MUTANT VIRUS, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF
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The present invention relates to a mutated virus. Said virus can be an influenza virus of human or other animal origin. The present invention also relates to a method for preparing the mutated virus, the method comprising introducing UAG codons into positions upstream of the stop codons per se of one or more genes of a viral genome by reverse genetic techniques. The present invention further relates to uses of the mutated virus, for example, as a live attenuated vaccine, or in replication of controllable and safe virus models, and the like.
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Paragraph 0161; 0162
(2020/09/09)
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- Compound, pharmaceutical composition, KDM5C inhibitor and antidepressant
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PROBLEM TO BE SOLVED: To provide a compound having a strong KDM5C inhibitory action, and an antidepressant. SOLUTION: The present invention provides a triazole-4-ylpyridine compound represented by the following formula. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0072
(2021/01/21)
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- Pyrrolopyridone double-functional molecule compound based on Cereblon ligand induced BET degradation
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The invention relates to a novel pyrrolopyridone double-functional molecule, and pharmaceutically acceptable salts, hydrates, prodrug thereof, and a pharmaceutical composition taking the novel pyrrolopyridone double-functional molecule as an active component, and applications of the above compounds and the pharmaceutical composition in treatment or prevention of tumor, inflammation, and immunity diseases. The double-functional molecule is a proteolytic targeting chimera (PROTAC); the preparation method is mature; connecting arms are adopted to connect BET protein small molecular inhibitors andCereblon protein ligand in E3 ubiquitin ligase complex so as to obtain the double-functional molecule; the obtained compound is capable of realizing selective induction of BET protein degradation; and the tumor prevention effect is obvious.
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Paragraph 0097; 0104-0107
(2019/10/01)
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- Pyrrolopyridone bifunctional molecular compound based on VHL ligand-induced BET degradation
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The invention relates to a novel kind of pyrrolopyridone bifunctional molecule and its pharmaceutically acceptable salt, hydrate and prodrug and a pharmaceutical composition using the compounds as active ingredients, and application in the preparation of these compounds and their pharmaceutical composition and in the treatment or prevention of tumors, inflammation, diseases related immunity, etc.The bifunctional molecule involved in the invention is a proteolytic targeting chimera (PROTAC). A small molecule inhibitor of BET protein and a Von Hippel-Lindau (VHL) protein ligand in E3 ubiquitinligase complex are linked by a connecting arm to obtain the bifunctional molecule. The obtained compound can selectively induce the degradation of BET protein, and has significant anti-tumor effect.
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Paragraph 0092; 0099-0102
(2019/08/30)
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- Medicine conjugate and method for prolonging half-life of medicine molecule
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The invention discloses a medicine conjugate and a method for prolonging half-life of a medicine molecule. The medicine conjugate is prepared through modifying the medicine molecule with a micromolecule combined with a half antigen, wherein the half antigen is the half antigen having an endogenous antibody. The half antigen molecule is modified on the medicine molecule, and the modified medicine molecule can be specifically combined with the endogenous antibody in accordance with the half antigen, so that the in vivo half-life of the medicine molecule can be notably prolonged.
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Paragraph 0091-0092; 0097
(2019/11/19)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 2073; 2074
(2019/07/10)
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- 18F-LABELED PEPTIDE LIGANDS USEFUL IN PET AND CERENKOV LUMINESCENE IMAGING
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The present technology is directed to compounds, intermediates thereof, compositions thereof, medicaments thereof, and methods related to the imaging of mammalian tissue via 18F- labeled peptide ligands disclosed herein.
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Paragraph 0132
(2019/07/13)
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- High hole mobility and light-harvesting in discotic nematic dendrimers prepared: Via 'click' chemistry
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We report a new family of liquid crystalline porphyrin-core dendrimers with coumarin units at the periphery of the dendrimer. These compounds have been prepared by copper-catalyzed azide-alkyne "click" cycloaddition (CuAAC). The mesomorphic properties have been investigated via polarized optical microscopy (POM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The peripheral coumarin units play a key role in the liquid crystal behavior, contributing to the appearance of discotic nematic mesophases with hole mobility values among the highest values reported for discotic liquid crystals (of the order of 1 cm2 V-1 s-1). It has also been demonstrated that excitation of the coumarin moieties leads to energy transfer (antenna effect) to the luminescent porphyrin core. Therefore, this strategy, which involves 'click' chemistry, has been proven to be a powerful and elegant synthetic tool for the preparation of optoelectronic materials based on complex dendritic architectures.
- Concellón, Alberto,Termine, Roberto,Golemme, Attilio,Romero, Pilar,Marcos, Mercedes,Serrano, José Luis
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supporting information
p. 2911 - 2918
(2019/03/14)
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- PYRIDAZINE DERIVATIVES AS SMARCA2/4 DEGRADERS
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The present invention provides pyridazine derivatives of formula (I), which are therapeutically useful as SMARCA2/4 degraders. These compounds are useful in the treatment and/or prevention of diseases or disorders dependent upon SMARCA2/4 in a mammal. The present invention also provides preparation of the compounds and pharmaceutical compositions comprising at least one of the pyridazine derivatives of formula (I) or a pharmaceutically acceptable salt, or a stereoisomer thereof.
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Page/Page column 100
(2019/11/12)
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- Designed P-glycoprotein inhibitors with triazol-tetrahydroisoquinoline-core increase doxorubicin-induced mortality in multidrug resistant K562/A02 cells
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Multidrug resistance (MDR) refers to the cross-resistance of cancer cells to one drug, accompanied by other drugs with different mechanisms and structures, which is one of the main obstacles of clinical chemotherapy. Overexpression of P-glycoprotein (P-gp) was an extensively studied cause of MDR. Therefore, inhibiting P-gp have become an important strategy to reverse MDR. In this study, two series of triazole-tetrahydroisoquinoline-core P-gp inhibitors were designed and synthesized. Among them, compound I-5 had a remarkable reversal activity of MDR activity and the preliminary mechanism study was also carried out. All the results proved that compound I-5 was considered as a promising P-gp-mediated MDR reversal candidate.
- Kairuki,Qiu, Qianqian,Pan, Miaobo,Li,Zhou,Ghaleb, Hesham,Huang, Wenlong,Qian, Hai,Jiang
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p. 3347 - 3357
(2019/06/17)
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- Discovery to solve multidrug resistance: Design, synthesis, and biological evaluation of novel agents
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Chemotherapy remains a pillar in the treatment and management of various cancers. However, multidrug resistance (MDR) becomes a severe problem after long-term administration of chemotherapy drugs. Overexpression of P-glycoprotein (P-gp) is a significant cause for tumor MDR. Therefore, P-gp inhibition is considered as an effective strategy to reverse MDR. A third-generation P-gp inhibitor tariquidar was selected as a lead compound, and a new series of triazol-N-ethyl tetrahydroisoquinoline based compounds were designed as novel P-gp inhibitors and synthesized through click chemistry. These compounds presented higher reversal activities than the positive-control verapamil (VRP). Among 18 compounds, compound 11 without cytotoxicity reversed MDR in a dose-dependent manner, with a persistent longer chemosensitizing effect and reversibility compared to others. Mechanism studies discovered that compound 11 could escalate the intracellular accumulation of rhodamine-123 and doxorubicin in K562/A02 cells as well as inhibit their efflux from cells. The results obtained suggest that compound 11 is more potent than VRP administered under the same conditions; it may be a potent and safe candidate for P-gp modulation for further development.
- Qiu, Qianqian,Shi, Wei,Zhao, Shiyuan,Zhu, Yan,Ding, Zhengquan,Zhou, Shaoyang,Kairuki, Mutta,Huang, Wenlong,Qian, Hai
-
-
- Exploring Rigid and Flexible Core Trivalent Sialosides for Influenza Virus Inhibition
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Herein, the chemical synthesis and binding analysis of functionalizable rigid and flexible core trivalent sialosides bearing oligoethylene glycol (OEG) spacers interacting with spike proteins of influenza A virus (IAV) X31 is described. Although the flexible Tris-based trivalent sialosides achieved micromolar binding constants, a trivalent binder based on a rigid adamantane core dominated flexible tripodal compounds with micromolar binding and hemagglutination inhibition constants. Simulation studies indicated increased conformational penalties for long OEG spacers. Using a systematic approach with molecular modeling and simulations as well as biophysical analysis, these findings emphasize on the importance of the scaffold rigidity and the challenges associated with the spacer length optimization.
- Kiran, Pallavi,Bhatia, Sumati,Lauster, Daniel,Aleksi?, Stevan,Fleck, Carsten,Peric, Natalija,Maison, Wolfgang,Liese, Susanne,Keller, Bettina G.,Herrmann, Andreas,Haag, Rainer
-
supporting information
p. 19373 - 19385
(2018/11/27)
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- Glycosyl-Substituted Dicarboxylates as Detergents for the Extraction, Overstabilization, and Crystallization of Membrane Proteins
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To tackle the problems associated with membrane protein (MP) instability in detergent solutions, we designed a series of glycosyl-substituted dicarboxylate detergents (DCODs) in which we optimized the polar head to clamp the membrane domain by including, on one side, two carboxyl groups that form salt bridges with basic residues abundant at the membrane–cytoplasm interface of MPs and, on the other side, a sugar to form hydrogen bonds. Upon extraction, the DCODs 8 b, 8 c, and 9 b preserved the ATPase function of BmrA, an ATP-binding cassette pump, much more efficiently than reference or recently designed detergents. The DCODs 8 a, 8 b, 8 f, 9 a, and 9 b induced thermal shifts of 20 to 29 °C for BmrA and of 13 to 21 °C for the native version of the G-protein-coupled adenosine receptor A2AR. Compounds 8 f and 8 g improved the diffraction resolution of BmrA crystals from 6 to 4 ?. DCODs are therefore considered to be promising and powerful tools for the structural biology of MPs.
- Nguyen, Kim-Anh,Peuchmaur, Marine,Magnard, Sandrine,Haudecoeur, Romain,Boyère, Cédric,Mounien, Saravanan,Benammar, Ikram,Zampieri, Veronica,Igonet, Sébastien,Chaptal, Vincent,Jawhari, Anass,Boumendjel, Ahcène,Falson, Pierre
-
supporting information
p. 2948 - 2952
(2018/02/19)
-
- Effect of Anomeric Configuration on Stereocontrolled α-Glycosylation of l -Fucose
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In this letter, we report an approach to the stereoselective α-glycosylation of l -fucose that is exemplified by effect of anomeric configuration. The neighboring group participation is not compatible with α-glycosylation of l -fucose, therefore the remote participation by 4- O -Bz was employed to control the formation of 1,2- cis -glycosidic bond. Furthermore, we found the anomeric configuration of fucose donor is crucial to stereoselectivity of the glycosylated products. The α/β-mixed products were generated by using β-anomeric donor while the glycosyl donor in α configuration yielded products in high α-selectivity possibly due to the distinct pathway to forming the key intermediates. This phenomenon supplies the basis for the synthesis of complicated natural carbohydrates containing fucose α-glycoside, such as fucoidans, fucosylated N -glycans, and fucosylated chondroitin sulfates, etc.
- Wang, Lihao,Fan, Fei,Wu, Haotian,Gao, Lei,Zhang, Ping,Sun, Tiantian,Yang, Chendong,Yu, Guangli,Cai, Chao
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supporting information
p. 2701 - 2706
(2018/12/13)
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- Target-specific anti-cancer prodrug and method for preparing the same
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The present invention refers to target specific anticancer drugs precursor and the manufacturing method are disclosed. According to the present invention, cancer cells compared to normal cells only for highly selective has, from being degraded by proteolytic enzymes are effective anticancer drug can be improve by, in accordance with the drug monitoring through imaging of a level with simultaneously. (by machine translation)
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Paragraph 0042
(2019/01/05)
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- Cereblon ligand mediated novel BET protein degradation bifunctional molecules, preparation and application thereof
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The invention relates to a preparation method of new bifunctional small molecules and pharmaceutically acceptable salts, hydrates or prodrugs thereof, and application of the compounds and pharmaceutical compositions thereof in treatment of tumors, inflammation, immunity and other diseases. The bifunctional small molecules involved in the invention are protein degradation targeting chimeras (PROTACs), and can selectively induce BET protein degradation. According to the invention, a connecting arm is employed to connect a BET protein small molecule inhibitor and a cereblon protein ligand in theE3 ubiquitin ligase complex so as to obtain the bifunctional small molecules.
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Paragraph 0101-0103
(2018/04/02)
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- Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as P-glycoprotein-mediated multidrug resistance inhibitors
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Multidrug resistance (MDR) is one of the main obstacles of clinical chemotherapy. A great deal of research shows that the occurrence of drug resistance in various malignant tumors is closely related to the expression of P-glycoprotein (P-gp) on the surface of the cell membrane. In this paper, based on the structure-activity relationship of phenylethyl tetrahydroisoquinoline, we choose tariquidar as the lead compound for the design and synthesis of 17 novel tetrahydroisoquinoline P-gp inhibitors. Additionally, in vitro and in vivo cytotoxicity assays and reversed MDR activity assays were evaluated. Among them, compound 3 had a good reversal of MDR activity and the reversal mechanism study of it was carried out. All of these results demonstrated that compound 3 was considered to be a promising P-gp-mediated MDR reversal candidate.
- Gao, Yang,Shi, Wei,Cui, Jian,Liu, Chunxia,Bi, Xinzhou,Li, Zhuo,Huang, Wenlong,Wang, Guangji,Qian, Hai
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supporting information
p. 2420 - 2427
(2018/04/10)
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- 18F-LABELED TRIAZOLE CONTAINING PSMA INHIBITORS
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The present technology is directed to compounds, intermediates thereof, compositions thereof, medicaments thereof, and methods related to the imaging of mammalian tissue overexpressing PSMA. The compounds are of Formula I or a pharmaceutically acceptable salt thereof, wherein one of R1, R2, and R3 is and of Formula IV or a pharmaceutically acceptable salt thereof.
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-
Paragraph 0126
(2018/02/03)
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- Topological Defects in Hyperbranched Glycopolymers Enhance Binding to Lectins
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Central scaffold topology and carbohydrate density are important features in determining the binding mechanism and potency of synthetic multivalent of poly- versus monodisperse carbohydrate systems against a model plant toxin (Ricinus communis agglutinin (RCA120)). Lower densities of protein receptors favour the use of heterogeneous, polydisperse glycoconjugate presentations, as determined by surface plasmon resonance and dynamic light scattering.
- Salvadó, Míriam,Reina, José J.,Rojo, Javier,Castillón, Sergio,Boutureira, Omar
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supporting information
p. 15790 - 15794
(2017/10/23)
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- Chiral induction, transfer and modulation in C 3-symmetric columnar liquid crystalline assemblies
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Circularly polarized light (CPL), regarded as a true chiral entity, has been suggested as one possible origin of homochirality in nature. It still remains difficult to understand the exact mechanism of chiral induction, transfer and amplification in supramolecular assemblies. Herein, we designed and synthesized three discotic diacetylene LC monomers, in which the peripheral diacetylene flexible chains linked to the triazole derivative cores through H-bonding or covalent bonds. We established links between the primary chemical structures of discotic diacetylene monomers, liquid crystal phase structures and optically active properties in the final supramolecular assemblies. Moreover, the type of junction bonding interaction exhibited a significant influence on the chiral transfer in a supramolecular columnar LC system.
- Hu, Jingang,Zhu, Tianyi,He, Chenlu,Zhang, Yan,Zhang, Qijin,Zou, Gang
-
supporting information
p. 5135 - 5142
(2017/07/10)
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- PURINONES AS UBIQUITIN-SPECIFIC PROTEASE 1 INHIBITORS
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The application relates to inhibitors of USP1 useful in the treatment of cancers, and other USP1 associated diseases and disorders, having the Formula: (I), where R1, R2, R3, R3', R4, R5, X1, X2, X3, X4, and n are described herein.
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-
Paragraph 00545
(2017/06/12)
-
- Cereblon ligand-induced BET degradation-based bifunctional molecule and preparation and application thereof
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The invention relates to a novel preparation method of a bifunctional molecule and a pharmaceutically acceptable salt, hydrate or prodrug thereof and application of these compounds and a medicinal composition thereof in treatment of diseases such as tumors, inflammation and immunity. The bifunctional molecule is a protein degradation-targeted complex (PROTACs), and is capable of selectively inducing BET protein degradation. A BET protein small-molecule inhibitor is connected with a cereblon protein ligand in an E3 ubiquitin ligase complex to obtain the bifunctional molecule.
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Paragraph 0073; 0074; 0075; 0076
(2017/09/02)
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- A glycosylation strategy to develop a low toxic naphthalimide fluorescent probe for the detection of Fe3+ in aqueous medium
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A glycosylation strategy based on click chemistry was employed to develop a naphthalimide-based Fe3+ fluorescent probe with low cytotoxicity and good water-solubility. The selectivity and sensitivity to Fe3+ of three synthesized naphthalimide-based fluorescent probes follows a Nap-PZ Nap-OH > Nap-Glc trend, because the exposed toxic group of Nap-PZ was shielded by a good biocompatible group. The detection limit toward Fe3+ ion follows a Nap-PZ (7.40 × 10-6 M) > Nap-OH (2.73 × 10-7 M) > Nap-Glc (4.27 × 10-8 M) trend. Moreover, Nap-Glc could be used to detect Fe3+ in living cells. The fluorescent "off-on" response of Nap-Glc towards Fe3+ could be recognized by the naked eye, and the "off-on" fluorescent mechanism also was demonstrated by theoretical calculations. Therefore, Nap-Glc is a novel glucosyl naphthalimide fluorescent probe for environmental or biological detection of Fe3+ with low cytotoxicity and good water-solubility.
- Liu, Feiyang,Tang, Piaoping,Ding, Ruihua,Liao, Lujuan,Wang, Lisheng,Wang, Mian,Wang, Jianyi
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supporting information
p. 7515 - 7522
(2017/07/10)
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- Synthesis and biological evaluation of JL-A7 derivatives as potent ABCB1 inhibitors
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Cancer chemotherapy failure is often due to the overexpression of ATP-binding cassette (ABC) transporters (particularly ABCB1), resulting in a variety of structurally and pharmacologically unrelated drugs efflux. The multidrug resistance (MDR) phenomenon could be reversed by ABCB1 inhibitors. Now, JL-A7 as the lead compound based on a triazol-N-ethyl-tetrahydroisoquinoline scaffold, 18 compounds were designed and synthesized. Substitution in para positions yielded high activities toward ABCB1. Moreover, compound 5 could effectively block the drug efflux function of ABCB1 and increase the accumulation of anti-cancer drugs to achieve effective treatment concentration in MDR cells.
- Pan, Miaobo,Cui, Jian,Jiao, Lei,Ghaleb, Hesham,Liao, Chen,Zhou, Jiaqi,Kairuki, Mutta,Lin, Haiyan,Huang, Wenlong,Qian, Hai
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p. 4194 - 4202
(2017/07/05)
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- Unexpected Direct Synthesis of N-Vinyl Amides through Vinyl Azide–Enolate [3+2] Cycloaddition
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The unexpected synthesis of industrially important N-vinyl amides directly from aldehydes and α,β-unsaturated N-vinyl amides from esters is reported. This reaction probably proceeds through an initial [3+2] azide–enolate cycloaddition involving a vinyl azide generated in situ. A survey of the reaction scope and preliminary mechanistic findings supported by quantum computational analysis are reported, with implications for the future development of atom-efficient amide synthesis. Intriguingly, this study suggests that (cautious) reevaluation of azidoethene as a synthetic reagent may be warranted.
- Choi, Hans,Shirley, Harry J.,Hume, Paul A.,Brimble, Margaret A.,Furkert, Daniel P.
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supporting information
p. 7420 - 7424
(2017/06/13)
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- Design and synthesis of dendrimers with facile surface group functionalization, and an evaluation of their bactericidal efficacy
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We report a versatile divergent methodology to construct dendrimers from a tetrafunctional core, utilizing the robust copper(I) catalyzed alkyne-azide cycloaddition (CuAAC, "click") reaction for both dendrimer synthesis and post-synthesis functionalization. Dendrimers of generations 1-3 with 8-32 protected or free OH and acetylene surface groups, were synthesized using building blocks that included acetylene- or azide-terminated molecules with carboxylic acid or diol end groups, respectively. The acetylene surface groups were subsequently used to covalently link cationic amino groups. A preliminary evaluation indicated that the generation one dendrimer with terminal NH3+ groups was the most effective bactericide, and it was more potent than several previously studied dendrimers. Our results suggest that size, functional end groups and hydrophilicity are important parameters to consider in designing efficient antimicrobial dendrimers.
- Ladd, Elizabeth,Sheikhi, Amir,Li, Na,Van De Ven, Theo G.M.,Kakkar, Ashok
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- Discovery of Novel 11-Triazole Substituted Benzofuro[3,2-b]quinolone Derivatives as c-myc G-Quadruplex Specific Stabilizers via Click Chemistry
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The specificity of nucleic acids' binders is crucial for developing this kind of drug, especially for novel G-quadruplexes' binders. Quindoline derivatives have been developed as G-quadruplex stabilizers with good interactive activities. In order to improve the selectivity and binding affinity of quindoline derivatives as c-myc G-quadruplex binding ligands, novel triazole containing benzofuroquinoline derivatives (T-BFQs) were designed and synthesized by using the 1,3-dipolar cycloaddition of a series of alkyne and azide building blocks. The selectivity toward c-myc G-quadruplex DNA of these novel T-BFQs was significantly improved, together with an obvious increase on binding affinity. Further cellular and in vivo experiments indicated that the T-BFQs showed inhibitory activity on tumor cells' proliferation, presumably through the down-regulation of transcription of c-myc gene. Our findings broadened the modification strategies of specific G-quadruplex stabilizers.
- Zeng, De-Ying,Kuang, Guo-Tao,Wang, Shi-Ke,Peng, Wang,Lin, Shu-Ling,Zhang, Qi,Su, Xiao-Xuan,Hu, Ming-Hao,Wang, Honggen,Tan, Jia-Heng,Huang, Zhi-Shu,Gu, Lian-Quan,Ou, Tian-Miao
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supporting information
p. 5407 - 5423
(2017/07/22)
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- Highly Ordered Self-Assembly of Native Proteins into 1D, 2D, and 3D Structures Modulated by the Tether Length of Assembly-Inducing Ligands
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In nature, proteins self-assemble into various structures with different dimensions. To construct these nanostructures in laboratories, normally proteins with different symmetries are selected. However, most of these approaches are engineering-intensive and highly dependent on the accuracy of the protein design. Herein, we report that a simple native protein LecA assembles into one-dimensional nanoribbons and nanowires, two-dimensional nanosheets, and three-dimensional layered structures controlled mainly by small-molecule assembly-inducing ligands RnG (n=1, 2, 3, 4, 5) with varying numbers of ethylene oxide repeating units. To understand the formation mechanism of the different morphologies controlled by the small-molecule structure, molecular simulations were performed from microscopic and mesoscopic view, which presented a clear relationship between the molecular structure of the ligands and the assembled patterns. These results introduce an easy strategy to control the assembly structure and dimension, which could shed light on controlled protein assembly.
- Yang, Guang,Ding, Hong-Ming,Kochovski, Zdravko,Hu, Rongting,Lu, Yan,Ma, Yu-Qiang,Chen, Guosong,Jiang, Ming
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supporting information
p. 10691 - 10695
(2017/08/30)
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