- Rhenium(I) polypyridine dibenzocyclooctyne complexes as phosphorescent bioorthogonal probes: Synthesis, characterization, emissive behavior, and biolabeling properties
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We report the development of rhenium(I) polypyridine complexes appended with a dibenzocyclooctyne (DIBO) moiety as bioorthogonal probes for azide-modified biomolecules. Three phosphorescent rhenium(I) polypyridine DIBO complexes [Re(N^N)(CO)3(py-C6-DIBO)][CF3SO3] (py-C6-DIBO = 3-(N-(6-(3,4:7,8-dibenzocyclooctyne-5-oxycarbonylamino)hexyl)aminocarbonyl)pyridine; N^N = 1,10-phenanthroline (phen) (1a), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4-phen) (2a), 4,7-diphenyl-1,10-phenanthroline (Ph2-phen) (3a)) and their DIBO-free counterparts [Re(N^N)(CO)3(py-C6-BOC)][CF3SO3] (py-C6-BOC = 3-(N-(6-(tert-butoxycarbonylamino)hexyl)aminocarbonyl)pyridine; N^N = phen (1b), Me4-phen (2b), Ph2-phen (3b)) were synthesized and characterized. Upon photoexcitation, all the complexes displayed intense and long-lived yellow triplet metal-to-ligand charge-transfer (3MLCT) (dπ(Re) → π?(N^N)) emission. The DIBO complexes underwent facile reactions with benzyl azide in methanol at 298 K with second-order rate constants (k2) in the range of 0.077 to 0.091 M- 1 s- 1. As revealed from SDS-PAGE analysis, the DIBO complexes can selectively label azide-modified proteins and the resulting bioconjugates displayed strong phosphorescence upon photoexcitation. Results of inductively coupled plasma mass spectrometry (ICP-MS) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays indicated that the DIBO complexes accumulated in Chinese Hamster Ovary (CHO) cells with considerable cytotoxic activity. Upon incubation of CHO cells with these complexes, relatively weak intracellular emission was observed. In contrast, upon pretreatment of the cells with 1,3,4,6-tetra-O-acetyl-N-azidoacetyl-d-mannosamine (Ac4ManNAz), intense emission was observed from the cell membrane and some internal compartments. The results suggest that the DIBO complexes are promising candidates for imaging azide-labeled biomolecules.
- Choi, Alex Wing-Tat,Liu, Hua-Wei,Lo, Kenneth Kam-Wing
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- Moxifloxacin/Gatifloxacin-1,2,3-triazole-isatin Hybrids with Hydrogen-Bond Donor and Their In Vitro Anticancer Activity
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A series of novel moxifloxacin/gatifloxacin-1,2,3-triazole-isatin hybrids (8a–i) were designed, synthesized, and screened for their in vitro anticancer activity in this paper. All of the synthesized hybrids were active against A549 and HepG2 cancer cell lines, whereas the parent drugs moxifloxacin and gatifloxacin were devoid of activity. Among them, hybrid 8i (IC50: 41.1–98.3 μM) showed considerable activity against A549, HepG2, and MCF-7 cancer cell lines, and it was no inferior to Vorinostat (IC50: 64.32 to >100 μM) against the three cancer cell lines. Thus, this kind of hybrids has potentiality for discovery of new anticancer candidates for clinical deployment in the control and eradication of cancers.
- Chen, Rongxing,Zhang, Hao,Ma, Tianwei,Xue, Huarui,Miao, Zhong,Chen, Liyan,Shi, Xiangkui
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- On-resin cyclization of peptide ligands of the Vascular Endothelial Growth Factor Receptor 1 by copper(I)-catalyzed 1,3-dipolar azide-alkyne cycloaddition
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Cyclic peptides were obtained, on-resin, by the copper (I) catalysed 1,3-dipolar cycloaddition of azides and alkynes. The reaction led exclusively to the formation of the expected cyclomonomeric products which acted as ligands of the Vascular Endothelial Growth Factor receptor 1.
- Goncalves, Victor,Gautier, Benoit,Regazzetti, Anne,Coric, Pascale,Bouaziz, Serge,Garbay, Christiane,Vidal, Michel,Inguimbert, Nicolas
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- Novel N-acetyl-Glycol-split heparin biotin-conjugates endowed with anti-heparanase activity
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Heparanase is regarded as a promising target for anticancer drugs and Ronepastat is one of the most promising heparanase inhibitors insert in clinical study for Multiple Myeloma Therapy. To improve its pharmacokinetic/pharmacodynamic profile, as well to have an antidote able to neutralize its activity in case of over dosages or intolerance, a new class of its derivatives was obtained inserting non-carbohydrate moieties of different length between the polysaccharide chain and biotin or its derivatives. In vitro these novel derivatives maintain the anti-heparanase activity without induced toxicity. The newly synthesized compounds retained the ability to attenuate the growth of CAG myeloma tumors in mice with potency similar, or in one case even higher than that of the reference compound Roneparstat as well as inhibited metastatic dissemination (lung colonization) of murine B16-F10 melanoma cells in vivo.
- Esposito, Emiliano,Vlodavsky, Israel,Barash, Uri,Roscilli, Giuseppe,Milazzo, Ferdinando M.,Giannini, Giuseppe,Naggi, Annamaria
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- Synthesis and Properties of 3-Azido-2,2-bis(azidomethyl)propyl 2-Azidoacetate: A Potential Azido Ester Plasticizer
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This study reports the synthesis and characterization of a novel azido ester plasticizer, 3-azido-2,2-bis(azidomethyl)propyl 2-azidoacetate (ABAMPA), with good yield and high purity. The density, impact sensitivity, friction sensitivity, thermal decomposition temperature and glass transition temperature were determined to be 1.326 g ? cm?3, 16 J, 324 N, 235.9 °C and ?50.4 °C, respectively. The plasticizing effect of ABAMPA on glycidyl azide polymer (GAP) was calculated by molecular dynamics, the solubility parameter difference value was 1.7(J ? cm?3)0.5, and the glass transition temperature of GAP was reduced from ?35 °C to ?43 °C when the weight ratio of ABAMPA and GAP was 50 : 50. The new azido ester exhibits high energy, remarkable thermostability and good compatibility with GAP, which indicates that it would have potential application in explosive and propellant formulations.
- Wang, Yinglei,Liu, Yajing,Lu, Tingting,Gao, Fulei,Zhao, Baodong
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- Supramolecular dendrimers: Convenient synthesis by programmed self-assembly and tunable thermoresponsivity
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We report here the noncovalent synthesis of thermosensitive dendrimers. Short oligoguanosine strands were linked to the focal point of a dendron by using "click chemistry", and quadruplex formation was used to drive the self-assembly process in the presence of metal ions. The dynamic nature of these noncovalent assemblies can be exploited to create combinatorial libraries of dendrimers as demonstrated by the co-assembly of two components. These supramolecular dendrimers showed thermoresponsive behavior that can be tuned by varying the templating cations or the number of guanines in the oligonucleotide strand. Copyright
- Ghosh, Partha S.,Hamilton, Andrew D.
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- Light-induced tryptophan radical generation in a click modular assembly of a sensitiser-tryptophan residue
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Click chemistry was used as an efficient method to covalently attach a chromophore to an amino acid. Such easily prepared model systems allow for time-resolved studies of one-electron oxidation reactions by the excitation of the chromophore by a laser flash. The model complex ruthenium-tryptophan (Ru-Trp) has been synthesised and studied for its photophysical and electrochemical properties. Despite a small driving force of less than 100 meV, excitation with a laser flash results in fast internal electron transfer leading to the formation of the protonated radical (TrpH+). At neutral pH electron transfer is followed by deprotonation to form the neutral Trp radical with the rate depending on the concentration of water acting as the proton acceptor. The formation of the tryptophan radical was confirmed by EPR. The Royal Society of Chemistry and Owner Societies 2013.
- Sheth, Sujitraj,Baron, Aurelie,Herrero, Christian,Vauzeilles, Boris,Aukauloo, Ally,Leibl, Winfried
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- A Merged Aldol Condensation, Alkene Isomerization, Cycloaddition/Cycloreversion Sequence Employing Oxazinone Intermediates for the Synthesis of Substituted Pyridines
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A domino reaction sequence has been evaluated that begins with union of novel dihydrooxazinone precursors with 2-alkynyl-substituted benzaldehyde components through aldol condensation. Ensuing operations, including alkene isomerization, Diels-Alder, and retrograde Diels-Alder with loss of CO 2 occurs in the same reaction vessel to provide polysubstituted tricyclic pyridine products.
- Williamson, Jill B.,Smith, Emily R.,Scheerer, Jonathan R.
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- Magnetic silica nanoparticle-supported copper complex as an efficient catalyst for the synthesis of novel triazolopyrazinylacetamides with improved antibacterial activity
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[Figure not available: see fulltext.] A novel superparamagnetic iron oxide modified with copper via 2-aminobenzamide is synthesized by the modification of Fe3O4@SiO2 with amine, followed by the reaction with isatoic anhydride. The catalyst is fully characterized by various methods. The catalytic activity of the catalyst is evaluated in the synthesis of a series of novel N-alkyl-2-aryl-2-(6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)acetamide analogs. Antibacterial activity of the synthesized compounds is evaluated. The catalyst is recoverable and shows excellent reusability in 10 sequential runs.
- Asgari, Mohammad Sadegh,Sepehri, Saghi,Bahadorikhalili, Saeed,Ranjbar, Parviz Rashidi,Rahimi, Rahmatollah,Gholami, Ahmad,Kazemi, Aboozar,Khoshneviszadeh, Mehdi,Larijani, Bagher,Mahdavi, Mohammad
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- Synthesis and biological evaluation of moxifloxacin-acetyl-1,2,3-1H-triazole-methylene-isatin hybrids as potential anti-tubercular agents against both drug-susceptible and drug-resistant Mycobacterium tuberculosis strains
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Herein, synthesis and biological evaluation of fourteen moxifloxacin-acetyl-1,2,3-1H-triazole-methylene-isatin hybrids as potential anti-tubercular agents against both drug-susceptible (MTB H37Rv), rifampicin-resistant and multidrug-resistant Mycobacterium tuberculosis strains were reported, and cytotoxicity towards VERO cells as well as inhibitory activity against MTB DNA gyrase were also discussed in this paper. The structure-activity relationship and structure-cytotoxicity relationship demonstrated that substituents on the C-3 and C-5/C-7 positions of isatin framework were closely related with the anti-mycobacterial activity and cytotoxicity. The most active hybrids 8h and 8l (MIC: 0.12–0.5 μg/mL) showed excellent activity which was no inferior to the parent moxifloxacin against the tested drug-susceptible, rifampicin-resistant and multidrug-resistant Mycobacterium tuberculosis strains, demonstrating their potential application as novel anti-tubercular candidates.
- Gao, Feng,Chen, Zijian,Ma, Long,Fan,Chen, Linjun,Lu, Guangming
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- Study of the thermal decomposition of 2-Azidoacetic acid by photoelectron and matrix isolation infrared spectroscopy
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2-Azidoacetic acid (N3CH2CO2H) has been synthesized and characterized by a variety of spectroscopic techniques, and the thermal decomposition of this molecule studied by matrix isolation infrared spectroscopy and real- time ultraviolet photoelectron spectroscopy. The results are consistent with the vapor phase thermal decomposition following a pathway involving concerted ejection of molecular N2 and the simultaneous formation of CO2 and methanimine (CH2NH). No evidence was found for the presence of intermediates such as the nitrene NCH2CO2H or the imine HNCHCO2H. At higher temperatures. CH2NH further decomposes to give HCN and H2.
- Dyke,Groves,Morris,Ogden,Dias,Oliveira,Costa,Barros,Cabral,Moutinho
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- Design and synthesis of cyclo[-Arg-Gly-Asp-Ψ(triazole)-Gly-Xaa-] peptide analogues by click chemistry
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A simple and mild synthesis of a new family of cyclopeptide analogues cyclo[-Arg-Gly-Asp-Ψ(triazole)-Gly-Xaa-] that is obtained by cyclization with click chemistry was investigated. In addition, the method was also successfully expanded to the synthesis of their analogues of different ring sizes. The result supports the potential utility of click chemistry in the preparation of novel integrin domain-binding antagonists and other cyclopeptide analogues.
- Liu, Yaqin,Zhang, Lihui,Wan, Jieping,Li, Yesen,Xu, Yuhong,Pan, Yuanjiang
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- Ciprofloxacin-1,2,3-triazole-isatin hybrids tethered via amide: Design, synthesis, and in vitro anti-mycobacterial activity evaluation
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The purpose of this study was to prepare various novel amide tethered ciprofloxacin-1,2,3-triazole-isatin hybrids 7a-l, and evaluate their in vitro anti-mycobacterial activity as well as cytotoxicity in VERO cells. The synthesized hybrids showed considerable in vitro activity against both MTB H37Rv and MDR-MTB with MIC of 0.12 to 32 μg/mL, and acceptable cytotoxicity in VERO cells (CC50: 8.0–>128.0 μg/mL). In particular, the most active hybrid 7a (MICMTB H37Rv: 0.5 μg/mL and MICMDR-MTB: 0.12 μg/mL) had the activity in the same level with the first-line anti-tubercular agents isoniazid (MIC: 0.12 μg/mL) and rifampicin (MIC: 0.25 μg/mL), and it was 2-fold more active than the parent ciprofloxacin (MIC: 1.0 μg/mL) against MTB H37Rv, and ≥16 folds more potent than ciprofloxacin (MIC: 2.0 μg/mL), isoniazid (MIC: >64 μg/mL) and rifampicin (MIC: >64 μg/mL) against MDR-MTB. Moreover, hybrid 7a (CC50: 16.0 μg/mL) also displayed considerable cytotoxicity towards VERO cells. Thus, hybrid 7a could act as a platform for further investigations.
- Chen, Rongxing,Zhang, Hao,Ma, Tianwei,Xue, Huarui,Miao, Zhong,Chen, Liyan,Shi, Xiangkui
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- Design of phosphonate analogs of short peptides by “click” chemistry
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Methods were developed for the first time for the modification of the natural neuropeptides Ile–Gly–Leu and Leu–Gly–Leu simultaneously with the phosphonate moiety and the triazole ring or solely with the triazole ring by means of click chemistry. All of the peptidomimetics synthesized were isolated as a mixture of diastereomers and were characterized by spectroscopic methods.
- Artyushin,Sharova,Yarkevich,Genkina,Vinogradova,Brel
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- Design, synthesis and antibacterial activity evaluation of moxifloxacin-amide-1,2,3-triazole-isatin hybrids
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In this work, a series of novel moxifloxacin-amide-1,2,3-triazole-isatin hybrids 7a-l were designed and synthesized. The in vitro antibacterial activity against a panel of clinically important Gram-positive and Gram-negative bacteria including drug-resistant pathogens was also evaluated. All hybrids showed considerable activity against the tested pathogens with MIC values of ≤0.03 to 128 μg/mL, and some of them such as hybrids 7e, 7g and 7j were comparable to or better than the parent moxifloxacin (MIC: ≤0.03–8 μg/mL). Moreover, hybrids 7e, 7g and 7j also demonstrated low cytotoxicity towards CHO cells. However, the in vivo pharmacokinetic profiles of these three hybrids were generally far inferior to the parent moxifloxacin. The structure-activity relationship and structure-cytotoxicity relationship were also studied and discussed which may help with the identification of new chemical entities as potent antibacterial agents.
- Gao, Feng,Ye, Lei,Kong, Fangong,Huang, Gang,Xiao
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- Spontaneous Single-Crystal-to-Single-Crystal Evolution of Two Cross-Laminated Polymers
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Two cases of spontaneous evolution of monomers to linear polymers having novel cross-laminated topology are reported. We synthesized two peptide monomers N3-Gly-Gly-NH-CH2-CCH and N3-Gly-Gly-Gly-CH2-CCH and solved their crystal structures by single-crystal X-ray diffraction. They adopt H-bonded crisscrossed layered packing in their crystals such that: (a) the monomers are aligned head-to-tail in 1D-chain-like arrays and parallel arrangement of such arrays forms a layer; (b) the proximally placed azide and alkyne motifs are in an orientation apt for their regiospecific cycloaddition; (c) each monomer having x peptide bonds is H-bonded with 2x monomers disposed in intersecting arrangement, which pre-organize 1D-chain-like arrays in adjacent layers in perpendicular orientation. These crystals underwent spontaneous single-crystal-to-single-crystal (SCSC) polymerization via azide–alkyne cycloaddition reaction to form triazolyl-polyglycines, at room temperature. The crisscrossed arrangement of monomers in adjacent layers ensured the formation of cross-laminated polymers.
- Athiyarath, Vignesh,Sureshan, Kana M.
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- Synthesis of Tc-99m labeled 1,2,3-triazole-4-yl c-met binding peptide as a potential c-met receptor kinase positive tumor imaging agent
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The mesenchymal-epithelial transition factor (c-Met), which is related to tumor cell growth, angiogenesis and metastases, is known to be overexpressed in several tumor types. In this study, we synthesized technetium-99m labeled 1,2,3-triazole-4-yl c-Met binding peptide (cMBP) derivatives, prepared by solid phase peptide synthesis and the 'click-to-chelate' protocol for the introduction of tricarbonyl technetium-99m, as a potential c-Met receptor kinase positive tumor imaging agent, and evaluated their in vitro c-Met binding affinity, cellular uptake, and stability. The 99mTc labeled cMBP derivatives ([99mTc(CO)3]12, [99mTc(CO)3]13, and [99mTc(CO)3]14) were prepared in 85-90% radiochemical yields. The cold surrogate cMBP derivatives, [Re(CO)3]12, [Re(CO)3]13, and [Re(CO)3]14, were shown to have high binding affinities (0.13 μM, 0.06 μM, and 0.16 μM, respectively) to a purified cMet/Fc chimeric recombinant protein. In addition, the in vitro cellular uptake and inhibition studies demonstrated the high specific binding of these 99mTc labeled cMBP derivatives ([99mTc(CO)3]12-14) to c-Met receptor positive U87MG cells.
- Kim, Eun-Mi,Joung, Min-Hee,Lee, Chang-Moon,Jeong, Hwan-Jeong,Lim, Seok Tae,Sohn, Myung-Hee,Kim, Dong Wook
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- Ciprofloxacin/Gatifloxacin-1,2,3-triazole-isatin Hybrids and Their In Vitro Anticancer Activity
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Eleven novel ciprofloxacin/gatifloxacin-1,2,3-triazole-isatin hybrids (8a–k) were designed, synthesized, and screened for their in vitro anticancer activity in this paper. A significant part of the synthesized hybrids was active against A549, HepG2, and SF-268 cancer cell lines, whereas the parent drugs ciprofloxacin and gatifloxacin were devoid of activity. Among them, hybrid 8i (IC50: 78.1–90.7 μM) was found to be the most active against A549, HepG2, and SF-268 cancer cell lines, and it was comparable with or better than Vorinostat (IC50: 71.1 to >100 μM). Thus, these kind hybrids have potentiality for discovery of new anticancer candidates for clinical deployment in the control and eradication of cancers.
- Jiang, Dan,Zhang, Guifu
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- The modular synthesis of multivalent functionalised glycodendrons for the detection of lectins including DC-SIGN
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Glycodendrons are excellent tools for the biological evaluation of lectins. Herein, we present the expedient and efficient synthesis of a versatile second generation dendron scaffold using double exponential growth methodology. The dendron scaffold can be rapidly functionalised, as illustrated by the conjugation of the dendron scaffold to biotin or a fluorescent probe, followed by oxyamine glycan conjugation to the glycan of choice. The use of a fluorescent LewisX glycodendron for the detection of the C-type lectin DC-SIGN on macrophages is then demonstrated.
- Munneke, Stefan,Kodar, Kristel,Painter, Gavin F.,Stocker, Bridget L.,Timmer, Mattie S. M.
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- Site-Specific 64Cu Labeling of the Serine Protease, Active Site Inhibited Factor Seven Azide (FVIIai-N3), Using Copper Free Click Chemistry
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A method for site-specific radiolabeling of the serine protease active site inhibited factor seven (FVIIai) with 64Cu has been applied using a biorthogonal click reaction. FVIIai binds to tissue factor (TF), a trans-membrane protein involved in hemostasis, angiogenesis, proliferation, cell migration, and survival of cancer cells. First a single azide moiety was introduced in the active site of this 50 kDa protease. Then a NOTA moiety was introduced via a strain promoted azide-alkyne reaction and the corresponding conjugate was labeled with 64Cu. Binding to TF and the stability was evaluated in vitro. TF targeting capability of the radiolabeled conjugate was tested in vivo by positron emission tomography (PET) imaging in pancreatic human xenograft cancer mouse models with various TF expressions. The conjugate showed good stability (>91% at 16 h), an immunoreactivity of 93.5%, and a mean tumor uptake of 2.1 ± 0.2%ID/g at 15 h post injection. In conclusion, FVIIai was radiolabeled with 64Cu in single well-defined position of the protein. This method can be utilized to prepare conjugates from serine proteases with the label at a specific position.
- Jeppesen, Troels E.,Kristensen, Lotte K.,Nielsen, Carsten H.,Petersen, Lars C.,Kristensen, Jesper B.,Behrens, Carsten,Madsen, Jacob,Kjaer, Andreas
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- Cyclometalated iridium(iii) polypyridine dibenzocyclooctyne complexes as the first phosphorescent bioorthogonal probes
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We report the synthesis, photophysical behavior, and biological properties of new cyclometalated iridium(iii) polypyridine complexes appended with a dibenzocyclooctyne (DIBO) moiety; these complexes have been utilized as the first phosphorescent bioorthogonal probes for azide-modified biomolecules.
- Lo, Kenneth Kam-Wing,Chan, Bruce Ting-Ngok,Liu, Hua-Wei,Zhang, Kenneth Yin,Li, Steve Po-Yam,Tang, Tommy Siu-Ming
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- Stereoselective and Catalytic Synthesis of anti-β-Alkoxy-α-azido Carboxylic Derivatives
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Direct addition of a chiral N-azidoacetyl thiazolidinethione to a variety of dialkyl acetals catalyzed by a commercially available and structurally simple nickel(II) complex gives access in good yields and a highly stereocontrolled manner to anti-β-alkoxy-α-azido carboxylic derivatives which, in turn, can be easily converted into a wide array of enantiomerically pure compounds.
- Fernández-Valparis, Javier,Romea, Pedro,Urpí, Fèlix,Font-Bardia, Mercè
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- Gatifloxacin-1,2,3-triazole-isatin hybrids and their antimycobacterial activities
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A series of gatifloxacin-1,2,3-triazole-isatin hybrids 8a–l were designed, synthesized, and screened for their in vitro antimycobacterial activity as well as cytotoxicity toward Chinese Hamster Ovary (CHO) cells. The synthesized hybrids showed considerable activity against MTB H37Rv and two MDR-MTB strains with minimal inhibitory concentration (MIC) of 0.25–8 μg/ml, and the hybrid 8a (MICMTB H37Rv: 0.25 μg/ml and MICMDR-MTB: 0.5 and 1 μg/ml) was found to be most active against the tested strains, which was not inferior to the parent gatifloxacin (MIC: 0.5, 0.25, and 0.5 μg/ml) against all three tested strains, and was ≥128-fold more active than isoniazid (MIC: ≥64 μg/ml) and rifampicin (MIC: >128 μg/ml) against the two MDR-MTB strains. Moreover, hybrid 8a (CC50: 8.0 μg/ml) also displayed acceptable cytotoxicity toward CHO cells, and the selectivity index was 32. The structure–activity relationship and structure–cytotoxicity relationship were also enriched.
- Ding, Zhen,Hou, Panfei,Liu, Bi
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- Click strategy using disodium salts of amino acids improves the water solubility of plinabulin and KPU-300
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Plinabulin and KPU-300 are promising anti-microtubule agents; however, the low water solubility of these compounds (0.1?μg/mL) has limited their pharmaceutical advantages. Here, we developed five water-soluble derivatives of plinabulin and KPU-300 with a click strategy using disodium salts of amino acids. The mother skeleton, diketopiperazine (DKP), was transformed into a monolactim-type alkyne and a copper-catalyzed alkyne azide cycloaddition (CuAAC) combined azides that was derived from amino acids as a water-solubilizing moiety. The conversion of carboxyl groups into disodium salts greatly improved the water solubility by 0.8 million times compared to the solubility of the parent molecules. In addition, the α-amino acid side chains of the water-solubilizing moieties affected both the water solubility and the half-lives of the compounds during enzymatic hydrolysis. Our effort to develop a variety of water-soluble derivatives using the click strategy has revealed that the replaceable water-solubilizing moieties can alter molecular solubility and stability under enzymatic hydrolysis. With this flexibility, we are approaching to the in vivo study using water-soluble derivative.
- Yakushiji, Fumika,Muguruma, Kyohei,Hayashi, Yoshiki,Shirasaka, Takuya,Kawamata, Ryosuke,Tanaka, Hironari,Yoshiwaka, Yushi,Taguchi, Akihiro,Takayama, Kentaro,Hayashi, Yoshio
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- A Sequential Ugi Multicomponent/Cu-Catalyzed Azide-Alkyne Cycloaddition Approach for the Continuous Flow Generation of Cyclic Peptoids
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The development of a continuous flow multistep strategy for the synthesis of linear peptoids and their subsequent macrocyclization via Click chemistry is described. The central transformation of this process is an Ugi four-component reaction generating the peptidomimetic core structure. In order to avoid exposure to the often toxic and malodorous isocyanide building blocks, the continuous approach was telescoped by the dehydration of the corresponding formamide. In a concurrent operation, the highly energetic azide moiety required for the subsequent intramolecular copper-catalyzed azide - alkyne cycloaddition (Click reaction) was installed by nucleophilic substitution from a bromide precursor. All steps yielding to the linear core structures can be conveniently coupled without the need for purification steps resulting in a single process generating the desired peptidomimetics in good to excellent yields within a 25 min reaction time. The following macrocyclization was realized in a coil reactor made of copper without any additional additive. A careful process intensification study demonstrated that this transformation occurs quantitatively within 25 min at 140 °C. Depending on the resulting ring strain, either a dimeric or a monomeric form of the cyclic product was obtained. (Chemical Equation Presented).
- Salvador, Carlos Eduardo M.,Pieber, Bartholom?us,Neu, Philipp M.,Torvisco, Ana,Kleber Z. Andrade, Carlos,Kappe, C. Oliver
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- Bioorthogonal chemistry for selective recognition, separation and killing bacteria over mammalian cells
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By taking advantage of metabolic engineering and bioorthogonal click chemistry, we report a new strategy for selective recognition, separation and killing bacteria over mammalian cells.
- Li, Zhenhua,Liu, Zhen,Chen, Zhaowei,Ju, Enguo,Li, Wei,Ren, Jinsong,Qu, Xiaogang
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- Design and automated generation of artificial estrogen receptor as potential endocrine disruptor chemical binders
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We here report on our results concerning the systematic design and synthesis of a new type of artificial estrogen receptor candidates. Our interest herein originates from the known estrogenic activity of endocrine disrupting chemicals, environmental pollutants that have attracted increased attention due to their interference with the endocrine and reproductive system of wildlife and humans. An automated protocol for the generation of libraries of potential artificial receptors is described. The resulting structures could find application in novel SPE cartridges for EDC-preconcentration.
- Figaroli, Sara,Madder, Annemieke
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- Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti-Proliferative Activity in Lung Cancer Cells
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Macrophage migration inhibitory factor (MIF) is involved in protein-protein interactions that play key roles in inflammation and cancer. Current strategies to develop small molecule modulators of MIF functions are mainly restricted to the MIF tautomerase active site. Here, we use this site to develop proteolysis targeting chimera (PROTAC) in order to eliminate MIF from its protein-protein interaction network. We report the first potent MIF-directed PROTAC, denoted MD13, which induced almost complete MIF degradation at low micromolar concentrations with a DC50 around 100 nM in A549 cells. MD13 suppresses the proliferation of A549 cells, which can be explained by deactivation of the MAPK pathway and subsequent induction of cell cycle arrest at the G2/M phase. MD13 also exhibits antiproliferative effect in a 3D tumor spheroid model. In conclusion, we describe the first MIF-directed PROTAC (MD13) as a research tool, which also demonstrates the potential of PROTACs in cancer therapy.
- Chen, Deng,Cool, Robbert H.,Dekker, Frank J.,Melgert, Barbro N.,Poelarends, Gerrit J.,Quax, Wim J.,Song, Shanshan,Xiao, Zhangping,van Merkerk, Ronald,van der Wouden, Petra E.
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supporting information
p. 17514 - 17521
(2021/07/02)
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- Following Molecular Mobility during Chemical Reactions: No Evidence for Active Propulsion
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The reported changes in self-diffusion of small molecules during reactions have been attributed to "boosted mobility". We demonstrate the critical role of changing concentrations of paramagnetic ions on nuclear magnetic resonance (NMR) signal intensities, which led to erroneous measurements of diffusion coefficients. We present simple methods to overcome this problem. The use of shuffled gradient amplitudes allows accurate diffusion NMR measurements, even with time-dependent relaxation rates caused by changing concentrations of paramagnetic ions. The addition of a paramagnetic relaxation agent allows accurate determination of both diffusion coefficients and reaction kinetics during a single experiment. We analyze a copper-catalyzed azide-alkyne cycloaddition "click"reaction, for which boosted mobility has been claimed. With our methods, we accurately measure the diffusive behavior of the solvent, starting materials, and product and find no global increase in diffusion coefficients during the reaction. We overcome NMR signal overlap using an alternative reducing agent to improve the accuracy of the diffusion measurements. The alkyne reactant diffuses slower as the reaction proceeds due to binding to the copper catalyst during the catalytic cycle. The formation of this intermediate was confirmed by complementary NMR techniques and density functional theory calculations. Our work calls into question recent claims that molecules actively propel or swim during reactions and establishes that time-resolved diffusion NMR measurements can provide valuable insight into reaction mechanisms.
- Beves, Jonathon E.,Fillbrook, Lucy L.,Fischer, Peer,Günther, Jan-Philipp,Majer, Günter,O'Leary, Daniel J.,Price, William S.,Van Ryswyk, Hal
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supporting information
p. 20884 - 20890
(2021/12/14)
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- Discovery of triazolyl thalidomide derivatives as anti-fibrosis agents
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Fibrosis with excessive accumulation of extracellular matrix (ECM) often causes progressive organ dysfunction and results in many inflammatory and metabolic diseases, including systemic sclerosis, pulmonary fibrosis, advanced liver disease and advanced kidney disease. The store-operated calcium entry (SOCE) pathway and the related signaling pathway were both found to be the important routes for fibrogenesis. Our aim in this study was to discover novel compounds to inhibit fibrogenesis. A number of triazolyl thalidomide derivatives were synthesized and evaluated for their anti-fibrosis activities. Compounds 7b-e, 8c-d, 10a-b and 10e inhibited intracellular Ca2+ activation and showed no cytotoxicity. Among them, 6-{4-[(3-(1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}hexanoic acid (10e) with the most potent inhibitory effect was chosen for further examination. The results revealed that compound 10e, a SOCE inhibitor, reversed the migratory ability of TGF-β1-induced myofibroblasts, dedifferentiated myofibroblasts to fibroblasts due to cytoskeleton remodeling, and restrained myofibroblast activation by targeting Orai1 and TGF-β1/SMAD2/3 signaling pathways. The in silico study indicated that compound 10e, with the appropriate lipophilic carbon chain and carboxylic acid, showed a good drug-likeness model score. Conclusively, the SOCE inhibitor, compound 10e, is used as a promising lead compound for the development of a new treatment for fibrosis. This journal is
- Tang, Kai-Wei,Hsu, Wen-Li,Chen, Cheng-Ru,Tsai, Ming-Hsien,Yen, Chia-Jung,Tseng, Chih-Hua
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p. 3589 - 3599
(2021/03/03)
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- On-Nanoparticle Gating Units Render an Ordinary Catalyst Substrate- And Site-Selective
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When an organometallic catalyst is tethered onto a nanoparticle and is embedded in a monolayer of longer ligands terminated in "gating"end-groups, these groups can control the access and orientation of the incoming substrates. In this way, a nonspecific catalyst can become enzyme-like: it can select only certain substrates from substrate mixtures and, quite remarkably, can also preorganize these substrates such that only some of their otherwise equivalent sites react. For a simple, copper-based click reaction catalyst and for gating ligands terminated in charged groups, both substrate- and site-selectivities are on the order of 100, which is all the more notable given the relative simplicity of the on-particle monolayers compared to the intricacy of enzymes' active sites. The strategy of self-assembling macromolecular, on-nanoparticle environments to enhance selectivities of "ordinary"catalysts presented here is extendable to other types of catalysts and gating based on electrostatics, hydrophobicity, and chirality, or the combinations of these effects. Rational design of such systems should be guided by theoretical models we also describe.
- Kim, Minju,Dygas, Miroslaw,Sobolev, Yaroslav I.,Beker, Wiktor,Zhuang, Qiang,Klucznik, Tomasz,Ahumada, Guillermo,Ahumada, Juan Carlos,Grzybowski, Bartosz A.
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supporting information
p. 1807 - 1815
(2021/02/05)
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- β-Sheet to Helical-Sheet Evolution Induced by Topochemical Polymerization: Cross-α-Amyloid-like Packing in a Pseudoprotein with Gly-Phe-Gly Repeats
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Protein-mimics are of great interest for their structure, stability, and properties. We are interested in the synthesis of protein-mimics containing triazole linkages as peptide-bond surrogate by topochemical azide-alkyne cycloaddition (TAAC) polymerization of azide- and alkyne-modified peptides. The rationally designed dipeptide N3-CH2CO-Phe-NHCH2CCH (1) crystallized in a parallel β-sheet arrangement and are head-to-tail aligned in a direction perpendicular to the β-sheet-direction. Upon heating, crystals of 1 underwent single-crystal-to-single-crystal polymerization forming a triazole-linked pseudoprotein with Gly-Phe-Gly repeats. During TAAC polymerization, the pseudoprotein evolved as helical chains. These helical chains are laterally assembled by backbone hydrogen bonding in a direction perpendicular to the helical axis to form helical sheets. This interesting helical-sheet orientation in the crystal resembles the cross-α-amyloids, where α-helices are arranged laterally as sheets.
- Hema, Kuntrapakam,Sureshan, Kana M.
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supporting information
p. 8854 - 8859
(2020/04/22)
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- Catechin-amantadine conjugate as well as preparation method and application thereof
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The invention discloses a catechin-amantadine conjugate as well as a preparation method and application thereof. The structure of the derivative is shown in the specification. The preparation method comprises the following steps: selectively protecting catechin; synthesizing a protected catechin terminal alkyne precursor under an alkaline condition; synthesizing an amantadine azide intermediate; carrying out click reaction on the terminal alkyne precursor and an azido adamantane precursor to synthesize a catechin adamantane conjugate; and in the presence of a hydrogenation catalyst, carrying out deprotection to synthesize the catechin-amantadine conjugate. The synthesized catechin-amantadine conjugate is novel in structure and simple in synthesis route, a noble metal catalyst is not used,and the synthesized catechin-amantadine has good anti-influenza activity.
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Paragraph 0028-0031
(2020/09/12)
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- Synthesis, Cytotoxicity and Antimicrobial Evaluation of New Coumarin-Tagged β-Lactam Triazole Hybrid
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A series of coumarin-tagged β-lactam triazole hybrids (10a–10o) were synthesized and tested for their cytotoxic activity against MDA-MB-231 (triple negative breast cancer), MCF-7 (estrogen receptor positive breast cancer (ER+)) and A549 (human lung carcinoma) cancer cell lines including one normal cell line, HEK-293 (human embryonic kidney). Two compounds 10b and 10d exhibited substantial cytotoxic effect against MCF-7 cancer cell lines with IC50 values of 53.55 and 58.62 μm, respectively. More importantly, compounds 10b and 10d were non-cytotoxic against HEK-293 cell lines. Structure–activity relationship (SAR) studies suggested that the nitro and chloro group at the C-3 position of phenyl ring are favorable for anticancer activity, particularly against MCF-7 cell lines. Furthermore, antimicrobial evaluation of these compounds revealed modest inhibition of examined pathogenic strains with compounds 10c and 10i being the most promising antimicrobial agents against Pseudomonas aeruginosa and Candida albicans, respectively.
- Awolade, Paul,Cele, Nosipho,Dhawan, Sanjeev,Jonnalagadda, Sreekantha B.,Kaur, Mandeep,Kisten, Prishani,Pillay, Ashona-Singh,Saha, SouravTaru,Singh, Parvesh
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- Gatifloxacin-1,2,3-triazole-isatin hybrids tethered through methylene and acetyl and their antibacterial activities
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In this work, a series of gatifloxacin-1,2,3-triazole-isatin hybrids tethered with methylene and acetyl (8a-n) were designed and synthesized, and the antibacterial activity profiles together with cytotoxicity were also investigated. The preliminary results indicated that all of the hybrids showed promising activity against a panel of Gram-positive and Gram-negative bacteria with MIC values in a range of ≤0.03 to 64 μg/mL. The cytotoxicity results demonstrated all hybrids displayed acceptable cytotoxicity towards VERO cells. Among these 14 hybrids, 8b and 8g with low cytotoxicity were no inferior to the parent gatifloxacin against Gram-positive and Gram-negative pathogens. Furthermore, we discussed the structure-activity relationship and structure-cytotoxicity relationship so as to point out the direction for further rationale design and modification of this series of hybrids.
- GUO, Hua,DIAO, Quan-Ping
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p. 239 - 246
(2020/10/06)
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- Novel Liposomal Azido Mannosamine Lipids on Metabolic Cell Labeling and Imaging via Cu-Free Click Chemistry
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In comparison with the popular Ac4ManNAz applied as cell labels via Cu-free click chemistry, two novel azido mannosamine lipids with C6 and C12 esters on anomeric hydroxyl groups were prepared and encapsulated in a liposome delivery system, which enhanced chemical stabilities and showed good cell-metabolizable labeling efficiency on MDA-MB-231 cells with strong fluorescence after the treatment of DBCO-Cy5 by triazole formation via click chemistry.
- Shen, Li,Cai, Kaimin,Yu, Jin,Cheng, Jianjun
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p. 2317 - 2322
(2019/09/06)
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- BIOTIN-CONJUGATED N-ACETYL GLYCOL SPLIT HEPARIN
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The present invention relates to N-acetyl glycol split heparin molecules conjugated with biotin having following formula (I), wherein the meanings of the substituents are disclosed in the description. The present invention also relates to such compounds for use as medicaments, in particular for the treatment of diseases and disorders associated with heparanase activity, and to pharmaceutical compositions comprising the same.
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Page/Page column 41
(2018/11/10)
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- Compatibility between the cysteine-cyclopentenedione reaction and the copper(i)-catalyzed azide-alkyne cycloaddition
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The cysteine-cyclopentenedione reaction can be combined with the copper(i)-catalyzed azide-alkyne cycloaddition provided that the former is carried out first. If not, the azide and the cyclopentenedione undergo a 1,3-dipolar cycloaddition, which furnishes triazole-containing compounds and products resulting from nitrogen loss. Both of these products were fully characterized. Attempts to obtain either of them as the main compound or to drive the reaction nearly to completion were unsuccessful, which points to the azide-cyclopentenedione reaction as not being useful for bioconjugation.
- Agramunt, Jordi,Saltor, Laia,Pedroso, Enrique,Grandas, Anna
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supporting information
p. 9185 - 9190
(2019/01/03)
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- TRIGGER-ACTIVATABLE SUGAR CONJUGATES FOR CANCER-SELECTIVE LABELING AND TARGETING
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Disclosed are compounds for the selective labeling of cell-surface sugars in cancer cells. The compounds are activatable by triggers specific to cancer cells, and, when metabolized, label a cancer cell surface sugar with an azide chemical group. Facilitated by a click chemistry reaction, combination of the cell surface-expressed azide with a alkynyl-drug conjugate enables efficient targeted drug delivery to cancer cells with reduced toxicity. Also disclosed are compounds for delivering a drug to an azide-bearing cancer cell, and methods of treating cancer using the compounds.
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Page/Page column 69
(2018/09/08)
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- ANTI-MICROBIAL AGENT-POLYMER CONJUGATES AND METHODS OF USE THEREOF
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The present disclosure provides a conjugate comprising an anti-microbial agent and a hydrophilic polymer; and compositions, including pharmaceutical compositions, comprising the conjugates. The present disclosure provides a conjugate comprising a polymyxin covalently linked to a maltodextrin polymer; and compositions, including pharmaceutical compositions, comprising the conjugates. The present disclosure provides methods of inhibiting growth of a bacterium, and methods of treating a bacterial infection.
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-
Paragraph 0028; 00502; 00507
(2018/11/22)
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- A BODIPY-Tagged Phosphono Peptide as Activity-Based Probe for Human Leukocyte Elastase
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Human leukocyte elastase plays a crucial role in a variety of inflammatory disorders and represents an important subject of biomedical studies. The chemotype of peptidic phosphonates was employed for the design of a new activity-based probe for human leukocyte elastase. Its structure combines the phosphonate warhead with an adequate peptide portion and a BODIPY fluorophore with a clickable ethinylphenyl moiety at meso position. The probe 6 was assembled by copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition. It was characterized as an active site-directed elastase inhibitor exhibiting a second-order rate constant of inactivation of 88400 M-1s-1. The suitability of 6 as a fluorescent probe for human leukocyte elastase was demonstrated by in-gel fluorescence analysis. Labeling experiments and inhibition data toward a panel of related proteases underlined the selectivity of the probe for the targeted leukocyte elastase.
- Schulz-Fincke, Anna-Christina,Blaut, Michael,Braune, Annett,Gütschow, Michael
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supporting information
p. 345 - 350
(2018/04/19)
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- Coumarin-based tripodal chemosensor for selective detection of Cu(II) ion and resultant complex as anion probe through a Cu(II) displacement approach
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In this paper, a novel tripodal fluorescent receptor based on naturally occurring coumarin was synthesized and its ionic recognition properties were fully investigated by spectroscopic techniques. As revealed by the results, tripodal 1 exhibits excellent selectivity toward copper(II) by forming a 1:1 complex with triazole N as the main binding sites. And the resulted 1·Cu2+ complex shows recognition ability toward H2PO4? by metal displacement approach. The recognition mechanism was further investigated by computer calculation.
- Sun, Jinzhi,Xu, Xiang,Yu, Guanghui,Li, Weina,Shi, Jinsheng
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supporting information
p. 987 - 991
(2018/01/27)
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- Synthesis and biological evaluation of azamacrolide comprising the triazole moiety as quorum sensing inhibitors
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Novel azamacrolides comprising the triazole moiety were synthesized and evaluated for their quorum sensing inhibitor activities on the Agrobacterium tumefaciens. It was found that the inhibition rate of compound Z12-3 at 200 mg/L (0.45 mM) can reach 67%. The potential binding modes between these molecules and the TraR QS receptor was performed by molecular docking. The results showed that the two nitrogen atoms in the triazole ring of Z12-3 formed hydrogen bonds with GLN-2, and the carbonyl group (C=O) in the amide formed hydrogen bonds with water. It was worth noting that the carbonyl group on the macrolides formed hydrogen bonds with the G-106 base in the DNA. These azamacrolides may block quorum sensing expression through key amino acid residues or DNA bases in the TraR QS receptor by hydrogen-bonded.
- Zhang, Bin,Guo, Bingyi,Bai, Yunlong,Lu, Huizhe,Dong, Yanhong
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-
- Sensor with a scaffold having changeable conformations
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The present invention relates to a scaffolded sensor with a container comprising a drug for triggering drug release, wherein the scaffold is intrinsically conformationally metastable and a method to its manufacture.
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Page/Page column 19; 20; 27
(2017/09/26)
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- TRIGGER-ACTIVATABLE METABOLIC SUGAR PRECURSORS FOR CANCER-SELECTIVE LABELING AND TARGETING
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Disclosed are compounds for the selective labeling of cell-surface sugars in cancer cells. The compounds are activatable by triggers specific to cancer cells, and, when metabolized, label a cancer cell surface sugar with an azide chemical group. Facilitated by a click chemistry reaction, combination of the cell surface-expressed azide with a alkynyl- drug conjugate enables efficient targeted drug delivery to cancer cells with reduced toxicity Also disclosed are compounds for delivering a drug to an azide-bearing cancer cell, and methods of treating cancer using the compounds of the invention.
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Page/Page column 51
(2017/08/01)
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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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supporting information
p. 1142 - 1151
(2017/07/25)
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- Synthesis and biological evaluation of salinomycin triazole analogues as anticancer agents
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Salinomycin, a polyether antibiotic used for treatment of coccidial disease in animal husbandry, has demonstrated promising efficacy for treating different cancers. To enrich structure-activity relationship of salinomycin in tumours, we prepared a series of new triazole derivatives in specific site of salinomycin by click cycloaddition reactions, and assessed their antiproliferative activities on breast cancer cell lines. The screening results indicated that most derivatives modified at the C20 hydroxyl group have potent antitumour activity. Notably, salinomycin triazole dimers were 3.27–4.97 times more toxic than the natural substance in ERα-positive breast cancer cells (MCF-7), and had moderately improved toxicity in triple-negative breast cancer cells (MDA-MB-231).
- Huang, Minjian,Deng, Zixin,Tian, Jian,Liu, Tiangang
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p. 900 - 908
(2017/02/18)
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- Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry
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An active site mapping of human cathepsin B with dipeptide nitrile inhibitors was performed for a combinatorial approach by introducing several points of diversity and stepwise optimizing the inhibitor structure. To address the occluding loop of cathepsin B by a carboxylate moiety, click chemistry to generate linker-connected molecules was applied. Inhibitor 17 exhibited Ki values of 41.3 nM, 27.3 nM, or 19.2 nM, depending on the substrate and pH of the assay. Kinetic data were discussed with respect to the conformational selection and induced fit models.
- Schmitz, Janina,Li, Tianwei,Bartz, Ulrike,Gütschow, Michael
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supporting information
p. 211 - 216
(2016/03/25)
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- Strain-promoted oxidation controlled cycloaddition with high reaction rate
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The invention provides a the use of a (hetero)cycloalkyne and an oxo-group containing (hetero)1,3-diene for coupling a first system (A) of interest to a second system (A') of interest, wherein a (hetero)cycloalkyne is created in one of the first system (A) of interest and the second system (A') of interest, and wherein an oxo-group containing (hetero)1,3-diene is created in the other system of interest, and allowing the (hetero)cycloalkyne and the oxo-group containing (hetero)1,3-diene to react to form an A-A' conjugate.
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-
Paragraph 0087
(2016/03/16)
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- A 'photorelease, catch and photorelease' strategy for bioconjugation utilizing a p-hydroxyphenacyl group
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A bioorthogonal 'catch and photorelease' strategy, which combines alkyne-azide cycloaddition between p-hydroxyphenacyl azide and alkyne derivatives to form a 1,2,3-triazole adduct and subsequent photochemical release of the triazole moiety via a photo-Favorskii rearrangement, is introduced. The first step can also involve photorelease of a strained alkyne and its Cu-free click reaction with azide.
- Madea,Slanina,Klán
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supporting information
p. 12901 - 12904
(2016/11/06)
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- Double conjugation strategy to incorporate lipid adjuvants into multiantigenic vaccines
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Conjugation of multiple peptides by their N-termini is a promising technique to produce branched multiantigenic vaccines. We established a double conjugation strategy that combines a mercapto-acryloyl Michael addition and a copper-catalysed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction to synthesise self-adjuvanting branched multiantigenic vaccine candidates. These vaccine candidates aim to treat cervical cancer and include two HPV-16 derived epitopes and a novel self-adjuvanting moiety. This is the first report of mercapto-acryloyl conjugation applied to the hetero conjugation of two unprotected peptides by their N-termini followed by a CuAAC reaction to conjugate a novel synthetic lipoalkyne self-adjuvanting moiety. In vivo experiments showed that the most promising vaccine candidate completely eradicated tumours in 46% of the mice (6 out of 13 mice).
- Hussein, Waleed M.,Liu, Tzu-Yu,Maruthayanar, Pirashanthini,Mukaida, Saori,Moyle, Peter M.,Wells, James W.,Toth, Istvan,Skwarczynski, Mariusz
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p. 2308 - 2321
(2016/03/05)
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- Targeted Ultrasound-Assisted Cancer-Selective Chemical Labeling and Subsequent Cancer Imaging using Click Chemistry
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Metabolic sugar labeling followed by the use of reagent-free click chemistry is an established technique for in vitro cell targeting. However, selective metabolic labeling of the target tissues in vivo remains a challenge to overcome, which has prohibited the use of this technique for targeted in vivo applications. Herein, we report the use of targeted ultrasound pulses to induce the release of tetraacetyl N-azidoacetylmannosamine (Ac4ManAz) from microbubbles (MBs) and its metabolic expression in the cancer area. Ac4ManAz-loaded MBs showed great stability under physiological conditions, but rapidly collapsed in the presence of tumor-localized ultrasound pulses. The released Ac4ManAz from MBs was able to label 4T1 tumor cells with azido groups and significantly improved the tumor accumulation of dibenzocyclooctyne (DBCO)-Cy5 by subsequent click chemistry. We demonstrated for the first time that Ac4ManAz-loaded MBs coupled with the use of targeted ultrasound could be a simple but powerful tool for in vivo cancer-selective labeling and targeted cancer therapies.
- Wang, Hua,Gauthier, Marianne,Kelly, Jamie R.,Miller, Rita J.,Xu, Ming,O'Brien, William D.,Cheng, Jianjun
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supporting information
p. 5452 - 5456
(2016/05/09)
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- Modified compstatin with peptide backbone and C-terminal modifications
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Compounds comprising peptides capable of binding C3 protein and inhibiting complement activation are disclosed. These compounds display greatly improved complement activation-inhibitory activity as compared with currently available compounds. The compounds comprise compstatin analogs having a constrained backbone at position 8 (glycine) and, optionally, specific substitutions for threonine at position 13.
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Page/Page column 24
(2016/07/27)
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- A flexible inner amide macrocyclic molecule and its preparation method
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The present invention discloses a flexible lactam macrocycle molecule and a preparation method thereof, wherein the structure general formula is represented by a formula I, A is one selected from pyrrolyl, 1,4-dimethylene-1,2,3-triazolyl, phenyl, pyridyl, imidazolyl and N-methyl imidazolyl, R is H or -(CH2)nR', R' is one selected from amino, C1-C6 alkyl amino, C5-C7 aryl, C5-C10 heterocyclic aryl and C6-C10 arylamino, and n is an integer of 1-3. The flexible lactam macrocycle molecule preparation method adopts the half long-chain substrate containing the alkyne-azide bifunctional group to carry out intermolecular cyclization through the clicking reaction, is different from the traditional preparation method adopting the full long-chain precursor to carry out intramolecular ring closing, and has advantages of simple synthesis method, green, high efficiency and the like. The formula I is defined in the instruction.
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Paragraph 0043; 0044; 0045; 0046; 0047
(2016/11/28)
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- A multigram-scale lower E-factor procedure for MIBA-catalyzed direct amidation and its application to the coupling of alpha and beta aminoacids
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The development of direct and atom-economical amidation methods is of high priority because of the importance of amides and peptides as components of pharmaceuticals and commodity chemicals. This article describes the identification of more economical and more practical conditions for direct amidation of carboxylic acids and amines using the MIBA catalyst (5-methoxy-2-iodophenylboronic acid, 6) and its application to the coupling of α- and β-amino acid derivatives. It is now possible to use half of the quantity of molecular sieves prescribed in the original procedure, at a higher concentration leading to a reduction of waste and a substantially improved E-factor. This procedure was validated in the multigram scale preparation of prototypical amides, including aminoacids, using toluene as the solvent. Because of substrate inhibition of the catalyst with monoprotected α-aminoacids, the use of doubly-protected N-phthaloyl α-aminoacids or α-azidoacids is required in order to produce dipeptide products in moderate yields. β-Aminoacids do not suffer from this problem, and Boc-β-aminoacids can be coupled successfully. Unlike other boronic acid catalysts, 6 is active under ambient and low-heat conditions, which helps prevent any epimerization of chiral α-aminoacid derivatives.
- Fatemi, Solmaz,Gernigon, Nicolas,Hall, Dennis G.
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p. 4016 - 4028
(2015/07/15)
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- Multifunctional Forms of Polyoxazoline Copolymers and Drug Compositions Comprising the Same
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The present disclosure provides copolymers of 2-substituted-2-oxazolines possessing two or three reactive functional groups which are also chemically orthogonal. The copolymers described may be random copolymers, block copolymers or a mixture of random and block copolymer configurations. Furthermore, the present disclosure provides novel methods for synthesizing the above polymers find for conjugating to molecules such as targeting, diagnostic and therapeutic agents.
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Paragraph 0192; 0196
(2015/12/12)
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- Development of a time-resolved fluorescence probe for evaluation of competitive binding to the cholecystokinin 2 receptor
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The synthesis, characterization, and use of Eu-DTPA-PEGO-Trp-Nle-Asp-Phe-NH2 (Eu-DTPA-PEGO-CCK4), a luminescent probe targeted to cholecystokinin 2 receptor (CCK2R, aka CCKBR), are described. The probe was prepared by solid phase synthesis. A Kd value of 17 ± 2 nM was determined by means of saturation binding assays using HEK-293 cells that overexpress CCK2R. The probe was then used in competitive binding assays against Ac-CCK4 and three new trivalent CCK4 compounds. Repeatable and reproducible binding assay results were obtained. Given its ease of synthesis, purification, receptor binding properties, and utility in competitive binding assays, Eu-DTPA-PEGO-CCK4 could become a standard tool for high-throughput screening of compounds in development targeted to cholecystokinin receptors.
- Elshan, N.G.R. Dayan,Jayasundera, Thanuja,Weber, Craig S.,Lynch, Ronald M.,Mash, Eugene A.
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p. 1841 - 1848
(2015/03/18)
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- Functionalized triazolopeptoids-a novel class for mitochondrial targeted delivery
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Here we introduce linear 1,4-triazolopeptoids as a novel class of cell penetrating peptidomimetics suitable as organ targeting molecular transporters of bioactive cargo. Repetitive triazole moieties with up to three residues were assembled on solid supports using copper-catalyzed alkyne-azide cycloadditions (CuAAC) in a submonomer approach. Depending on the lipophilicity of their side chain appendages the 1,4-triazolopeptoids showed either endosomal localization or a strong colocalization with the mitochondria of HeLa cells with moderate toxicity. While the basic triazolopeptoids mainly target the neuromast cells in zebrafish embryos, the lipophilic ones colocalize with either cartilage in the jaws and the blood vessel system. This journal is
- Althuon, Daniela,R?nicke, Franziska,Fürniss, Daniel,Quan, Jasmin,Wellh?fer, Isabelle,Jung, Nicole,Schepers, Ute,Br?se, Stefan
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supporting information
p. 4226 - 4230
(2015/04/14)
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- SURFACE FUNCTIONALIZED, HOST-GUEST POLYMER NANO-ASSEMBLIES AND METHODS THEREOF
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The invention generally relates to polymer-based nano-structures. More particularly, the invention relates to novel, surface-functionalized, guest-host polymer nano-assemblies and nano-delivery vehicles useful in diverse fields including drug delivery, diagnostics and specialty materials. The nano-assemblies and nano-delivery vehicles of the invention are afforded via simplify and reliable approaches.
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Paragraph 00116
(2015/09/28)
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