- Click chemistry in the synthesis of the first glycoconjugates of bacteriochlorin series
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A regioselective synthesis of glycoconjugates based on bacteriochlorophyll a and lactose derivatives has been carried out. The conjugation was achieved via 1,3-dipolar cycloaddition of bacteriochlorins containing a terminal triple bond and a lactose azide derivative. The conjugates obtained in this way had one or two disaccharide fragments attached to pyrrol A, the exocyclic imide ring of the tetrapyrrolyc macrocycle, or to both positions. Exhaustive NMR analysis by 1D and 2D NMR experiments (1H-1H COSY, TOCSY, ROESY, 1H-13C HSQC, HMBC, and 1H-15N HMBC) allowed us to determine the structures and configurations of the glycoconjugates obtained. A bioassay of the glycoconjugates using the Hep2 cell line showed that the highest efficiency was observed for the glycosylated bacteriopurpurinimide containing a lactose residue at pyrrole ring A.
- Grin, Mikhail A.,Lonin, Ivan S.,Likhosherstov, Leonid M.,Novikova, Olga S.,Plyutinskaya, Anna D.,Plotnikova, Ekaterina A.,Kachala, Vadim V.,Yakubovskaya, Raisa I.,Mironov, Andrey F.
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Read Online
- A new protein-coupled antigen of α-conotoxin MI displays high immunogenicity and can produce antiserum with high detoxification activity
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α-conotoxin (α-CTX) MI is a small peptide toxin with 14 amino acids and two disulfide bonds. It potently inhibits muscle-type nicotinic acetylcholine receptors (nAChRs), and poses a threat as a toxin to tropical fishermen. However, there are currently no effective drugs for the treatment of MI envenomation due to the toxin's low immunogenicity. In this report, we generated neutralizing antiserum and F(ab')2 to MI by synthesizing a new MI antigen through the coupling of alkynyl-modified MI and azide-modified bovine serum albumin (BSA), followed by immunization into mouse and horse. The new MI-BSA antigen generated high titers of mouse and horse antiserum (1:204,800 and 1:51,200, respectively), and both the antiserum as well as the horse F(ab')2 displayed highly potent neutralization and detoxification efficacy. 12.5 μL of mouse or horse antiserum preincubated with MI could completely neutralize a lethal dose of the MI (0.4 μg, 1.7 × LD50), while 6.25 μL (mouse) or 10.41 μL (horse) of the antiserum could exert complete detoxification of mice injected with 1.7 × LD50 of MI. Moreover, the mouse and horse antiserum exhibited medium cross-reactivity for highly toxic α-CTX GI. These results demonstrate that the integrity of MI's antigen epitope and carrier effect of BSA can improve MI's immunogenicity, and provides an effective detoxification treatment for highly toxic α-conotoxins as well as an effective method for the preparation of antiserum of small peptide toxins.
- Zhang, Min,Yu, Shuo,Zhang, Xin,Huang, Qiuyuan,Huang, Yue,Luo, Min,Wei, Yuanmei,Chen, Wenwen,Chen, Ze,Zhou, Xiaowei,Dai, Qiuyun
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- Supramolecular polymerization of sulfated dendritic peptide amphiphiles into multivalent L-selectin binders
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The synthesis of a sulfate-modified dendritic peptide amphiphile and its self-assembly into one-dimensional rod-like architectures in aqueous medium is reported. The influence of the ionic strength on the supramolecular polymerization was probed via circular dichroism spectroscopy and cryogenic transmission electron microscopy. Physiological salt concentrations efficiently screen the charges of the dendritic building block equipped with eight sulfate groups and trigger the formation of rigid supramolecular polymers. Since multivalent sulfated supramolecular structures mimic naturally occurring L-selectin ligands, the corresponding affinity was evaluated using a competitive SPR binding assay and benchmarked to an ethylene glycol-decorated supramolecular polymer.
- Stra?burger, David,Herziger, Svenja,Huth, Katharina,Urschbach, Moritz,Haag, Rainer,Besenius, Pol
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supporting information
p. 97 - 104
(2021/02/12)
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- Acetyl-linked gatifloxacin-1,2,3-triazole-isatin heterozygote as well as preparation method and application thereof
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The invention discloses an acetyl-linked gatifloxacin-1,2,3-triazole-isatin heterozygote as well as a preparation method and application thereof; the structural general formula of the heterozygote isshown in the specification, and the preparation method of the heterozygote comprises the steps: 1, reacting isatin and derivatives thereof with 3-propargyl bromide to obtain N-propargyl isatin and derivatives thereof; 2, reacting the N-propargyl isatin and the derivatives thereof with hydroxylamine hydrochloride or alkoxy amine hydrochloride to obtain an isatin intermediate; 3, carrying out a condensation reaction on the 2-azidoacetic acid and N-hydroxysuccinimide to obtain 2-azidoacetic acid succinimide active ester; 4, reacting the 2-azidoacetic acid succinimide active ester with gatifloxacin to obtain a gatifloxacin derivative; and 5, carrying out a copper-catalyzed cycloaddition reaction on the N-propargyl isatin and the derivatives thereof and the gatifloxacin derivative to generate the heterozygote. The heterozygote has good activity on pathogenic bacteria including gram-positive bacteria and gram-negative bacteria, and is a potential antibacterial drug candidate.
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Paragraph 0035; 0040-0043; 0081; 0090-0093; 0145; 0154-0157
(2021/01/29)
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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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- 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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p. 2691 - 2694
(2019/08/22)
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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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p. 2966 - 2969
(2019/08/30)
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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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p. 117 - 125
(2018/01/27)
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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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- 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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p. 45260 - 45268
(2017/10/06)
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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; 52
(2017/08/01)
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- Synthesis and Biological Activity of Mono- and Di-N-acylated Aminoglycosides
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Despite issues with oto/nephrotoxicity and bacterial resistance, aminoglycosides (AGs) remain an effective and widely used class of antibacterial agents. For decades now, efforts toward the development of novel AGs with potential to overcome some of these
- Chandrika, Nishad Thamban,Green, Keith D.,Houghton, Jacob L.,Garneau-Tsodikova, Sylvie
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supporting information
p. 1134 - 1139
(2015/11/24)
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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 00118; 00120
(2015/09/28)
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- Peptidoglycan Modifications Tune the Stability and Function of the Innate Immune Receptor Nod2
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Natural modifications of peptidoglycan modulate the innate immune response. Peptidoglycan derivatives activate this response via the intracellular innate immune receptor, Nod2. To probe how these modifications alter the response, a novel and efficient carbohydrate synthesis was developed to allow for late-stage modification of the amine at the 2-position. Modification of the carbohydrate was found to be important for stabilizing Nod2 and generating the proper response. The native Nod2 ligands demonstrate a significant increase in the cellular stability of Nod2. Moreover, changing the identity of the natural ligands at the carbohydrate 2-position allows for the Nod2-dependent immune response to be either up-regulated or down-regulated. The ligand structure can be adjusted to tune the Nod2 response, suggesting that other innate immune receptors and their ligands could use a similar strategy.
- Melnyk, James E.,Mohanan, Vishnu,Schaefer, Amy K.,Hou, Ching-Wen,Grimes, Catherine Leimkuhler
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supporting information
p. 6987 - 6990
(2015/06/25)
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- Chemical labeling of intracellular proteins via affinity conjugation and strain-promoted cycloadditions in live cells
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A versatile chemical labeling approach was developed, where intracellular proteins were first incorporated with a bioorthogonal group via affinity conjugation, and subsequently labeled via strain-promoted cycloaddition reactions in live cells.
- Chen, Xi,Li, Fu,Wu, Yao-Wen
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supporting information
p. 16537 - 16540
(2015/11/18)
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- A DNA-mediated homogeneous binding assay for proteins and small molecules
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Optical detection of molecular targets typically requires immobilization, separation, or chemical or enzymatic processing. An important exception is aptamers that allow optical detection in solution based on conformational changes. This method, however, requires the laborious selection of aptamers with high target specificity and affinity, and the ability to undergo the required conformational changes. Here we report on an alternative generic scheme for detecting small molecules and proteins in solution based on a shift in the equilibrium of DNA-based strand displacement competition reaction. The shift occurs upon binding of a protein, for example, an antibody to its target. We demonstrate nanomolar detection of small molecules such as biotin, digoxigenin, vitamin D, and folate, in buffer and in plasma. The method is flexible, and we also show nanomolar detection of the respective antibodies or protein targets of these molecules. The detection scheme provides a generic alternative to aptamers for detection of analytes.
- Zhang, Zhao,Hejesen, Christian,Kjelstrup, Michael B.,Birkedal, Victoria,Gothelf, Kurt V.
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supporting information
p. 11115 - 11120
(2014/08/18)
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- CONJUGATES OF A GLYCOPROTEIN OR A GLYCAN WITH A TOXIC PAYLOAD
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The invention relates to a glycoprotein-toxic pay- load molecule conjugate, a toxic payload molecule- glycan conjugate, and a pharmaceutical composi- tion.The invention further relates to a method for preparing the glycoprotein-toxic payload mole- cule conjugate, the method for modulating growth of a cell population and a method of treating tu- mour cells.
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Page/Page column 112
(2014/11/13)
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- Histidine-functionalized water-soluble nanoparticles for biomimetic nucleophilic/general-base catalysis under acidic conditions
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Cross-linking the micelles of 4-dodecyloxybenzyltripropargylammonium bromide by 1,4-diazidobutane-2,3-diol in the presence of azide-functionalized imidazole derivatives yielded surface-cross-linked micelles (SCMs) with imidazole groups on the surface. The
- Chadha, Geetika,Zhao, Yan
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supporting information
p. 6849 - 6855
(2013/10/01)
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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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supporting information; experimental part
p. 2361 - 2365
(2012/03/27)
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- A straightforward preparation of aminoglycoside-dinucleotide and -diPNA conjugates via click ligation assisted by microwaves
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An alternative and straightforward method to prepare aminoglycoside- dinucleotide and -diPNA conjugates is reported, which is based, on copper-catalyzed Huisgen azidealkyne cycloaddition (click chemistry ligation) assisted by microwave irradiation. This method permitted conjugations to be performed in aqueous solution, in very short times and with readily prepared, precursors.
- Alguacil, Javier,Defaus, Sira,Claudio, Ana,Trapote, Alejandro,Masides, Marta,Robles, Jordi
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experimental part
p. 3102 - 3109
(2010/08/19)
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