- Glycodendrimers and modified ELISAs: Tools to elucidate multivalent interactions of galectins 1 and 3
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Multivalent protein-carbohydrate interactions that are mediated by sugar-binding proteins, i.e., lectins, have been implicated in a myriad of intercellular recognition processes associated with tumor progression such as galectin-mediated cancer cellular migration/metastatic processes. Here, using a modified ELISA, we show that glycodendrimers bearing mixtures of galactosides, lactosides, and N-acetylgalactosaminosides, galectin-3 ligands, multivalently affect galectin-3 functions. We further demonstrate that lactose functionalized glycodendrimers multivalently bind a different member of the galectin family, i.e., galectin-1. In a modified ELISA, galectin-3 recruitment by glycodendrimers was shown to directly depend on the ratio of low to high affinity ligands on the dendrimers, with lactose-functionalized dendrimers having the highest activity and also binding well to galectin-1. The results depicted here indicate that synthetic multivalent systems and upfront assay formats will improve the understanding of the multivalent function of galectins during multivalent protein carbohydrate recognition/interaction.
- Wolfenden, Mark,Cousin, Jonathan,Nangia-Makker, Pratima,Raz, Avraham,Cloninger, Mary
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Read Online
- Synthesis and biological evaluation of 3β-O-neoglycosides of caudatin and its analogues as potential anticancer agents
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In order to study the structure–activity relationship (SAR) of C21-steroidal glycosides toward human cancer cell lines and explore more potential anticancer agents, a series of 3β-O-neoglycosides of caudatin and its analogues were synthesized. The results revealed that most of peracetylated 3β-O-monoglycosides demonstrated moderate to significant antiproliferative activities against four human cancer cell lines (MCF-7, HCT-116, HeLa, and HepG2). Among them, 3β-O-(2,3,4-tri-O-acetyl-β-L-glucopyranosyl)-caudatin (2k) exhibited the highest antiproliferative activity aganist HepG2 cells with an IC50 value of 3.11 μM. Mechanical studies showed that compound 2k induced both apoptosis and cell cycle arrest at S phase in a dose dependent manner. Overall, these present findings suggested that glycosylation is a promising scaffold to improve anticancer activity for naturally occurring C21-steroidal aglycones, and compound 2k represents a potential anticancer agent deserved further investigation.
- Li, Xiao-San,Chen, Tang-Ji,Xu, Zhi-Peng,Long, Juan,He, Miao-Ying,Zhan, He-Hui,Zhuang, Hai-Cai,Wang, Qi-Lin,Liu, Li,Yang, Xue-Mei,Tang, Jin-Shan
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- 2,3-Carbamate mannosamine glycosyl donors in glycosylation reactions of diacetone-D-glucose. An experimental and theoretical study
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The role of the cyclic 2,3-N,O-carbamate protecting group in directing the selectivity of mannosylation reactions of diacetone-D-glucose, promoted by BSP/Tf2O via α-triflate intermediates, has been investigated through a combined computational
- Morelli, Laura,Legnani, Laura,Ronchi, Silvia,Confalonieri, Laura,Imperio, Daniela,Toma, Lucio,Compostella, Federica
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- S-ANTIGEN TRANSPORT INHIBITING OLIGONUCLEOTIDE POLYMERS AND METHODS
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Various embodiments provide STOPS? polymers that are S-antigen transport inhibiting oligonucleotide polymers, processes for making them and methods of using them to treat diseases and conditions. In some embodiments the STOPS? modified oligonucleotides include an at least partially phosphorothioated sequence of alternating A and C units having modifications as described herein. The sequence independent antiviral activity against hepatitis B of embodiments of STOPS? modified oligonucleotides, as determined by HBsAg Secretion Assay, is an EC50 that is less than 100 nM.
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Paragraph 0068; 0467
(2021/06/22)
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- A silyl ether-protected building block forO-GlcNAcylated peptide synthesis to enable one-pot acidic deprotection
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In this report, we introduce a novel building block for Fmoc/tBu solid phase peptide synthesis (SPPS) of β-linkedO-GlcNAcylated peptides. This building block carries acid labile silyl ether protecting groups, which are fully removed under TFA-mediated peptide cleavage conditions from the resin, thus requiring fewer synthetic steps and no intermediate purification as compared to other acid or base labile protecting group strategies.
- Yan, Bingjia,Li, Wenyi,Hackenberger, Christian P. R.
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supporting information
p. 8014 - 8017
(2021/10/04)
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- Synthesis of Asparagine Derivatives Harboring a Lewis X Type DC-SIGN Ligand and Evaluation of their Impact on Immunomodulation in Multiple Sclerosis
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The protein myelin oligodendrocyte glycoprotein (MOG) is a key component of myelin and an autoantigen in the disease multiple sclerosis (MS). Post-translational N-glycosylation of Asn31 of MOG seems to play a key role in modulating the immune response towards myelin. This is mediated by the interaction of Lewis-type glycan structures in the N-glycan of MOG with the DC-SIGN receptor on dendritic cells (DCs). Here, we report the synthesis of an unnatural Lewis X (LeX)-containing Fmoc-SPPS-compatible asparagine building block (SPPS=solid-phase peptide synthesis), as well as asparagine building blocks containing two LeX-derived oligosaccharides: LacNAc and Fucα1-3GlcNAc. These building blocks were used for the glycosylation of the immunodominant portion of MOG (MOG31-55) and analyzed with respect to their ability to bind to DC-SIGN in different biological setups, as well as their ability to inhibit the citrullination-induced aggregation of MOG31-55. Finally, a cytokine secretion assay was carried out on human monocyte-derived DCs, which showed the ability of the neoglycopeptide decorated with a single LeX to alter the balance of pro- and anti-inflammatory cytokines, inducing a tolerogenic response.
- Doelman, Ward,Marqvorsen, Mikkel H. S.,Chiodo, Fabrizio,Bruijns, Sven C. M.,van der Marel, Gijsbert A.,van Kooyk, Yvette,van Kasteren, Sander I.,Araman, Can
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supporting information
p. 2742 - 2752
(2020/12/29)
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- A terpyridine zinc complex for selective detection of lipid pyrophosphates: A model system for monitoring bacterial O- And N-transglycosylations
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To develop an effective method for probing O- and Nglycosyltransfer reactions that are accompanied by the release of undecaprenyl pyrophosphate, solanesyl pyrophosphate (SPP) is used as a surrogate to bind a terpyridine zinc complex (Tpy-Zn), forming a fluorescent [Tpy-Zn]-SPP complex (Kass 106,000 M-1 in EtOH-CHCl3) with 5.8 μM LOD in HEPES buffer (10 mM, pH 7.4) containing 10 mM CaCl2 and 0.08% decyl PEG, which is similar to the bioassay conditions for lipid II polymerization.
- Fang, Jim-Min,Hsu, Tse-Wei,Hsu, Hsin-Chuan,Chan, Hsin-Yu
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p. 12747 - 12753
(2020/11/10)
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- Receptor-Specific Delivery of Peptide Nucleic Acids Conjugated to Three Sequentially Linked N-Acetyl Galactosamine Moieties into Hepatocytes
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Peptide nucleic acids (PNAs) are DNA analogs that bind with high affinity to DNA and RNA in a sequence-specific manner but have poor cell permeability, limiting use as therapeutic agents. The work described here is motivated by recent reports of efficient gene silencing specifically in hepatocytes by small interfering RNAs conjugated to triantennary N-acetyl galactosamine (GalNAc), the ligand recognized by the asialoglycoprotein receptor (ASGPR). PNAs conjugated to either triantennary GalNAc at the N-terminus (the branched architecture) or monomeric GalNAc moieties anchored at Cγ of three consecutive PNA monomers of N-(2-aminoethyl)glycine (aeg) scaffolds (the sequential architecture) were synthesized on the solid phase. These formed duplexes with complementary DNA and RNA as shown by UV and circular dichroism spectroscopy. The fluorescently labeled analogs of GalNAc-conjugated PNAs were internalized by HepG2 cells that express the ASGPR but were not taken up by HEK-293 cells that lack this receptor. The sequential conjugate was internalized about 13-fold more efficiently than the branched conjugate into HepG2 cells, as demonstrated by confocal microscopy. The results presented here highlight the potential significance of the architecture of GalNAc conjugation for efficient uptake by target liver cells and indicate that GalNAc-conjugated PNAs have possible therapeutic applications.
- Bhingardeve, Pramod,Madhanagopal, Bharath Raj,Naick, Hemanth,Jain, Prashant,Manoharan, Muthiah,Ganesh, Krishna
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supporting information
p. 8812 - 8824
(2020/08/14)
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- A hepatocyte-targeting fluorescent probe for imaging isoniazid-induced hydrazine in HepG2 cells and zebrafish
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A hepatocyte-targeting fluorescent N2H4 probe, GHP, was first designed and synthesized employing N-acetylgalactosamine (GalNAc) as the hepatocyte-targeting group and 3-nitrophthalimide as the recognition moiety. The probe can be used to selectively image N2H4 produced by the hydrolysis of isoniazid in HepG2 cells and the liver of zebrafish in situ. This journal is
- Guo, Zhenbo,Wang, Mei,Li, Xueyan,Jia, Xu,Wang, Xiaoli,Zhang, Pingzhu,Wei, Chao,Li, Xiaoliu
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supporting information
p. 14183 - 14186
(2020/11/24)
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- THERAPEUTIC METHODS
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The invention provides methods and compositions for delivering a nucleic acid to a cell or the cytosol of the target cell. The method includes contacting the cell with, 1) a membrane-destabilizing polymer; and 2) a nucleic acid conjugate. The nucleic acid conjugate includes a targeting ligand bound to an optional linker and a nucleic acid.
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Page/Page column 97; 99-100; 189; 191; 197; 199
(2020/05/28)
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- Protein S-Glyco-Modification through an Elimination-Addition Mechanism
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Per-O-acetylated unnatural monosaccharides containing a bioorthogonal group have been widely used for metabolic glycan labeling (MGL) in live cells for two decades, but it is only recently that we discovered the existence of an artificial "S-glycosylation" between protein cysteines and per-O-acetylated sugars. While efforts are being made to avoid this nonspecific reaction in MGL, the reaction mechanism remains unknown. Here, we present a detailed mechanistic investigation, which unveils the "S-glycosylation" being an atypical glycosylation termed S-glyco-modification. In alkaline protein microenvironments, per-O-acetylated monosaccharides undergo base-promoted β-elimination to form thiol-reactive α,β-unsaturated aldehydes, which then react with cysteine residues via Michael addition. This S-glyco-modification produces 3-thiolated sugars in hemiacetal form, rather than typical glycosides. The elimination-addition mechanism guides us to develop 1,6-di-O-propionyl-N-azidoacetylgalactosamine (1,6-Pr2GalNAz) as an improved unnatural monosaccharide for MGL.
- Qin, Ke,Zhang, Hao,Zhao, Zhenqi,Chen, Xing
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supporting information
p. 9382 - 9388
(2020/06/04)
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- Substituted pyrazole compound, preparation method, pharmaceutical composition and applications thereof
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The invention discloses a substituted pyrazole compound represented by a formula I, and a preparation method, a pharmaceutical composition and applications thereof, wherein the compound has characteristics of good stability, excellent solubility, low cytotoxicity and remarkable neuroprotective effect, can effectively prevent and treat nerve cell injury, and is an ideal medicinal compound for preventing or treating cerebral stroke, cerebral embolism, cerebral stroke sequelae, cerebral stroke dyskinesia, mitochondrial encephalomyopathy and amyotrophic lateral sclerosis of spinal cord.
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Paragraph 0346-0350
(2020/03/12)
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- Modified oligonucleotides and compound that can be used for synthesizing same
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The present disclosure falls within the field of biomedical technology, and in particular relates to modified oligonucleatides and a compound that can be used for synthesizing same and a method for modifying oligonucleotides. The present disclosure also relates to the use of the modified oligonucleotides for preventing and/or treating diseases associated with the liver in a subject.
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Paragraph 0135; 0138
(2020/12/08)
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- GalNAc-modified methylene blue derivative, preparation method and application thereof, liver-targeted fluorescent probe and HClO detection method
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The invention provides a GalNAc-modified methylene blue derivative, a preparation method and an application thereof, a liver-targeted fluorescent probe and an HClO detection method. The fluorescent probe takes N-acetyl-D-galactosamine as a liver targeting group, can be used as an HClO detection reagent, and shows extremely high response speed, extremely high selectivity and extremely low detectionlimit on HClO. The preparation method of the fluorescent probe is simple, the fluorescent probe is targeted to hepatocytes and liver tissues, and the HClO level can be monitored in real time.
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Paragraph 0050-0051
(2020/10/20)
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- N-acetamido galactose modified 3-nitrophthalimide derivative, preparation method, application and liver targeting probe
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The invention provides an N-acetamido galactose modified 3-nitrophthalimide derivative, a preparation method and an application of the N-acetamido galactose modified 3-nitrophthalimide derivative, anda liver targeting probe. The preparation method of the fluorescent probe is simple, and the obtained fluorescent probe takes N-acetamido galactose as a liver targeting group and 3-nitrophthalimide asa CO response group, can be used as a CO detection reagent, is good in selectivity and high in sensitivity, can target liver cells and liver tissues, and can be used for dynamically monitoring the COlevel.
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Paragraph 0041-0042
(2020/10/20)
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- Pseudo-enantiomeric carbohydrate-based N-heterocyclic carbenes as promising chiral ligands for enantiotopic discrimination
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The practical synthesis of carbohydrate-based NHC-Rh complexes bearing C1 or C3 sterically differentiated positions, accessed by glycosylation or SNAr strategies, is reported. These catalysts exhibit pseudo-enantiomeric behaviour in the hydrosilylation of acetophenone. We show that steric bulk at C1 gives preference for (S)-phenyl-1-ethanol, while bulk at C3 leads to the (R)-enantiomer. These results represent the first example of pseudo-enantiomeric carbohydrate-based NHC ligands leading to enantiotopic discrimination.
- Bower, John F.,Galan, M. Carmen,Henderson, Alexander S.
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supporting information
p. 3012 - 3016
(2020/05/08)
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- SYNTHESIS OF DISACCHARIDE BLOCKS FROM NATURAL POLYSACCHARIDES FOR HEPARAN SULFATE OLIGOSACCHARIDE ASSEMBLY
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Methods for the preparation of oligosaccharide products from polysaccharide starting materials are disclosed. The methods include: hydrolyzing a glucosamine-containing polysaccharide starting material, such as heparin or heparosan, under conditions sufficient to form an oligosaccharide intermediate (e.g., a GlcN-IdoA disaccharide intermediate or a GlcA-GlcN disaccharide intermediate), and converting the oligosaccharide intermediate to the oligosaccharide product. Conversion of the oligosaccharide intermediates to the oligosaccharide products may include one or more esterification, acylation, epimerization, protection, and deprotection steps. Preparation of higher-order oligomers is described, as well as methods for selective oligosaccharide sulfation.
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Paragraph 0009; 0108; 0118; 0123-0124
(2020/07/14)
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- Water-soluble Glucosamine-coated AIE-Active Fluorescent Organic Nanoparticles: Design, Synthesis and Assembly for Specific Detection of Heparin Based on Carbohydrate–Carbohydrate Interactions
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Two water-soluble carbohydrate-coated AIE-activate fluorescent organic nanoparticles TPE3G and TPE4G were designed and synthesized for the detection of heparin. Different from the reported strategy, we not only utilized the general detection mechanism of
- Ji, Yan-ming,Liu, Guang-jian,Li, Cui-yun,Liu, Yi-chen,Hou, Min,Xing, Guo-wen
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supporting information
p. 3295 - 3300
(2019/11/05)
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- Monosaccharide Analogues of Anticancer Peptide R-Lycosin-I: Role of Monosaccharide Conjugation in Complexation and the Potential of Lung Cancer Targeting and Therapy
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Glycoconjugation is a promising modification strategy for the optimization of peptide drugs. In this study, five different monosaccharide derivatives (7a-e) were covalently linked to the N-terminal of R-lycosin-I, which yielded five glycopeptides (8a-e). They demonstrated increased or reduced cytotoxicity depending on monosaccharide types, which might be explained by the changes of physicochemical properties. Among all synthesized glycopeptides, only 8a exhibited increased cytotoxicity (IC50 = 9.6 ± 0.3 μM) and selectivity (IC50 = 37.4 ± 5.9 μM). The glucose transporter 1 (GLUT1) with high expression in cancer cells was approved to be involved in the cytotoxicity and selectivity enhancement of 8a. Furthermore, 8a but not R-lycosin-I inhibited tumor growth in the nude mice xenograft model without generating side effects intraperitoneally. Taken together, this study reveals the different monosaccharide roles in peptide modification and also provides an optimized anticancer peptide with high activity and selectivity, that is, 8a might be a promising lead for developing anticancer drugs.
- Zhang, Peng,Ma, Jing,Zhang, Qianqian,Jian, Shandong,Sun, Xiaoliang,Liu, Bobo,Nie, Liqin,Liu, Meiyan,Liang, Songping,Zeng, Youlin,Liu, Zhonghua
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p. 7857 - 7873
(2019/10/11)
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- Synthesis and Biological Activity of 3,4,-Tri-О-Acetyl-N-Acetylglucosamine and Tetraacetylglucopyranose Conjugated with Alkyl Phosphates
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Abstract: Conjugates of 3,4,6-tri-О-acetyl-N-acetylglucosamine and tetraacetyl glucopyranose with alkyl phosphates were synthesized. The dependence of their antibacterial and antituberculosis activities on the length of the alkyl substituent at the phosphate group was found. The conjugates with a decyl substituent exhibited in vitro the highest antituberculosis activity against Mycobacterium tuberculosis H37Rv (MIC 3?μg/mL) but the weakest effect towards Streptococcus aureus and Bacillus cereus (≤MIC 125 μg/mL). Vice versa, the conjugates with a cetyl substituent demonstrated the highest antibacterial activity in vitro towards S. aureus and B. cereus (MIC 16 μg/mL) but showed the lowest antituberculosis activity (MIC 12 μg/mL) among the compounds under study.
- Sharipova,Garifullin,Sapunova,Voloshina,Kravchenko,Kataev
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p. 155 - 164
(2019/06/14)
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- METHODS FOR TREATING HEPATITIS B INFECTIONS
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Certain embodiments of the invention provide a method for identifying a patient that has a higher likelihood of responding to an HBV antigen inhibitor, such a method comprising detecting a hepatitis B virus (HBV) infected patient's genotype at one or more of the IL28B/A associated SNPs described herein, wherein the relevant genotype(s) described herein are indicative of a patient that has a higher likelihood of responding to an HBV antigen inhibitor as compared to an HBV infected patient having different genotypes at these locations.
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Page/Page column 167; 259; 267
(2019/04/09)
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- INHIBITION OF NGLY1 FOR THE TREATMENT OF CANCER
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In one aspect, the present disclosure provides GlcNAc-Asn analogs of the formula (I): wherein the variables are as defined herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of using the compounds disclosed herein. Additionally, the present disclosure also provides methods of treating cancer comprising inhibiting NGLY1.
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Page/Page column 58; 60
(2019/03/05)
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- COMPOSITIONS AND METHODS FOR FACILITATING DELIVERY OF SYNTHETIC NUCLEIC ACIDS TO CELLS
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Provided herein are compositions and methods for facilitating or enhancing delivery of nucleic acids, such as synthetic mRNAs, into cells or tissues. Such compositions and methods may include use of a targeting moiety-conjugated, such as an N-acetylgalactosamine (GalNAc)-conjugated, oligonucleotide to facilitate or enhance delivery.
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Page/Page column 81-82
(2019/08/20)
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- Synthesis, Characterization, X-Ray Crystallography, and Antileishmanial Activities of N-Linked and O-Linked Glycopyranosides
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Novel N-linked 5a-e and O-linked glycopyranosides 7a-e were synthesized in high yield from commercially available L-tartaric acid containing two asymmetric centers and C2 axis of symmetry. The compound L-tartaric acid was completely protected and then partially hydrolyzed to get the monoester, which upon treatment with different amino and hydroxyl derivatives of glycopyranoses gave the desired amides and esters. The synthesized derivatives were purified by chromatography and characterized by spectroanalytical techniques. The structure of compound 7c in the series was supported by X-ray analysis. Leishmanicidal activities of compounds 5a-e and 7a-e were investigated which showed moderate to good activities.
- Rashid, Haroon Ur,Khan, Sher Wali,Khan, Momin,Nadhman, Akhtar,Rehman, Noor,Tariq, Muhammad,Yousuf, Sammer
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- Synthesis and biological evaluation of novel doxorubicin-containing ASGP-R-targeted drug-conjugates
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Asialoglycoprotein receptor (ASGP-R) belongs to a wide family of C-type lectins and it is currently regarded as an attractive protein in the field of targeted drug delivery (TDD). It is abundantly expressed in hepatocytes and can be found predominantly on the sinusoidal surface especially of HepG2 cells. Therefore, ASGP-R can be used for the TDD of anticancer therapeutics against HCC and molecular diagnostic tools. To date, a variety of mono- and multivalent selective ASGP-R ligands have been discovered. Although many of these compounds have demonstrated a relatively high binding affinity towards the target, the reported synthetic schemes are not handled, complicated and include many non-trivial steps. In the current study, we describe a convenient and versatile synthetic approach to novel monovalent drug-conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose fragment as an ASGP-R-recognition “core-head” and well-known nonselective cytostatic – Doxorubicin (Dox). This is the first example of the direct conjugation of a drug molecule to the ASGP-targeted warhead by a really convenient manner via a simple linker sequence. The performed MTS-based biological evaluation in HepG2 cells revealed the novel conjugates as having anticancer activity. Confocal microscopy showed that the molecules readily penetrated HepG2 membrane and were mainly localized within the cytoplasm instead of the nucleus. Per contra, Dox under the same conditions demonstrated good anticancer activity and was predominantly concentrated in the nucleus. Therefore, we speculate that the amide “trigger” that we have used in this study for linker attachment is a sufficiently stable inside the cells to be enzymatically or spontaneously degraded. As a consequence, we did not observe the release of the drug. Ligands containing triggers that are more liable towards endogenous hydrolysis within the tissue of targeting are strongly required.
- Ivanenkov, Yan A.,Majouga, Alexander G.,Petrov, Rostislav A.,Petrov, Stanislav A.,Kovalev, Sergey V.,Maklakova, Svetlana Yu.,Yamansarov, Emil Yu.,Saltykova, Irina V.,Deyneka, Ekaterina V.,Filkov, Gleb I.,Kotelianski, Victor E.,Zatsepin, Timofey S.,Beloglazkina, Elena K.
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p. 503 - 508
(2018/01/02)
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- TARGETED COMPOSITIONS
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The invention provides certain nucleic acids (e.g., double stranded siRNA molecules), as well as conjugates that comprise a targeting moiety, a double stranded siRNA, and optional linking groups. Certain embodiments also provide synthetic methods useful for preparing the conjugates. The conjugates are useful to target therapeutic double stranded siRNA to the liver and to treat liver diseases including hepatitis (e.g. hepatitis B and hepatitis D).
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Page/Page column 85; 87; 88
(2018/11/10)
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- Extra Sugar on Vancomycin: New Analogues for Combating Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci
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Lipophilic substitution on vancomycin is an effective strategy for the development of novel vancomycin analogues against drug-resistant bacteria by enhancing bacterial cell wall interactions. However, hydrophobic structures usually lead to long elimination half-life and accumulative toxicity; therefore, hydrophilic fragments were also introduced to the lipo-vancomycin to regulate their pharmacokinetic/pharmacodynamic properties. Here, we synthesized a series of new vancomycin analogues carrying various sugar moieties on the seventh-amino acid phenyl ring and lipophilic substitutions on vancosamine with extensive structure-activity relationship analysis. The optimal analogues indicated 128-1024-fold higher activity against methicillin-susceptible S. aureus, vancomycin-intermediate resistant S. aureus (VISA), and vancomycin-resistant Enterococci (VRE) compared with that of vancomycin. In vivo pharmacokinetics studies demonstrated the effective regulation of extra sugar motifs, which shortened the half-life and addressed concerns of accumulative toxicity of lipo-vancomycin. This work presents an effective strategy for lipo-vancomycin derivative design by introducing extra sugars, which leads to better antibiotic-like properties of enhanced efficacy, optimal pharmacokinetics, and lower toxicity.
- Guan, Dongliang,Chen, Feifei,Xiong, Lun,Tang, Feng,Faridoon,Qiu, Yunguang,Zhang, Naixia,Gong, Likun,Li, Jian,Lan, Lefu,Huang, Wei
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supporting information
p. 286 - 304
(2018/02/10)
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- COMPOSITIONS AND METHODS FOR INDUCING IMMUNE TOLERANCE
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Several embodiments provided in the present disclosure relate to compositions that carry an antigen to which tolerance is desired, the antigen being coupled, bound, or otherwise joined to a targeting moiety, the targeting moiety configured to direct the composition to the liver of a subject. In several embodiments, the antigen in coupled to the targeting moiety by way of a polymeric linker. In several embodiments, the polymeric linker is configured to liberate the antigen in vivo. Methods of using the compositions to reduce and/or prevent unwanted immune responses against an antigen of interest are also provided.
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Paragraph 0308
(2019/01/08)
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- Synthesis and Antitubercular and Antibacterial Activities of Triethylammonium 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-glucopyranosyl Decyl Phosphate
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Phosphorylation of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-glucose at the anomeric hydroxy group gave previously unknown triethylammonium 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-glucopyranosyl phosphonate, and successive treatment of the latter with decan-1-ol and aqueous iodine afforded triethylammonium 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl phosphate.
- Garifullin,Sharipova,Voloshina,Kravchenko,Kataev
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p. 1333 - 1336
(2018/11/21)
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- UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies
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A series of glycomimetics of UDP-GlcNAc, in which the β-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring, has been synthesized by the application of different click-chemistry procedures. Their affinities for human O-GlcNAc transferase (hOGT) have been evaluated and studied both spectroscopically and computationally. The binding epitopes of the best ligands have been determined in solution by means of saturation transfer difference (STD) NMR spectroscopy. Experimental, spectroscopic, and computational results are in agreement, pointing out the essential role of the binding of β-phosphate. We have found that the loss of interactions from the β-phosphate can be counterbalanced by the presence of hydrophobic groups at a pyrroline ring acting as a surrogate of the carbohydrate unit. Two of the prepared glycomimetics show inhibition at a micromolar level.
- Ghirardello, Mattia,Perrone, Daniela,Chinaglia, Nicola,Sádaba, David,Delso, Ignacio,Tejero, Tomas,Marchesi, Elena,Fogagnolo, Marco,Rafie, Karim,van Aalten, Daan M. F.,Merino, Pedro
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supporting information
p. 7264 - 7272
(2018/05/04)
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- POLYNUCLEOTIDE CONSTRUCTS
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Disclosed are polynucleotide constructs having a strand linked to a moiety carrying one or more auxiliary moieties. Also disclosed are polynucleotide constructs interrupted with a sugar analogue, and polynucleotide constructs with stereochemical^ enriched phosphorothioates. The polynucleotide constructs may be provided as hybridized polynucleotide constructs. Also featured are methods of delivery a polynucleotide construct to a cell and methods of reducing the expression of a protein in a cell by contacting the cell with the disclosed polynucleotide construct or hybridized polynucleotide construct.
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Page/Page column 93
(2018/03/09)
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- A stereoselective and flexible synthesis to access both enantiomers of N-acetylgalactosamine and peracetylated N-acetylidosamine
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Synthetic approaches towards N-acetylgalactosamine (GalNAc) have been attracting considerable interest since this compound is known for its pivotal role in cell-cell interaction and receptor induced cell signaling. Herein, we present a synthetic route in which two of the four stereogenic centers present in the target compound are derived from enantiopure tartaric acid being selectively converted to epoxy alcohols. The key step is the Pd-catalyzed, stereo- and regioselective epoxide opening and subsequent nucleophilic substitution of an azide functionality. This approach enables the synthesis of the naturally D- and unnaturally L-configured GalNAc, as well as both enantiomers of the largely unknown N-acetylidosamine (IdoNAc).
- Riedl, Bettina,Schmid, Walther
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supporting information
p. 856 - 860
(2018/04/30)
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- Synthesis and biological evaluation of novel mono- and bivalent ASGP-R-targeted drug-conjugates
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Asialoglycoprotein receptor (ASGP-R) is a promising biological target for drug delivery into hepatoma cells. Nevertheless, there are only few examples of small-molecule conjugates of ASGP-R selective ligand equipped by a therapeutic agent for the treatment of hepatocellular carcinoma (HCC). In the present work, we describe a convenient and versatile synthetic approach to novel mono- and multivalent drug-conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose and anticancer drug – paclitaxel (PTX). Several molecules have demonstrated high affinity towards ASGP-R and good stability under physiological conditions, significant in vitro anticancer activity comparable to PTX, as well as good internalization via ASGP-R-mediated endocytosis. Therefore, the conjugates with the highest potency can be regarded as a promising therapeutic option against HCC.
- Petrov, Rostislav A.,Maklakova, Svetlana Yu.,Ivanenkov, Yan A.,Petrov, Stanislav A.,Sergeeva, Olga V.,Yamansarov, Emil Yu.,Saltykova, Irina V.,Kireev, Igor I.,Alieva, Irina B.,Deyneka, Ekaterina V.,Sofronova, Alina A.,Aladinskaia, Anastasiia V.,Trofimenko, Alexandre V.,Yamidanov, Renat S.,Kovalev, Sergey V.,Kotelianski, Victor E.,Zatsepin, Timofey S.,Beloglazkina, Elena K.,Majouga, Alexander G.
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p. 382 - 387
(2017/12/26)
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- Syntheses and anti-cancer activity of CO-releasing molecules with targeting galactose receptors
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CO-releasing molecules (CORMs) containing cobalt have many bioactivities, but most of them do not dissolve in water and have no selectivity to tissue and organs. On the basis of the specific recognition of galactose or sialic acid by a receptor, a series of CORMs based on carbohydrates were synthesized and evaluated. The test results show that all the complexes displayed anticancer activity. Among them, the effects of the complexes of galactose (1), GalNAc (8) and sialic acid (10) were very distinct. Complex 1 displayed higher activity against HeLa, HePG2, MCF-7 and HT-29 cell proliferation than cis-platin (DDP), and its selectivity was far much better than DDP compared with normal cell W138. Furthermore, the uptakes of complexes 1, 8 and 10 by HePG2, HT-29, A549 and RAW264.7 cell lines were studied. The uptake ratio of each cell line for complex 1 was different, and the order of uptake ratio in the four cell lines was HePG2 > HT-29 > RAW264.7 > A549. The HePG2 cells absorbed complex 1 beyond 60% after incubation for 8 h, while A549 absorbed only 27.8%. For complex 8, the uptake trend was similar to that of complex 1 with it being absorbed by all the four cancer cells, but the uptake rate was lower. However, differently, complex 10 was absorbed heavily by macrophage RAW264.7, followed by HePG2; after 8 h incubation, the uptake ratio of RAW264.7 was over 50%. In addition, the mechanism of action was explored, and the results showed that the complexes inhibited cell cycle arrest at the G2/M phase; complex 1 up-regulated the expression levels of caspase-3 and Bax, and down-regulated the Bcl-2 expression, giving rise to HePG2 cell apoptosis.
- Li, Jili,Zhang, Jinlong,Zhang, Qiuping,Bai, Zhongjie,Zhao, Quanyi,He, Dian,Wang, Zhen,Chen, Yonglin,Liu, Bin
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p. 8115 - 8129
(2018/11/23)
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- ABIOTIC ANTI-VEGF NANOPARTICLE
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The present invention relates generally to compositions and methods comprising abiotic, synthetic polymers with affinity and specificity to proteins. The synthetic polymers are an improvement over biological agents by providing a simpler, less expensive, and customizable platform for binding to proteins. In one embodiment, the compositions and methods relate to synthetic polymers with affinity and specificity to vascular endothelial growth factor (VEGF). In one embodiment, the compositions are useful for treating diseases and disorders related to the overexpression of VEGF. In one embodiment, the compositions are useful for treating cancer. In one embodiment, the compositions are useful for detecting VEGF levels from biological samples. In one embodiment, the compositions are useful for detecting overexpression of VEGF from biological samples. In one embodiment, the compositions are used to diagnose cancer.
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Page/Page column 30
(2018/09/25)
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- NUCLEIC ACID CONJUGATES AND USES THEREOF
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Provided herein are conjugates comprising targeting moieties such as sugars, folates and cell-penetrating peptides, which can be used for the improved delivery of agents (e.g., nucleic acids, such as oligonucleotides or mRNAs, or other agents) to cells. The invention provides conjugates and compounds comprising targeting moieties, methods for preparing the same, and intermediates useful in their preparation. In another aspect, the present invention provides formulations (e.g., pharmaceutical compositions) comprising the targetting moiety-containing conjugates and compounds. The present invention also provides methods for delivering agents (e.g., nucleic acids such as oligonucleotides or mRNAs) to a cell, methods for treating and/or preventing a disease or condition in a subject, and methods for modulating gene expression in a cell or a subject. Further, provided herein are kits comprising the conjugates, or formulations thereof; and kits for the preparation of conjugates described herein.
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Paragraph 00363
(2018/03/09)
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- POLYNUCLEOTIDE CONSTRUCTS HAVING AN AUXILIARY MOIETY NON-BIOREVERSIBLY LINKED TO AN INTERNUCLEOSIDE PHOSPHATE OR PHOSPHOROTHIOATE
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The invention features a hybridized polynucleotide construct including a passenger strand, a guide strand loadable into a RISC complex, and one or more auxiliary moieties. At least one of the auxiliary moieties is non-bioreversibly linked to an internucleoside phosphate or phosphorothioate in the passenger strand. The invention further features methods of delivery a polynucleotide construct to a cell and methods of reducing the expression of a protein in a cell. The methods typically involve contacting the cell with the hybridized polynucleotide construct.
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Page/Page column 60
(2017/07/15)
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- TARGETED NUCLEIC ACID CONJUGATE COMPOSITIONS
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The invention provides conjugates that comprise a targeting moiety, a nucleic acid, and optional linking groups as well as synthetic intermediates and synthetic methods useful for preparing the conjugates. The conjugates are useful to target therapeutic nucleic acids to the liver and to treat liver diseases including hepatitis (e.g. hepatitis B and hepatitis D).
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Page/Page column 58; 61
(2017/11/10)
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- Sequential Dy(OTf)3-Catalyzed Solvent-Free Per-O-Acetylation and Regioselective Anomeric De-O-Acetylation of Carbohydrates
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Dysprosium(III) trifluoromethanesulfonate-catalyzed per-O-acetylation and regioselective anomeric de-O-acetylation of carbohydrates can be tuned by adjusting the reaction medium. In this study, the per-O-acetylation of unprotected sugars by using a near-stoichiometric amount of acetic anhydride under solvent-free conditions resulted in the exclusive formation of acetylated saccharides as anomeric mixtures, whereas anomeric de-O-acetylation in methanol resulted in a moderate-to-excellent yield. Reactions with various unprotected monosaccharides or disaccharides followed by a semi-one-pot sequential conversion into the corresponding acetylated glycosyl hemiacetal also resulted in high yields. Furthermore, the obtained hemiacetals could be successfully transformed into trichloroimidates after Dy(OTf)3-catalyzed glycosylation.
- Yan, Yi-Ling,Guo, Jiun-Rung,Liang, Chien-Fu
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p. 2471 - 2479
(2017/09/06)
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- Synthesis and biological evaluation of chemical tools for the study of Dolichol Linked Oligosaccharide Diphosphatase (DLODP)
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Citronellyl- and solanesyl-based dolichol linked oligosaccharide (DLO) analogs were synthesized and tested along with undecaprenyl compounds for their ability to inhibit the release of [3H]OSP from [3H]DLO by mammalian liver DLO diphosphatase activity. Solanesyl (C45) and undecaprenyl (C55) compounds were 50–500 fold more potent than their citronellyl (C10)-based counterparts, indicating that the alkyl chain length is important for activity. The relative potency of the compounds within the citronellyl series was different to that of the solanesyl series with citronellyl diphosphate being 2 and 3 fold more potent than citronellyl-PP-GlcNAc2and citronellyl-PP-GlcNAc, respectively; whereas solanesyl-PP-GlcNAc and solanesyl-PP-GlcNAc2were 4 and 8 fold more potent, respectively, than solanesyl diphosphate. Undecaprenyl-PP-GlcNAc and bacterial Lipid II were 8 fold more potent than undecaprenyl diphosphate at inhibiting the DLODP assay. Therefore, at least for the more hydrophobic compounds, diphosphodiesters are more potent inhibitors of the DLODP assay than diphosphomonoesters. These results suggest that DLO rather than dolichyl diphosphate might be a preferred substrate for the DLODP activity.
- Bosco, Micha?l,Massarweh, Ahmad,Iatmanen-Harbi, Soria,Bouhss, Ahmed,Chantret, Isabelle,Busca, Patricia,Moore, Stuart E.H.,Gravier-Pelletier, Christine
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supporting information
p. 952 - 964
(2016/10/25)
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- NOVEL COMPOSITIONS AND THERAPEUTIC METHODS
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The present invention is directed to novel products, variants, pharmaceutically acceptable salts and prodrugs thereof, and medical use of such compounds for the treatment and/or management of sepsis, septicemia, septic shock, ocular infection, ocular inflammation, ocular angiogenesis, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel diseases (IBD), asthma, chronic obstructive pulmonary disease, fever syndromes, cachexia, psoriasis, autoimmune diseases, cardiac diseases, retinoblastoma, cancer and/or any disorder associated with inflammation, immunomodulation and microbial infection.
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Paragraph 0149
(2017/10/23)
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- Synthesis and Biological Evaluation of Novel Carbohydrate-Derived Derivatives of Erlotinib
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(Table presented.). A series of novel carbohydrate-derived Erlotinib derivatives were prepared by the copper-catalyzed cycloaddition reaction of erlotinib with various azido-sugars. The structures of the newly synthesized compounds were characterized and their cytostatic effects evaluated in vitro on human cancer cell lines MDA-MB-231, HEPG-2, A549, and MCF-7 using an MTS assay. The novel erlotinib derivatives had the expected inhibitory effects on MDA-MB-231 and HEPG-2 cell llines. Among the compounds evaluated the carbohydrate-derived compounds 5b, 5d, 6a, and 6c had more potent activities against MDA-MB-231 or HEPG-2 than Erlotinib. Drug Dev Res, 2016.
- Yu, Wenbo,Jiang, Luxia,Shen, Chao,Zhang, Pengfei
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p. 319 - 325
(2016/10/12)
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- An investigation of construction of chondroitin sulfate E (CS-E) repeating unit
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A series of the derivatives of chondroitin sulfate E (CS-E) disaccharide repeating unit were prepared by postglycosylation–oxidation strategy. The strategy showed excellent performance in glycosylation both on the reactivity and stereoselectivity. Different protecting methodologies were used for the manipulation of disaccharide building blocks. Substitutes at C-4 of glucosyl donors mildly influenced the glycosylation. The current synthesis afforded a feasible approach for the preparation of CS-E repeating unit.
- Yang, Shuang,Wang, A-peng,Zhang, Guangyan,Di, Xiangjie,Zhao, Zhehui,Lei, Pingsheng
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supporting information
p. 5659 - 5670
(2016/08/23)
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- Tetranuclear zinc cluster: A dual purpose catalyst for per-: O -acetylation and de- O -acetylation of carbohydrates
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The trifluoroacetic acid adduct of tetranuclear zinc cluster Zn4(OCOCF3)6O catalysis in per-O-acetylation and de-O-acetylation of carbohydrates at 70 °C can be tuned by adjusting the reaction medium. Per-O-acetylation of hexopyranoses with a near stoichiometric amount of acetic anhydride in toluene resulted in the exclusive formation of pyranosyl products as an anomeric mixture, whereas de-O-acetylation of acetates occurred in methanol in high yields. In the latter, methanol acts as both nucleophile and solvent, and the reaction conditions were compatible to acid- and base-sensitive groups and amino acid derivatives.
- Lin, Ting-Wei,Adak, Avijit K.,Lin, Hong-Jyune,Das, Anindya,Hsiao, Wei-Chen,Kuan, Ting-Chun,Lin, Chun-Cheng
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p. 58749 - 58754
(2016/07/07)
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- GEL FORMULATIONS FOR IMPROVING IMMUNOTHERAPY
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The present invention relates to a composition for use as controlled release of at least one active pharmaceutical ingredient that modulates an immunogenic response in a human or animal body, said composition comprising non-water soluble carbohydrates and wherein the composition is a liquid before administration into the human or animal body and increases in viscosity by more than 1,000 centipoise (cP) after administration.
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Page/Page column 63
(2016/06/21)
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- GEL FORMULATIONS FOR LOCAL DRUG RELEASE
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The present invention relates to a composition comprising non-water soluble carbohydrates, wherein at least 50% of the non-water soluble carbohydrates are carbohydrates selected from derivatives of lactose, maltose, trehalose, raffinose, glucosamine, galactosamine, lactosamine, or derivatives of disaccharides with at least two pyranose saccharide units, trisaccharides, tetrasaccharides, or mixtures thereof, and wherein the composition is a liquid before administration into the human or animal body and increases in viscosity by more than 1,000 centipoise (cP) after administration, for use as a medicament.
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Page/Page column 81; 82
(2016/06/15)
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- GEL FORMULATIONS FOR ENHANCING THE EFFECT OF RADIOTHERAPY
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The present invention relates to a composition comprising: a. non-water soluble carbohydrates b. a contrast agent for imaging, wherein at least 60% of the contrast agent remains within 10 cm from the injection site after 24h, for use in local co-administration into a human or animal body, and wherein the composition is a liquid before administration into the human or animal body and increases in viscosity by more than 1,000 centipoise (cP) after administration.
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Page/Page column 66; 67
(2016/06/15)
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- Targeted dendrimer-drug conjugates
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The invention provides for dendrimer conjugates useful for liver-specific delivery of therapeutic agents. The therapeutic agent is associated to the dendrimer through a enzyme-cleavable covalent linkage.
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Page/Page column 69
(2016/06/13)
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- Nucleophilic Aromatic Substitution (SNAr) as an Approach to Challenging Carbohydrate-Aryl Ethers
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A general and practical route to carbohydrate-aryl ethers by nucleophilic aromatic substitution (SNAr) is reported. Upon treatment with KHMDS, C-O bond formation occurs between carbohydrate alcohols and a diverse range of fluorinated (hetero)ar
- Henderson, Alexander S.,Medina, Sandra,Bower, John F.,Galan, M. Carmen
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supporting information
p. 4846 - 4849
(2015/10/12)
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- Stereoselective Synthesis of Quercetin 3-O-Glycosides of 2-Amino-2-Deoxy-d-Glucose under Phase Transfer Catalytic Conditions
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This article describes the stereoselective synthesis of quercetin 3-O-glycosides of 2-amino-2-deoxy-d-glucose. Efficient 1,2-trans-glycosylation of protected quercetin with N-acetyl-protected 2-amino-2-deoxy-d-glucose chloride was achieved under phase transfer catalytic conditions in a 0.15 M aqueous K2CO3/chloroform system using tetrabutylammonium bromide as the catalyst. On the contrary, glycosylation with the N-phthalimido-protected bromide donor under the same conditions was found to give predominantly 1,2-cis-glycoside product.
- Cao, Zhiling,Qu, Yingying,Zhou, Jiexing,Liu, Weiwei,Yao, Guowei
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- Synthesis of NAG-thiazoline-derived inhibitors for β-N-acetyl-d-hexosaminidases
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Abstract β-N-Acetyl-d-hexosaminidases are responsible for the metabolism of glycoconjugates in diverse physiological processes that are important targets for medicine and pesticide development. Fourteen new NAG-thiazoline derivatives were synthesized by cyclization and click reaction using d-glucosamine hydrochloride as the starting material. All the compounds created were characterized by NMR and HRMS spectra. A preliminary bioassay, using four enzymes from two β-N-acetyl-d-hexosaminidase families, showed that most of the compounds synthesized exhibit selective inhibition of GH84 β-N-acetyl-d-hexosaminidase. Among the compounds tested, compounds 5a (IC50=12.6 μM, hOGA) and 5e (IC50=12.5 μM, OfOGA) proved to be a highly selective and potent inhibitor.
- Kong, Hanchu,Chen, Wei,Lu, Huizhe,Yang, Qing,Dong, Yanhong,Wang, Daoquan,Zhang, Jianjun
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p. 135 - 144
(2015/07/07)
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