- Stereoselective O-Glycosylations by Pyrylium Salt Organocatalysis**
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Despite many years of invention, the field of carbohydrate chemistry remains rather inaccessible to non-specialists, which limits the scientific impact and reach of the discoveries made in the field. Aiming to increase the availability of stereoselective
- Nielsen, Michael Martin,Holmstr?m, Thomas,Pedersen, Christian Marcus
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supporting information
(2021/12/30)
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- Synthesis of Glycosyl Fluorides by Photochemical Fluorination with Sulfur(VI) Hexafluoride
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This study describes a new convenient method for the photocatalytic generation of glycosyl fluorides using sulfur(VI) hexafluoride as an inexpensive and safe fluorinating agent and 4,4′-dimethoxybenzophenone as a readily available organic photocatalyst. This mild method was employed to generate 16 different glycosyl fluorides, including the substrates with acid and base labile functionalities, in yields of 43%-97%, and it was applied in continuous flow to accomplish fluorination on an 7.7 g scale and 93% yield.
- Bannykh, Anton,Khomutnyk, Yaroslav,Kim, Sungjin,Nagorny, Pavel
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supporting information
p. 190 - 194
(2021/01/13)
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- Concise Synthesis of 1-Thioalkyl Glycoside Donors by Reaction of Per-O-acetylated Sugars with Sodium Alkanethiolates under Solvent-Free Conditions
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A relatively green method for synthesizing 1-thioalkyl glycosides has been developed, where sodium alkanethiolates were used to react with per-O-acetylated sugars instead of odorous alkyl mercaptans in the presence of BF3·Et2O without the use of solvents under mild conditions. Furthermore, we found that 1,2-trans-β-thioglycosides can be converted into corresponding 1,2-cis-α-thioglycosides in the presence of trifluoromethanesulfonic acid in nonpolar solvents under mild conditions. This provides a simple and efficient new approach for synthesizing challenging 1,2-cis-α-thioglycosides.
- Dong, Hai,Feng, Guang-Jing,Guo, Yang-Fan,Liu, Chun-Yang,Luo, Tao
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- Transition-metal-free synthesis of aryl 1-thioglycosides with arynes at room temperature
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A mild, convenient and transition-metal-free protocol for the synthesis of aryl 1-thioglycosides is presentedviaarynes generatedin situcombined with glycosyl thiols in the presence of TBAF(tBuOH)4. The methodology provides a general and efficient way to prepare a series of functionalized thioglycosides in good to excellent yields with a perfect control of the anomeric configuration at room temperature. In addition, the reaction conditions tolerate a variety of the pentoses and hexoses, and the reaction also performs smoothly on protected monosaccharides and disaccharides.
- Liao, Li-Hua,Liu, Yao,Yan, Nan,Yu, Xiao-Bing,Zhang, Xiang-Mei,Zhong, Qian
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p. 26666 - 26671
(2021/08/17)
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- Total Synthesis of a Partial Structure from Arabinogalactan and Its Application for Allergy Prevention
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Arabinogalactan, a microheterogeneous polysaccharide occurring in plants, is known for its allergy-protective activity, which could potentially be used for preventive allergy treatment. New treatment options are highly desirable, especially in a preventive manner, due to the constant rise of atopic diseases worldwide. The structural origin of the allergy-protective activity of arabinogalactan is, however, still unclear and isolation of the polysaccharide is not feasible for pharmaceutical applications due to a variation of the activity of the natural product and contaminations with endotoxins. Therefore, a pentasaccharide partial structure was selected for total synthesis and subsequently coupled to a carrier protein to form a neoglycoconjugate. The allergy-protective activity of arabinogalactan could be reproduced with the partial structure in subsequent in vivo experiments. This is the first example of a successful simplification of arabinogalactan with a single partial structure while retaining its allergy-preventive potential.
- Krumb, Matthias,J?ger, Maximilian,Voss, Alice,Immig, Loreen,Peters, Karin,Kowalczyk, Danuta,Bufe, Albrecht,Opatz, Till,Holst, Otto,Vogel, Christian,Peters, Marcus
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supporting information
p. 928 - 933
(2020/10/29)
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- Rhamnogalacturonan II: Chemical Synthesis of a Substructure Including α-2,3-Linked Kdo**
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The synthesis of a fully deprotected Kdo-containing rhamnogalacturonan II pentasaccharide is described. The strategy relies on the preparation of a suitably protected homogalacturonan tetrasaccharide backbone, through a post-glycosylation oxidation approach, and its stereoselective glycosylation with a Kdo fluoride donor.
- Mancuso, Enzo,Romanò, Cecilia,Trattnig, Nino,Gritsch, Philipp,Kosma, Paul,Clausen, Mads H.
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supporting information
p. 7099 - 7102
(2021/04/19)
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- Reactivity–Stereoselectivity Mapping for the Assembly of Mycobacterium marinum Lipooligosaccharides
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The assembly of complex bacterial glycans presenting rare structural motifs and cis-glycosidic linkages is significantly obstructed by the lack of knowledge of the reactivity of the constituting building blocks and the stereoselectivity of the reactions i
- Hansen, Thomas,Ofman, Tim P.,Vlaming, Joey G. C.,Gagarinov, Ivan A.,van Beek, Jessey,Goté, Tessa A.,Tichem, Jacoba M.,Ruijgrok, Gijs,Overkleeft, Herman S.,Filippov, Dmitri V.,van der Marel, Gijsbert A.,Codée, Jeroen D. C.
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supporting information
p. 937 - 945
(2020/12/09)
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- How do Various Reaction Parameters Influence Anomeric Selectivity in Chemical Glycosylation with Thioglycosides and NIS/TfOH Activation?
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The reaction of glycosyl donor phenyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranoside with NIS/TfOH(cat.) was systematically studied under various reaction conditions. Neither the molecular sieve pore size nor amount of NIS activator was found to have a
- Andersen, Sofie M.,Heuckendorff, Mads,Jensen, Henrik H.,Trinderup, Helle H.
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p. 3251 - 3259
(2021/06/25)
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- Chemical Synthesis and Biological Evaluations of Adiponectin Collagenous Domain Glycoforms
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The homogeneously glycosylated 76-amino acid adiponectin collagenous domains (ACDs) with all of the possible 15 glycoforms have been chemically and individually synthesized using stereoselective glycan synthesis and chemical peptide ligation. The following biological and pharmacological studies enabled correlating glycan pattern to function in the inhibition of cancer cell growth as well as the regulation of systemic energy metabolism. In particular, hAdn-WM6877 was tested in detail with different mouse models and it exhibited promising in vivo antitumor, insulin sensitizing, and hepatoprotective activities. Our studies demonstrated the possibility of using synthetic glycopeptides as the adiponectin downsized mimetic for the development of novel therapeutics to treat diseases associated with deficient adiponectin.
- Wu, Hongxiang,Zhang, Yiwei,Li, Yuanxin,Xu, Jianchao,Wang, Yu,Li, Xuechen
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supporting information
p. 7808 - 7818
(2021/05/26)
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- Fighting Shigella by Blocking Its Disease-Causing Toxin
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Shiga toxin is an AB5 toxin produced by Shigella species, while related toxins are produced by Shiga toxin-producing Escherichia coli (STEC). Infection by Shigella can lead to bloody diarrhea followed by the often fatal hemolytic uremic syndrome (HUS). In the present paper, we aimed for a simple and effective toxin inhibitor by comparing three classes of carbohydrate-based inhibitors: glycodendrimers, glycopolymers, and oligosaccharides. We observed a clear enhancement in potency for multivalent inhibitors, with the divalent and tetravalent compounds inhibiting in the millimolar and micromolar range, respectively. However, the polymeric inhibitor based on galabiose was the most potent in the series exhibiting nanomolar inhibition. Alginate and chitosan oligosaccharides also inhibit Shiga toxin and may be used as a prophylactic drug during shigella outbreaks.
- Haksar, Diksha,Asadpoor, Mostafa,Heise, Torben,Shi, Jie,Braber, Saskia,Folkerts, Gert,Ballell, Lluis,Rodrigues, Janneth,Pieters, Roland J.
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p. 6059 - 6069
(2021/06/01)
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- Carbohydrate-Based NK1R Antagonists with Broad-Spectrum Anticancer Activity
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NK1R antagonists, investigated for the treatment of several pathologies, have shown encouraging results in the treatment of several cancers. In the present study, we report on the synthesis of carbohydrate-based NK1R antagonists and their evaluation as anticancer agents against a wide range of cancer cells. All of the prepared compounds, derived from either-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity, comparable to Cisplatin. This strategy has allowed us to identify the galactosyl derivative 14α , as an interesting hit exhibiting significant NK1R antagonist effect (kinact0.209 ± 0.103 μM) and high binding affinity for NK1R (IC50= 50.4 nM,Ki= 22.4 nM by measuring the displacement of [125I] SP from NK1R). Interestingly, this galactosyl derivative has shown marked selective cytotoxic activity against 12 different types of cancer cell lines.
- Recio, Rocío,Lerena, Patricia,Pozo, Esther,Calderón-Monta?o, José Manuel,Burgos-Morón, Estefanía,López-Lázaro, Miguel,Valdivia, Victoria,Pernia Leal, Manuel,Mouillac, Bernard,Organero, Juan ángel,Khiar, Noureddine,Fernández, Inmaculada
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p. 10350 - 10370
(2021/07/28)
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- NEW IMMUNOSTIMULATORS AND USE THEREOF IN IMMUNOTHERAPY
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The present invention relates to a new family of iNKT stimulators, referred to as 6"-O-PEGm-NHR-GalCer, which are potent analogues of KRN7000. These iNKT stimulators can advantageously be used in therapy, in particular for the prevention and/or treatment of many diseases requiring a stimulation of an immune response, such as cancer, viral, bacterial or parasitic diseases, autoimmune diseases or inflammatory diseases. The iNKT cell stimulator of the invention may be coupled to a biological carrier, such as a therapeutic and/or targeting agent, or be vectorized, for example in nanoparticles, to be specifically delivered to target cells.
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Page/Page column 30
(2021/07/17)
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- Photooxidation of thiosaccharides mediated by sensitizers in aerobic and environmentally friendly conditions
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A series of β-d-glucopyranosyl derivates have been synthesized and evaluated in photooxidation reactions promoted by visible light and mediated by organic dyes under aerobic conditions. Among the different photocatalysts employed, tetra-O-acetyl riboflavin afforded chemoselectively the respective sulfoxides, without over-oxidation to sulfones, in good to excellent yields and short reaction times. This new methodology for the preparation of synthetically useful glycosyl sulfoxides constitutes a catalytic, efficient, economical, and environmentally friendly oxidation process not reported so far for carbohydrates.
- Traverssi, Miqueas G.,Pe?é?ory, Alicia B.,Varela, Oscar,Colomer, Juan P.
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p. 9262 - 9273
(2021/03/16)
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- Total Synthesis of the Echinodermatous Ganglioside LLG-3 Possessing the Biological Function of Promoting the Neurite Outgrowth
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A total synthesis of echinodermatous ganglioside LLG-3 with neuritogenic activity was accomplished by a convergent strategy. The synthesis of 2-hydroxyethyl 8-O-Me-α-sialoside 2 was started from the phenyl 7,8-di-O-Pico-thiosialoside 5, which can be chemoselectively removed the picoloyl group, and then the methyl group in 8-O-MeNeu5Ac moiety was chemoselectively prepared using TMSCHN2/FeCl3. For preparation of the terminal disialic unit, oxidative amidation was initially utilized by our group to efficiently construct the α(2,11) linkage of 8-O-Me-Neu5Acα(2,11)Neu5Gc. Herein, we also demonstrate that the synthesized ganglioside LLG-3 exhibited the neuritogenic activity toward the primary cortical neurons and that biological activity is superior to that of ganglioside DSG-A.
- Huang, Yuahn-Sieh,Shih, Jing-Feng,Tsai, Yow-Fu,Wu, Yu-Fa
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supporting information
p. 7491 - 7495
(2020/10/09)
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- Synthesis of glycoimmunogen Tn-Thr-PS A1 via hydrazone bond and stability optimization of PS A1 monosaccharide mimics under vaccine development conditions
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Previously, our group constructed several immunogens utilizing oxime linkage to conjugate a T-cell stimulatory zwitterionic polysaccharide PS A1 and tumor associated carbohydrate antigens (TACAs) in acetate buffer. Here, a semi-synthetic immunogen was synthesized using hydrazone conjugation between PS A1 and a glycopeptide hydrazide (α-D-GalNAc-L-Thr-NH-NH2) with an excellent loading in PBS buffer. To get robust immune response, the retention of zwitterionic character of PS A1 under vaccine construction conditions is essential. In this regard, the stability of embedded pyruvate acetal moiety in tetrasaccharide repeating unit of PS A1 can validate the retention of the dual charges. Therefore, rather than utilizing this highly immunogenic PS A1 fully, stability studies were performed with synthetic 1-thiophenyl-4,6-O-pyruvate acetal-D-galactopyranose in varying acetate buffer pHs and time intervals. Furthermore, 1-propyl-D-galactofuranose was synthesized to mimick the D-Galf of PS A1 to examine regioselective hydrazone and oxime formation with α-D-GalNAc-L-Thr-NH-NH2 and α-D-GalNAc-ONH2 moieties respectively.
- Hossain,Nishat,Ghosh,Boga,Hymel,Andreana
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p. 107 - 129
(2020/02/11)
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- Total Synthesis of Beshanzuenone D and Its Epimers and Abiespiroside A
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A unified and protecting-group-free six-step total synthesis of bisabolane-type sesquiterpenoid beshanzuenone D and its stereoisomers and abiespiroside A using S-(+)-carvone as a common chiral-pool building block is disclosed. This synthetic route feature
- Borade, Balasaheb R.,Dixit, Ruchi,Kontham, Ravindar
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supporting information
p. 8561 - 8565
(2020/11/12)
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- Studies towards the total synthesis of repeating unit of O-sulfated polysaccharide from marine bacterium Cobetia pacifica KMM 3878
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Herein we report assembly of the appropriately protected trisaccharide repeating unit of Cobetia pacifica KMM 3878 O-sulfated polysaccharide. Our synthesis involves 3,4-O-pyruvilated galactose as the key building block which acts as a donor as well as acceptor in the construction of trisaccharide. We obtained the R isomer as a major stereoisomer in the pyruvilation reaction. The glycosylations proceeded with high stereo and regioselectivity.
- Pradhan, Kabita,Podilapu, Ananda Rao,Kulkarni, Suvarn S.
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p. 255 - 264
(2020/03/18)
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- Glycosylation of Glaucocalyxin a and Evaluation of Its Cytotoxic Activity
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The 7,14-diglucoside of glaucocalyxin A was prepared by a five-step reaction. Its structure was confirmed by spectroscopic methods, and its cytotoxic activity was tested by the MTT method.
- Xiang, Zhaobao,Zhang, Yan,Jin, Yongsheng,Sun, Bin,Chen, Gang
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p. 861 - 864
(2020/09/21)
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- Electrochemical nickel-catalyzed Migita cross-coupling of 1-thiosugars with aryl, alkenyl and alkynyl bromides
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Here we report a simple route towards the synthesis of thioglycosides, in which electrochemical cross-coupling is used to form a S-C glycosidic bond from protected and unprotected thiosugars with functionalized aryl bromides under base free conditions. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly complex glycosides under mild conditions.
- Alami, Mouad,Messaoudi, Samir,Zhu, Mingxiang
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supporting information
p. 4464 - 4467
(2020/05/05)
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- Access to Galectin-3 Inhibitors from Chemoenzymatic Synthons
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Chemoenzymatic strategies are useful for providing both regio- and stereoselective access to bioactive oligosaccharides. We show herein that a glycosynthase mutant of a Thermus thermophilus α-glycosidase can react with unnatural glycosides such as 6-azido
- Dussouy, Christophe,Téletchéa, Stéphane,Lambert, Annie,Charlier, Cathy,Botez, Iuliana,De Ceuninck, Frédéric,Grandjean, Cyrille
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p. 16099 - 16114
(2020/12/01)
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- Chemical glucosylation of pyridoxine
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The chemical synthesis of pyridoxine-5′-β-D-glucoside (5′-β-PNG) was investigated using various glucoside donors and promoters. Hereby, the combination of α4,3-O-isopropylidene pyridoxine, glucose vested with different leaving and protecting groups and the application of stoichiometric amounts of different promoters was examined with regards to the preparation of the twofold protected PNG. Best results were obtained with 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl fluoride and boron trifluoride etherate (2.0 eq.) as promoter at 0 °C (59%). The deprotection was accomplished stepwise with potassium/sodium hydroxide in acetonitrile/water followed by acid hydrolysis with formic acid resulting in the chemical synthesis of 5′-β-PNG.
- Bachmann, Thomas,Rychlik, Michael
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- Total Syntheses of Conjugation-Ready Trisaccharide Repeating Units of Pseudomonas aeruginosa O11 and Staphylococcus aureus Type 5 Capsular Polysaccharide for Vaccine Development
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Pseudomonas aeruginosa belongs to the group of three "critical priority" multi-drug-resistant pathogens listed by WHO and is responsible for severe and often deadly infections such as bloodstream infections and pneumonia. Staphylococcus aureus is also a "high priority" pathogen which is a major cause of serious nosocomial infections such as bacteremia, sepsis, and endocarditis. Owing to their ability to adapt resistance to almost any antibiotics, vaccines against these pathogens are urgently required. These pathogens express structurally unique and densely functionalized glycans on their surfaces which are absent on the host cells. Such carbohydrate antigens are valuable targets for the development of glycoconjugate vaccines and diagnostics. Here, we report the first total synthesis of the conjugation-ready trisaccharide repeating unit of Pseudomonas aeruginosa O11 via a highly stereoselective and efficient assembly of a rare l-fucosamine- A nd d-fucosamine-containing 1,2-cis-linked disaccharide motif and its regioselective glycosylation at O3. A systematic study was conducted for the notoriously difficult glycosylation with the most unreactive axial 4-OH of the rare disaccharide, and the successful outcome was utilized to accomplish the total synthesis of an aminopropyl linker-attached trisaccharide repeating unit of Staphylococcus aureus capsular polysaccharide type 5, which is also a potential antigen for immunotherapy and vaccine development. The judicious selection of protecting groups and reaction conditions allowed the stereoselective assembly and selective functional group interconversions to access the structurally complex linker-attached trisaccharide repeating units, which are valuable tools for immunological evaluation and vaccine development. The strategy is useful for the synthesis of other structurally related complex glycans.
- Behera, Archanamayee,Rai, Diksha,Kulkarni, Suvarn S.
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supporting information
p. 456 - 467
(2020/02/20)
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- VANCOMYCIN DERIVATIVE, PREPARATION METHOD, PHARMACEUTICAL COMPOSITION AND USE THEREOF
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Provided are a class of vancomycin derivatives with a structure as shown in the general formula below and pharmaceutically acceptable salts thereof, a preparation method, a pharmaceutical composition containing the compound thereof, and the use of these compounds in preparing drugs for treating and/or preventing bacterial infection diseases, in particular drugs for treating infection diseases caused by Gram-positive bacteria.
- -
-
Paragraph 0041; 0051; 0053
(2019/03/13)
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- Visible Light Enables Aerobic Iodine Catalyzed Glycosylation
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A versatile protocol for light induced catalytic activation of thioglycosides using iodine as an inexpensive and readily available photocatalyst was developed. Oxygen serves as a green and cost-efficient terminal oxidant and irradiation is performed with a common household LED-bulb. The scope of this glycosylation protocol was investigated in the synthesis of O-glycosides with yields up to 95 %.
- Krumb, Matthias,Lucas, Tobias,Opatz, Till
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supporting information
p. 4517 - 4521
(2019/08/06)
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- Triflic acid-mediated synthesis of thioglycosides
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An efficient synthesis of thioglycosides from per-acetates in the presence of triflic acid is described. The developed protocol features high reaction rates and product yields. Some reactive sugar series give high efficiency in the presence of sub-stoichiometric trifluoromethanesulfonic acid (TfOH) in contrast to other known protocols that require multiple equivalents of Lewis acids to reach high conversion rates.
- Escopy, Samira,Singh, Yashapal,Demchenko, Alexei V.
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supporting information
p. 8379 - 8383
(2019/09/30)
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- Chemoenzymatic Synthesis of C6-Modified Sugar Nucleotides to Probe the GDP- d -Mannose Dehydrogenase from Pseudomonas aeruginosa
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The chemoenzymatic synthesis of a series of C6-modified GDP-d-Man sugar nucleotides is described. This provides the first structure-function tools for the GDP-d-ManA producing GDP-d-mannose dehydrogenase (GMD) from Pseudomonas aeruginosa. Using a common C6 aldehyde functionalization strategy, chemical synthesis introduces deuterium enrichment, alongside one-carbon homologation at C6 for a series of mannose 1-phosphates. These materials are shown to be substrates for the GDP-mannose pyrophosphorylase from Salmonella enterica, delivering the required toolbox of modified GDP-d-Mans. C6-CH3 modified sugar-nucleotides are capable of reversibly preventing GDP-ManA production by GMD. The ketone product from oxidation of a C6-CH3 modified analogue is identified by high-resolution mass spectrometry.
- Ahmadipour, Sanaz,Pergolizzi, Giulia,Rejzek, Martin,Field, Robert A.,Miller, Gavin J.
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supporting information
p. 4415 - 4419
(2019/06/17)
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- Towards a Synthetic Strategy for the Ten Canonical Carrageenan Oligosaccharides – Synthesis of a Protected γ-Carrageenan Tetrasaccharide
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Herein, we report a synthetic strategy aiming at synthesizing the ten canonical carrageenan oligosaccharides from one single precursor. The key β-(1→4)-linked disaccharide was synthesized from commercially available galactose pentaacetate. The notoriously difficult formation of β-(1→4)-d-galactan linkages was successfully optimized on the differentially substituted monosaccharides to afford the desired disaccharide in 55 % yield. Following a convergent strategy, two disaccharides were then glycosylated to form the fully protected α-(1→4)-linked tetrasaccharide backbone of the carrageenans. The careful selection of protecting groups provides the opportunity to access all ten carrageenan substructures identified in polysaccharides isolated from red algae. Here, we demonstrate how one such target oligosaccharide can be obtained in a protected form.
- Kinnaert, Christine,Clausen, Mads H.
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supporting information
p. 3236 - 3243
(2019/06/08)
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- Optical Control of Cytokine Production Using Photoswitchable Galactosylceramides
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α-Galactosylceramides are glycosphingolipids that show promise in cancer immunotherapy. After presentation by CD1d, they activate natural killer T cells (NKT), which results in the production of a variety of pro-inflammatory and immunomodulatory cytokines. Herein, we report the synthesis and biological evaluation of photochromic derivatives of KRN-7000, the activity of which can be modulated with light. Based on established structure–activity relationships, we designed photoswitchable analogues of this glycolipid that control the production of pro-inflammatory cytokines, such as IFN-γ. The azobenzene derivative α-GalACer-4 proved to be more potent than KRN-7000 itself when activated with 370 nm light. Photolipids of this type could improve our mechanistic understanding of cytokine production and could open new directions in photoimmunotherapy.
- Baumann, Andreas,Hartrampf, Nina,Hetzler, Belinda E.,Hoffmann-R?der, Anja,Seki, Toshiyuki,Trauner, Dirk,Tsuji, Moriya,Vep?ek, Nynke A.,Watson, Philip
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supporting information
(2020/03/23)
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- Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of α-Oxo-vinylsulfones to Prepare C-Aryl Glycals and Acyclic Vinyl Ethers
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We demonstrate that readily available and bench-stable α-oxo-vinylsulfones are competent electrophiles in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions. The C-sulfone bond in the α-oxo-vinylsulfone motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These reactions proceed under mild conditions and tolerate a remarkable scope of heterocycles and functional groups. Preliminary mechanistic studies revealed the importance of an α-heteroatom in facilitating these transformations.
- Gong, Liang,Sun, Hong-Bao,Deng, Li-Fan,Zhang, Xia,Liu, Jie,Yang, Shengyong,Niu, Dawen
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- Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of α-Oxo-vinylsulfones to Prepare C-Aryl Glycals and Acyclic Vinyl Ethers
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We demonstrate that readily available and bench-stable α-oxo-vinylsulfones are competent electrophiles in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions. The C-sulfone bond in the α-oxo-vinylsulfone motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These reactions proceed under mild conditions and tolerate a remarkable scope of heterocycles and functional groups. Preliminary mechanistic studies revealed the importance of an α-heteroatom in facilitating these transformations.
- Gong, Liang,Sun, Hong-Bao,Deng, Li-Fan,Zhang, Xia,Liu, Jie,Yang, Shengyong,Niu, Dawen
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p. 7680 - 7686
(2019/05/22)
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- Synthesis of Glycosylated 1-Deoxynojirimycins Starting from Natural and Synthetic Disaccharides
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Iminosugars are an important class of natural products and have been subject to extensive studies in organic synthesis, bioorganic chemistry and medicinal chemistry, yet only a limited number of these studies are on glycosylated iminosugars. Here, a general route of synthesis is presented towards glycosylated 1-deoxynojirimycin derivatives based on the oxidation–reductive amination protocol that in the past has also been shown to be a versatile route towards 1-deoxynojirimycin. The strategy can be applied on commercial disaccharides, as shown in four examples, as well as on disaccharides that are not commercially available and are synthesized for this purpose, as shown by a fifth example.
- Liu, Bing,van Mechelen, Jeanine,van den Berg, Richard J. B. H. N.,van den Nieuwendijk, Adrianus M. C. H.,Aerts, Johannes M. F. G.,van der Marel, Gijsbert A.,Codée, Jeroen D. C.,Overkleeft, Herman S.
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p. 118 - 129
(2019/01/04)
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- Conformationally Switchable Glycosyl Donors
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Glycosyl donors functionalized with 2,2′-bipyridine moieties on the 3-OH and 6-OH or the 2-OH and 4-OH undergo a conformational change when forming 1:1 complexes with Zn2+ ions. The pyranoside ring of the zinc complexes adopted axial-rich skew boat conformations. The reactivities of the two glycosyl donors were investigated by performing a series of glycosylations in the presence or absence of Zn2+ ions. These glycosylations suggested a decrease in reactivity when binding Zn2+. The conformational effect of binding Zn2+ was therefore studied using a third glycosyl donor, unable to undergo conformational changes when binding Zn2+. From competition experiments, it was observed that the binding-induced conformational change increased the reactivity slightly compared to the glycosyl donor unable to undergo a conformational change.
- Holmstr?m, Thomas,Pedersen, Christian Marcus
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p. 13242 - 13251
(2019/11/03)
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- Molecular-Level Understanding of the Major Fragmentation Mechanisms of Cellulose Fast Pyrolysis: An Experimental Approach Based on Isotopically Labeled Model Compounds
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Evaluation of the feasibility of various mechanisms possibly involved in cellulose fast pyrolysis is challenging. Therefore, selectively 13C-labeled cellotriose, 18O-labeled cellobiose, and 13C- and 18O-doubly-labeled cellobiose were synthesized and subjected to fast pyrolysis in an atmospheric pressure chemical ionization source of a linear quadrupole ion trap/orbitrap mass spectrometer. The initial products were immediately quenched, ionized using ammonium cations, and subsequently analyzed using the mass spectrometer. The loss or retention of isotope labels upon pyrolysis unambiguously revealed three major competing mechanisms - sequential losses of glycolaldehyde/ethenediol molecules from the reducing end (the reducing-end unraveling mechanism), hydroxymethylene-assisted glycosidic bond cleavage (HAGBC mechanism), and Maccoll elimination. Important discoveries include the following: (1) Reducing-end unraveling is the predominant mechanism occurring at the reducing end; (2) Maccoll elimination facilitates the cleaving of aglyconic bonds, and it is the mechanism leading to formation of reducing carbohydrates; 3) HAGBC occurs for glycosides but not at the reducing end of cellodextrins; 4) HAGBC and water loss are the predominant reactions for fast pyrolysis of 1,6-anhydrocellodextrins; and 5) HAGBC can proceed after reducing-end unraveling but unraveling does not occur once the HAGBC reaction pathway is initiated. Moreover, hydrolysis was conclusively ruled out for fast pyrolysis of cellobiose, cellotriose, and 1,6-anhydrocellodextrins up to cellotetraosan. No radical reactions were observed.
- Yu, Zaikuan J.,Easton, McKay W.,Murria, Priya,Xu, Lan,DIng, Duanchen,Jiang, Yuan,Zhang, Jifa,Kentt?maa, Hilkka I.
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p. 7037 - 7050
(2019/06/14)
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- Regio/Stereoselective Glycosylation of Diol and Polyol Acceptors in Efficient Synthesis of Neu5Ac-α-2,3-LacNPhth Trisaccharide
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A concise approach to a Neu5Ac-α-2,3-LacNPhth trisaccharide derivative was developed. First, the regio/stereoselective glycosylation between glycoside donors and glucoNPhth diol acceptors was investigated. It was found that the regioselectivity depends not only on the steric hindrance of the C2-NPhth group and the C6-OH protecting group of the glucosamine acceptors, but also on the leaving group and protecting group of the glycoside donors. Under optimized conditions, LacNPhth derivatives were synthesized in up to 92 % yield through a regio/stereoselective glycosylation between peracetylated-α-galactopyranosyl trichloroacetimidate and p-methoxyphenyl 6-O-tert-butyldiphenylsilyl-2-deoxy-2-phthalimido-β-d-glucopyranoside, avoiding the formation of glycosylated orthoesters and anomeric aglycon transfer. Then, the LacNPhth derivative was deacylated and then protected on the primary position by TBDPS to form a LacNPhth polyol acceptor. Finally, the Neu5Ac-α-2,3-LacNPhth derivative was synthesized in 48 % yield through the regio/stereoselective glycosylation between the LacNPhth polyol acceptor and a sialyl phosphite donor. Starting from d-glucosamine hydrochloride, the target Neu5Ac-α-2,3-LacNPhth derivative was synthesized in a total yield of 18.5 % over only 10 steps.
- Zhang, Ying,Zhao, Fu-Long,Luo, Tao,Pei, Zhichao,Dong, Hai
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p. 223 - 234
(2018/12/05)
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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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- Conformational Distortion Using a Molecular Lever: Synthesis and Conformational Studies of Galactoside Derivatives
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Novel bicyclic d-galactose derivatives containing a molecular lever were synthesized and their conformations studied by 1H-NMR and crystallography. Increasing the bulkiness in the alkylidene ring in combination with introducing bulky O-protective groups on the pyranoside ring, causes a ring flip from a 4C1 into the axial rich 1C4 conformation. With less bulky protective groups, the pyranoside ring resides in the 4C1 conformation despite distortion of the external alkylidene ring.
- H?ner, Markus,Herrstedt Hammelev, Christian,Pedersen, Christian Marcus
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supporting information
p. 5532 - 5537
(2018/10/24)
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- ANTAGONISTS OF NK1 RECEPTORS DERIVED FROM CARBOHYDRATES, PRODUCTION METHOD AND MEDICAL USE
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The invention relates to a compound of general formula (I), and to the use thereof in medicine, or for the production of a medicament for the treatment of different diseases, preferably a cancer such as melanoma, lung carcinoma or breast cancer. For this purpose, the invention also relates to a pharmaceutical composition comprising said compound. In addition, the invention relates to a method for producing the compound of general formula (I).
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Page/Page column 0055; 0056
(2018/04/19)
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- Reengineering Chemical Glycosylation: Direct, Metal-Free Anomeric O-Arylation of Unactivated Carbohydrates
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To sustain innovation in glycobiology, effective routes to well-defined carbohydrate probes must be developed. For over a century, glycosylation has been dominated by the formation of the anomeric Csp3?O acetal junction in glycostructures. A dissociative mechanistic spectrum spanning SN1 and SN2 is frequently operational thereby reducing the efficiency. By reengineering this fundamental process, an orthogonal disconnection allows the acetal to be formed directly from the reducing sugar without the need for substrate pre-functionalisation. The use of stable aryliodonium salts facilitates a formal O?H functionalisation reaction. This allows lactols to undergo mild, metal-free O-arylation at ambient temperature. The efficiency of the transformation has been validated using a variety of pyranoside and furanoside monosaccharides in addition to biologically relevant di- and trisaccharides (up to 85 %). Fluorinated mechanistic probes that augment the anomeric effect were employed. It is envisaged that this strategy will prove expansive for the construction of complex acetals under substrate-based stereocontrol.
- Lucchetti, Nicola,Gilmour, Ryan
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supporting information
p. 16266 - 16270
(2018/10/24)
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- Secondary amine salt catalyzed controlled activation of 2-deoxy sugar lactols towards alpha-selective dehydrative glycosylation
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A new organocatalytic glycosylation method exploiting the lactol functionality has been disclosed. The catalytic generation of glycosyl oxacarbenium ions from lactols under forcible conditions via weakly Br?nsted-acidic, readily available secondary amine salts affects the diastereoselective glycosylation of 2-deoxypyranoses and furanoses. This operationally simple iminium catalyzed activation of 2-deoxy hemi-acetals is a potential alternative to the existing cumbersome methods that need specialized handling. The mechanisms for this unique transformation and kinetic/thermodynamic effects have been discussed based on both experimental evidence and theoretical studies.
- Ghosh, Titli,Mukherji, Ananya,Srivastava, Hemant Kumar,Kancharla, Pavan K.
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supporting information
p. 2870 - 2875
(2018/05/03)
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- Urea–hydrogen peroxide prompted the selective and controlled oxidation of thioglycosides into sulfoxides and sulfones
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A practical method for the selective and controlled oxidation of thioglycosides to corresponding glycosyl sulfoxides and sulfones is reported using urea–hydrogen peroxide (UHP). A wide range of glycosyl sulfoxides are selectively achieved using 1.5 equiv of UHP at 60 °C while corresponding sulfones are achieved using 2.5 equiv of UHP at 80 °C in acetic acid. Remarkably, oxidation susceptible olefin functional groups were found to be stable during the oxidation of sulfide.
- Singh, Adesh Kumar,Tiwari, Varsha,Mishra, Kunj Bihari,Gupta, Surabhi,Kandasamy, Jeyakumar
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supporting information
p. 1139 - 1144
(2017/06/20)
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- Synthesis and immunological evaluation of a low molecular weight saccharide with TLR-4 agonist activity
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The paucity of FDA approved adjuvants renders the synthesis, characterization, and use of new compounds as vaccine adjuvants, a necessity. For this purpose, a novel saccharide analog has been synthesized from glucosamine, pyruvylated galactose and 1,4-cyclohexanediol and its biological efficacy was determined in innate immune cells. More specifically, we assessed the production of pro-inflammatory cytokines from the murine monocyte cell line, Raw 264.7 and from C57 BL/6 mouse peritoneal macrophages following exposure to the saccharide analog. Our data conclude that the novel saccharide has immunostimulatory activity on mouse macrophages as indicated by the elevated levels of IL-6 and TNF-α in culture supernatants. This effect was TLR-4-dependent but TLR-2-independent. Our data, suggest TLR-4 agonism; a key feature of vaccine adjuvants.
- Basava, Vikram,Romlein, Heather,Bitsaktsis, Constantine,Marzabadi, Cecilia H.
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p. 697 - 705
(2017/01/03)
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- Chemical Synthesis of Modified Hyaluronic Acid Disaccharides
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Herein we report a chemical synthesis towards new modified hyaluronic acid oligomers by using only commercially available d-glucose and d-glucosamine hydrochloride. The various protected hyaluronic acid disaccharides were synthesized bearing new functional groups at C-6 of the β-d-glucuronic acid moiety with a view to structure-related biological activity tests. The orthogonal protecting group pattern allows ready access to the corresponding higher oligomers. Also, 1H NMR studies of the new derivatives demonstrated the effect of the various functional groups on the intramolecular electronic environment.
- Mende, Marco,Nieger, Martin,Br?se, Stefan
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supporting information
p. 12283 - 12296
(2017/09/14)
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- Dehydrative Thioglycosylation of 1-Hydroxyl Glycosides Catalyzed by In Situ-Generated AlI3
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Thioglycosylation of 1-hydroxyl glycosides catalyzed by in situ-generated AlI3 from elemental aluminium and molecular iodine has been developed. This method provides an alternative route to access anomeric thioglycosides without the use of hazard Lewis acidic activators or per-modified activated thiol sources. The major advantages of this dehydrative procedure are environmental friendly, ease of operation, high anomeric diastereoselectivity, and mild reaction conditions.
- Weng, Shiue-Shien,Hsieh, Kun-Yi,Zeng, Zih-Jian
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p. 464 - 473
(2017/05/19)
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- Synthesis of LewisX-O-Core-1 threonine: A building block for O-linked LewisX glycopeptides
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LewisX (LeX) is a branched trisaccharide Galβ1→4(Fucα1→3)GlcNAc that is expressed on many cell surface glycoproteins and plays critical roles in innate and adaptive immune responses. However, efficient synthesis of glycopeptides bearing LeX remains a major limitation for structure-function studies of the LeX determinant. Here we report a total synthesis of a LeX pentasaccharide 1 using a regioselective 1-benzenesulfinyl piperidine/triflic anhydride promoted [3 + 2] glycosylation. The presence of an Fmoc-threonine amino acid facilitates incorporation of the pentasaccharide in solid phase peptide synthesis, providing a route to diverse O-linked LeX glycopeptides. The described approach is broadly applicable to the synthesis of a variety of complex glycopeptides containing O-linked LeX or sialyl LewisX (sLeX).
- Sardar, Mohammed Y.R.,Krishnamurthy, Venkata R.,Park, Simon,Mandhapati, Appi Reddy,Wever, Walter J.,Park, Dayoung,Cummings, Richard D.,Chaikof, Elliot L.
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- Synthetic Routes toward Acidic Pentasaccharide Related to the O-Antigen of E. coli 120 Using One-Pot Sequential Glycosylation Reactions
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Concise syntheses of the acidic pentasaccharide, related to the O-antigenic polysaccharide of Escherichia coli 120, as its p-methoxyphenyl glycoside, have been achieved using a one-pot sequential glycosylation technique. The glycosylations have been accom
- Mukherjee, Mana Mohan,Ghosh, Rina
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supporting information
p. 5751 - 5760
(2017/06/07)
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- Oxidative activation of C-S bonds with an electropositive nitrogen promoter enables orthogonal glycosylation of alkyl over phenyl thioglycosides
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A method for the selective activation of thioglycosides that uses the N+-thiophilic reagent Omesitylenesulfonylhydroxylamine (MSH) as a promoter is presented. The reaction proceeds via anomeric mesitylensulfonate intermediates, which could be isolated and fully characterized by placing a fluorine atom at the C2 position. In the presence of a soft Lewis acid, glycosylation reaction proceeds at ambient temperature with good yields. It is further demonstrated that it is possible to orthogonally activate S-ethyl in the presence of S-phenyl donors, enabling the design of sequential glycosylation strategies.
- Kitowski, Annabel,Jiménez-Moreno, Ester,Salvadó, Míriam,Mestre, Jordi,Castillón, Sergio,Jiménez-Osés, Gonzalo,Boutureira, Omar,Bernardes, Gon?alo J.L.
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supporting information
p. 5490 - 5493
(2017/11/07)
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- Glycosyl Fluorides as Intermediates in BF3·OEt2-Promoted Glycosylation with Trichloroacetimidates
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Glycosyl fluorides have been found to be important intermediates in glycosylations with trichloroacetimidate donors and BF3·OEt2 activation (0.2–1 equiv.). Low-temperature NMR spectroscopy experiments revealed that the α-trichloroacetimidate was transformed into the glycosyl fluoride with inversion of stereochemistry, whereas the β anomer was not. A concerted mechanism was suggested for the stereospecific formation of glycosyl fluorides, which is not accounted for in the classic mechanism.
- Nielsen, Michael M.,Stougaard, Bolette A.,Bols, Mikael,Glibstrup, Emil,Pedersen, Christian M.
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supporting information
p. 1281 - 1284
(2017/03/17)
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- ANTIBODY CONJUGATES AND METHODS OF MAKING THE ANTIBODY CONJUGATES
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Described herein are antibody conjugates and methods of making antibody conjugates.
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Paragraph 0192
(2017/01/02)
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- Remote Electronic Effects by Ether Protecting Groups Fine-Tune Glycosyl Donor Reactivity
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It was established that para-substituted benzyl ether protecting groups affect the reactivity of glycosyl donors of the thioglycoside type with the N-iodosuccinimide/triflic acid promoter system. Having electron donating p-methoxybenzyl ether (PMB) groups increased the reactivity of the donor in comparison to having electron withdrawing p-chloro (PClB) or p-cyanobenzyl ether (PCNB) protecting groups, which decreased the reactivity of the glycosyl donor relative to the parent benzyl ether (Bn) protected glycosyl donor. These findings were used to perform the first armed-disarmed coupling between two benzylated glucosyl donors by tuning their reactivity. In addition, the present work describes a highly efficient palladium catalyzed multiple cyanation and methoxylation of p-chlorobenzyl protected thioglycosides. The results of this paper regarding both the different electron withdrawing properties of various benzyl ethers and the efficient and multiple protecting group transformations are applicable in general organic chemistry and not restricted to carbohydrate chemistry.
- Heuckendorff, Mads,Poulsen, Lulu Teressa,Jensen, Henrik H.
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p. 4988 - 5006
(2016/07/06)
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- Design, synthesis, and biological evaluation of crenatoside analogues as novel influenza neuraminidase inhibitors
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Natural products, especially derived from TCMH, have been found to exert antiviral effects against influenza virus. Crenatoside, a phenylethanoid glycoside from Pogostemon cablin Benth, which has been shown as a novel effective NA inhibitor previously, is considered as the leading compound for our further SARs studies. This work presented design, synthesis of novel crenatoside analogues from readily available d-Glucose and l-rhamnose in a convergent manner. Furthermore, their biological activities and SARs were also investigated. Especially, compound 2 h showed impressive IC50 = 27.77 μg/mL against NAs, which is 3 folds more potent than the leading compound crenatoside (IC50 = 89.81 μg/mL). These results would promise their therapeutic potential for influenza disease.
- Chen, Bao-Long,Wang, Ya-Jing,Guo, Hong,Zeng, Guang-Yao
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p. 199 - 205
(2016/01/16)
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