- Genetically Introducing Biochemically Reactive Amino Acids Dehydroalanine and Dehydrobutyrine in Proteins
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Expansion of the genetic code with unnatural amino acids (Uaas) has significantly increased the chemical space available to proteins for exploitation. Due to the inherent limitation of translational machinery and the required compatibility with biological settings, function groups introduced via Uaas to date are restricted to chemically inert, bioorthogonal, or latent bioreactive groups. To break this barrier, here we report a new strategy enabling the specific incorporation of biochemically reactive amino acids into proteins. A latent bioreactive amino acid is genetically encoded at a position proximal to the target natural amino acid; they react via proximity-enabled reactivity, selectively converting the latter into a reactive residue in situ. Using this Genetically Encoded Chemical COnversion (GECCO) strategy and harnessing the sulfur-fluoride exchange (SuFEx) reaction between fluorosulfate-l-tyrosine and serine or threonine, we site-specifically generated the reactive dehydroalanine and dehydrobutyrine into proteins. GECCO works both inter- and intramolecularly, and is compatible with various proteins. We further labeled the resultant dehydroalanine-containing protein with thiol-saccharide to generate glycoprotein mimetics. GECCO represents a new solution for selectively introducing biochemically reactive amino acids into proteins and is expected to open new avenues for exploiting chemistry in live systems for biological research and engineering.
- Yang, Bing,Wang, Nanxi,Schnier, Paul D.,Zheng, Feng,Zhu, He,Polizzi, Nicholas F.,Ittuveetil, Avinash,Saikam, Varma,Degrado, William F.,Wang, Qian,Wang, Peng G.,Wang, Lei
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- Lapachol acetylglycosylation enhances its cytotoxic and pro-apoptotic activities in HL60 cells
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Lapachol is a plant-derived naphthoquinone that kills several types of cancer cells. Derivatives of this molecule may therefore prove to be useful chemotherapeutic agents. In this study, we explored whether glycosylation increases the cytotoxic potency of lapachol towards HL-60 human leukemia cells. Two beta-glycosides were synthesized and characterized: LA4A (lapachol-β-glucoside) and LA4C (lapachol-N-acetylglucosamine-β-glucoside). The sugar moieties of both novel molecules were per-acetylated to facilitate cellular uptake. The IC50 values (in μM) for LA4A (5.7) and LA4C (5.3) were lower than those for lapachol (25). LA4A and LA4C triggered typical signs of apoptosis, such as the exposure of phosphatidylserine on the outside of cells, chromatin condensation, DNA fragmentation and a decrease of the mitochondrial transmembrane potential (ΔΨm) prior to cell lysis. Moreover, DNA fragmentation triggered by the lapachol-glycosides was reduced by pre-treatment with the caspase inhibitor, z-VAD-fmk. While LA4A and LA4C activated caspases-3, -8 and -9, lapachol failed to activate these apoptotic proteases, even when used at high concentrations. Finally, the toxicity of lapachol and its derivatives was also tested on non-tumor cells. We used human peripheral neurons (PeriTox test) to evaluate the side effect potential of these compounds. LA4C was clearly less toxic than LA4A. We conclude that LA4C had the most favorable profile as drug candidate (high tumor cell toxicity, reduced neurotoxicity). In general, this study shows that the cytotoxicity of lapachol towards HL-60 can be enhanced by glycosylation, and that the therapeutic ratio may be modified by the type of sugar added.
- Alves, Ricardo José,Holzer, Anna-Katharina,Kisitu, Jaffar,Leist, Marcel,Marques, Lucas Bonfim,Ottoni, Flaviano Melo,Pinto, Mauro Cunha Xavier,Ribeiro, Juliana Martins,Souza-Fagundes, Elaine Maria,Weinlich, Ricardo,de Sousa, Fernanda S.,de Victo, Nathalia Cruz
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- A triply divergent reagent for glycoprotein synthesis
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Chemical synthesis of glycoproteins through three different strategies, from the same reagent, is herein described. The flexibility of this system, which allows the comparison of different linkage motifs between the same glycan and protein, is shown by one-step diversification of a GlcNAc-ylating reagent and its application in both site-specific and non-site-specific glycoprotein synthesis to create different conjugates from common representative protein scaffolds.
- De Munari, Sonia,Schiffner, Torben,Davis, Benjamin G.
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- Radical-Mediated Acyl Thiol-Ene Reaction for Rapid Synthesis of Biomolecular Thioester Derivatives
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The thiol-ene ‘click’ reaction has emerged as a versatile process for carbon–sulfur bond formation with widespread applications in chemical biology, medicinal chemistry and materials science. Thioesters are key intermediates in a wide range of synthetic and biological processes and efficient methods for their synthesis are of considerable interest. Herein, we report the first examples of acyl-thiol-ene (ATE) for the synthesis of biomolecular thioesters, including peptide, lipid and carbohydrate derivatives. A key finding is the profound effect of the amino acid side chain on the outcome of the ATE reaction. Furthermore, radical generated thioesters underwent efficient S-to-N acyl transfer and desulfurisation to furnish ‘sulfur-free’ ligation products in an overall amidation process with diverse applications for chemical ligation and bioconjugation.
- Lynch, Dylan M.,McLean, Joshua T.,McSweeney, Lauren,Milbeo, Pierre,Scanlan, Eoin M.
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supporting information
p. 4148 - 4160
(2021/08/24)
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- ANTIFUNGAL PRODRUGS
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The invention relates to an antifungal prodrug which comprises an antifungal moiety which is linked to a trigger moiety by means of a self-immolative spacer. The trigger moiety is selected from glycosyl residues and oligosaccharides, stabilizes the self-immolative spacer and is cleavable by a pathogen hydrolytic enzyme which is preferably an extracellular glycosidase (EC 3.2.1). When the trigger moiety is cleaved by the pathogen hydrolytic enzyme, the self-immolative spacer undergoes a spontaneous degradation so as to release the antifungal moiety. The invention also relates to pharmaceutical compositions comprising said prodrug and to its use in the treatment of infectious diseases.
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Page/Page column 6; 27; 28
(2021/12/08)
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- Rapid access to Asp/Glu sidechain hydrazides as thioester precursors for peptide cyclization and glycosylation
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Head-to-sidechain macrocylic peptides, and neoglycopeptides, were readily prepared by site-specific amidation of aspartic and glutamic acid sidechain hydrazides. Hydrazides, serving as latent thioesters, were introduced through regioselective opening of the corresponding Nα-Fmoc protected anhydride precursors.
- Barnes, Natalie G.,Nyandoro, Kudakwashe,Jin, Hanzhang,Macmillan, Derek
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supporting information
p. 1006 - 1009
(2021/02/05)
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- One pot synthesis of thio -glycosides via aziridine opening reactions
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A one-pot aziridine opening reaction by glycosyl thiols generated in situ from the corresponding anomeric thio-acetates affords thio-glycosides with a pseudo-disaccharide structure and an N-linked tether. The scope of the one-pot aziridine opening reaction was explored on a series of mono- and disaccharides, creating a class of pseudo-glycosidic compounds with potential for further functionalization. Unexpected anomerization of glycosyl thiols was observed under the reaction conditions and the influence of temperature, base and solvent on the isomerization was investigated. Single isomers were obtained in good to acceptable yields for mannose, rhamnose and sialic acid derivatives. The class of thio-glycomimetics synthesized can potentially be recognized by various lectins, while presenting hydrolytic and enzymatic stability. The nitrogen functionality incorporated in the glycomimetics can be exploited for further functionalization, including tethering to linkers, scaffolds or peptide residues.
- Hribernik, Nives,Tamburrini, Alice,Falletta, Ermelinda,Bernardi, Anna
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supporting information
p. 233 - 247
(2021/01/14)
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- Novel hymexazol oxyglycoside conjugate as well as preparation and application thereof
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The invention discloses a preparation method and application of a novel hymexazol oxyglycoside conjugate bactericide. Galactose, mannose, glucose, mannosamine, galactosamine, glucosamine, N-acetyl-galactosamine, N-acetyl-mannosamine and acetylglucosamine are respectively conjugated with hymexazol to obtain a series of hymexazol oxyglycoside conjugates. The structural general formula of the compound is shown as I, R is hydroxyl, oxyacetyl, amino and acetamido, and R1 is hydrogen and acetyl. The conjugate disclosed by the invention is novel in structure, has good solubility and antifungal activity, and has the potential of becoming a novel green bactericide.
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Paragraph 0038; 0050
(2021/08/19)
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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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- Halomethyl-triazoles for rapid, site-selective protein modification
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Post-translational modifications (PTMs) are used by organisms to control protein structure and function after protein translation, but their study is complicated and their roles are not often well understood as PTMs are difficult to introduce onto proteins selectively. Designing reagents that are both good mimics of PTMs, but also only modify select amino acid residues in proteins is challenging. Frequently, both a chemical warhead and linker are used, creating a product that is a misrepresentation of the natural modification. We have previously shown that biotin-chloromethyl-triazole is an effective reagent for cysteine modification to give S-Lys derivatives where the triazole is a good mimic of natural lysine acylation. Here, we demonstrate both how the reactivity of the alkylating reagents can be increased and how the range of triazole PTM mimics can be expanded. These new iodomethyl-triazole reagents are able to modify a cysteine residue on a histone protein with excellent selectivity in 30 min to give PTM mimics of acylated lysine side-chains. Studies on the more complicated, folded protein SCP-2L showed promising reactivity, but also suggested the halomethyl-triazoles are potent alkylators of methionine residues.
- Brewster, Richard C.,Hulme, Alison N.
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- Bisubstrate Ether-Linked Uridine-Peptide Conjugates as O-GlcNAc Transferase Inhibitors
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The O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a master regulator of installing O-GlcNAc onto serine or threonine residues on a multitude of target proteins. Numerous nuclear and cytosolic proteins of varying functional classes, including translational factors, transcription factors, signaling proteins, and kinases are OGT substrates. Aberrant O-GlcNAcylation of proteins is implicated in signaling in metabolic diseases such as diabetes and cancer. Selective and potent OGT inhibitors are valuable tools to study the role of OGT in modulating a wide range of effects on cellular functions. We report linear bisubstrate ether-linked uridine-peptide conjugates as OGT inhibitors with micromolar affinity. In vitro evaluation of the compounds revealed the importance of donor substrate, linker and acceptor substrate in the rational design of bisubstrate analogue inhibitors. Molecular dynamics simulations shed light on the binding of this novel class of inhibitors and rationalized the effect of amino acid truncation of acceptor peptide on OGT inhibition.
- Makwana, Vivek,Ryan, Philip,Malde, Alpeshkumar K.,Anoopkumar-Dukie, Shailendra,Rudrawar, Santosh
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supporting information
p. 477 - 483
(2020/10/26)
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- Total Synthesis of Glycosylated Human Interferon-γ
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Interferon-γ(IFN-γ) is a glycoprotein that is responsible for orchestrating numerous critical immune induction and modulation processes and is used clinically for the treatment of a number of diseases. Herein, we describe the total chemical synthesis of homogeneously glycosylated variants of human IFN-γusing a tandem diselenide-selenoester ligation-deselenization strategy in the C- to N-terminal direction. The synthetic glycoproteins were successfully folded, and the structures and antiviral functions were assessed.
- Ashhurst, Anneliese S.,Dowman, Luke J.,Fairbanks, Antony J.,Kwan, Ann,Larance, Mark,Li, Henry Y.,Payne, Richard J.,Wang, Xiaoyi,Watson, Emma E.
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supporting information
p. 6863 - 6867
(2020/09/15)
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- INTRACELLULAR SUBSTANCE TRANSPORT SYSTEM AND USE THEREOF
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The present invention pertains to a complex including nanoparticles and, carried on the surface of the nanoparticles, a lysosomal enzyme inhibitor or kinase inhibitor shown by general formula (A) and a phospholipid mimetic substance shown by general formula (B). In general formula (A), n1 is an integer of 2-30, n2 is an integer of 2-30, the -S- terminal is a nanoparticle-carrying site, and R10 is a suicide substrate site or a kinase inhibition site. In general formula (B), n3 is an integer in the range of 2-30, and the -S- terminal is a nanoparticle-carrying site. The present invention provides a versatile system capable of efficiently delivering a drug to endolysosomes and allowing the drug to function at a low concentration on lysosomal enzymes, and an anticancer agent in which this system is used.
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Paragraph 0132-0134
(2020/05/29)
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- Glycosides and Glycoconjugates of the Diterpenoid Isosteviol with a 1,2,3-Triazolyl Moiety: Synthesis and Cytotoxicity Evaluation
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Several glycoconjugates of the diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) with a 1,2,3-triazolyl moiety were synthesized, and their cytotoxicity was evaluated against some human cancer and normal cell lines. Most of the synthesized compounds demonstrated weak inhibitory activities against the M-HeLa and MCF-7 human cancer cell lines. Three lead compounds, 54, 56 and 57, exhibited high selective cytotoxic activity against M-HeLa cells (IC50 = 1.7-1.9 μM) that corresponded to the activity of the anticancer drug doxorubicin (IC50 = 3.0 μM). Moreover, the lead compounds were not cytotoxic with respect to a Chang liver human normal cell line (IC50 > 100 μM), whereas doxorubicin was cytotoxic to this cell line (IC50 = 3.0 μM). It was found that cytotoxic activity of the lead compounds is due to induction of apoptosis proceeding along the mitochondrial pathway. The present findings suggest that 1,2,3-triazolyl-ring-containing glycoconjugates of isosteviol are a promising scaffold for the design of novel anticancer agents.
- Andreeva, Olga V.,Garifullin, Bulat F.,Sharipova, Radmila R.,Strobykina, Irina Yu.,Sapunova, Anastasiya S.,Voloshina, Alexandra D.,Belenok, Mayya G.,Dobrynin, Alexey B.,Khabibulina, Leysan R.,Kataev, Vladimir E.
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p. 2367 - 2380
(2020/08/28)
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- NOVEL IMMUNODULATING SMALL MOLECULES
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The present invention includes novel compositions and methods for treating comprising a compound with the Formula I: where n = 0-5; X = NH, O, S, CH2; Y = Phenyl, a phenyl group substituted with at least one methyl, a phenyl group substituted with at least one nitro, a phenyl group substituted with at least one nitrogen, a phenyl group substituted with at least one boron, aryl, substituted aryl, heteroaryl, four to six membered cycloalkyl, four to six membered heterocycloalkyl; R = H, C(O)R2, SO2R2; R1 = H, C(O)R2, SO2R2; R2 = Ethyl, methyl, isopropyl, n-propyl, t-butyl, n- butyl, NH2, NR3R4; R3, R4 = Ethyl, methyl, isopropyl, n-propyl, t-butyl, n-butyl, three to six membered cycloalkyl and Z = NH, O, S, CH2 or none, wherein the amount of the compound is selected to either inhibit or activate the immune response.
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Paragraph 0186
(2020/01/31)
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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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- Total synthesis of TRADD death domain with arginine N-GlcNAcylation by hydrazide-based native chemical ligation
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TNFR1-associated death domain protein (TRADD) with arginine N-GlcNAcylation is a novel and structurally unique posttranslational modification (PTM) glycoprotein that blocks the formation of death-inducing signaling complex (DISC), orchestrating host nuclear factor κB (NF-κB) signaling in entero-pathogenic Escherichia coli (EPEC)-infected cells. This particular glycosylated modification plays an extremely vital role for the effective colonization and pathogenesis of pathogens in the gut. Herein we describe the total synthesis of TRADD death domain (residues 195–312) with arginine235 N-GlcNAcylation (Arg-GlcNAc TRADD (195–312)). Two longish peptidyl fragments of the wild-type primary sequence were obtained by robust, microwave-assisted, highly efficient, solid-phase peptide synthesis (SPPS), the N-GlcNAcylated sector was built by total synthesis and attached specifically to resin-bound peptide with an unprotected ornithine residue via silver-promoted on-resin guanidinylation, Arg-GlcNAc TRADD (195–312) was constructed by hydrazide-based native chemical ligation (NCL). The facile synthetic strategy is expected to be generally applicable for the rapid synthesis of other proteins with Arg-GlcNAc modification and to pave the way for the related chemically biological study.
- Wu, Ye,Li, Yulei,Cong, Wei,Zou, Yan,Li, Xiang,Hu, Honggang
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supporting information
(2019/05/24)
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- Combining Click Reactions for the One-Pot Synthesis of Modular Biomolecule Mimetics
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Here, we report on the first combined one-pot use of the two so-called "click reactions": The thiol-ene coupling and the copper-catalyzed alkyne-azide cycloaddition. These reactions were employed in an alternating and one-pot fashion to combine appropriately functionalized monomeric carbohydrate building blocks to create mimics of trisaccharides and tetrasaccharides as single anomers, with only minimal purification necessary. The deprotected oligosaccharide mimics were found to bind both plant lectins and human galectin-3.
- Brink?, Anne,Risinger, Christian,Lambert, Annie,Blixt, Ola,Grandjean, Cyrille,Jensen, Henrik H.
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supporting information
p. 7544 - 7548
(2019/10/08)
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- Synthesis and Structure-Activity Relationship Study of Antimicrobial Auranofin against ESKAPE Pathogens
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Auranofin, an FDA-approved arthritis drug, has recently been repurposed as a potential antimicrobial agent; it performed well against many Gram-positive bacteria, including multidrug resistant strains. It is, however, inactive toward Gram-negative bacteria, for which we are in dire need of new therapies. In this work, 40 auranofin analogues were synthesized by varying the structures of the thiol and phosphine ligands, and their activities were tested against ESKAPE pathogens. The study identified compounds that exhibited bacterial inhibition (MIC) and killing (MBC) activities up to 65 folds higher than that of auranofin, making them effective against Gram-negative pathogens. Both thiol and the phosphine structures influence the activities of the analogues. The trimethylphosphine and triethylphosphine ligands gave the highest activities against Gram-negative and Gram-positive bacteria, respectively. Our SAR study revealed that the thiol ligand is also very important, the structure of which can modulate the activities of the AuI complexes for both Gram-negative and Gram-positive bacteria. Moreover, these analogues had mammalian cell toxicities either similar to or lower than that of auranofin.
- Wu, Bin,Yang, Xiaojian,Yan, Mingdi
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supporting information
p. 7751 - 7768
(2019/09/10)
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- DRUG DELIVERY
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A drug delivery vehicle comprising a vesicle conjugated to one or more targeting groups, wherein the targeting groups comprise an oligosaccharide which is Lewis A or Lewis B or a mimetic thereof, or a pharmaceutically acceptable salt or PEGylated form of the oligosaccharide : (I) wherein R represents the pointof attachment to the vesicle.10
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Page/Page column 22
(2019/11/19)
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- Synthesis and cytotoxicity evaluation of glycosidic derivatives of lawsone against breast cancer cell lines
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Breast cancer is the most incident and mortal cancer type in women, with an estimated 2 million new cases expected by 2020 worldwide, with 600,000 deaths. As not all breast cancer types respond to the anti-hormonal therapy, the development of new antineoplastic drugs is necessary. Lawsone (2-hydroxy-1,4-naphtoquinone) is a natural bioactive naphtoquinone displaying a range of activities, with dozens of derivatives described in the literature, including some glycosides possessing antitumor activity. Here, a series of glycosides of lawsone are reported for the first time and all compounds displayed good activity against the SKBR-3 cell line, with IC50 below 10 μM. The most promising derivative was the glycosyl triazole derived from peracetylated D-glucose (11), which showed better cytotoxicity against SKBR-3 (IC50 = 0.78 μM), being the most selective toward this tumoral cell (SI > 20). All compounds described in this work were more active than lawsone, indicating the importance of the carbohydrate and glycosyl triazole moiety for activity.
- Alves, Ricardo J.,Gomes, Eliza R.,Oliveira, M?nica C.,Ottoni, Flaviano M.,Pádua, Rodrigo M.,Silva, Izabella T.
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- Design, Synthesis, and Preliminary Biological Evaluation of GlcNAc-6P Analogues for the Modulation of Phosphoacetylglucosamine Mutase 1 (AGM1/PGM3)
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A library of GlcNAc 6- or 1-phosphate analogues was designed, and each compound was evaluated computationally through docking studies for its binding affinity to AGM1/PGM3. The compounds with the highest binding affinity, as ranked through a docking score, were synthesised and screened for their ability to inhibit the production of UDP-GlcNAc. A glycofused oxazoline analogue showed good inhibition, and gave significant results in vitro.
- Paiotta, Alice,D'Orazio, Giuseppe,Palorini, Roberta,Ricciardiello, Francesca,Zoia, Luca,Votta, Giuseppina,De Gioia, Luca,Chiaradonna, Ferdinando,La Ferla, Barbara
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p. 1946 - 1952
(2018/05/15)
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- Thioglycosides Are Efficient Metabolic Decoys of Glycosylation that Reduce Selectin Dependent Leukocyte Adhesion
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Small-molecule inhibitors of glycosylation can be applied in basic science studies, and clinical investigations as anti-inflammatory, anti-metastatic, and anti-viral therapies. This article demonstrates that thioglycosides represent a class of potent metabolic decoys that resist hydrolysis, and block E-selectin-dependent leukocyte adhesion in models of inflammation. Metabolic decoys are synthetic analogs of naturally occurring biosynthetic acceptors. These compounds divert cellular biosynthetic pathways by acting as artificial substrates that usurp the activity of natural enzymes. While O-linked glycosides are common, they are only partially effective even at millimolar concentrations. In contrast, we report that N-acetylglucosamine (GlcNAc) incorporated into various thioglycosides robustly truncate cell surface N- and O-linked glycan biosynthesis at 10–100 μM concentrations. The >10-fold greater inhibition is in part due to the resistance of thioglycosides to hydrolysis by intracellular hexosaminidases. The thioglycosides reduce β-galactose incorporation into lactosamine chains, cell surface sialyl Lewis-X expression, and leukocyte rolling on selectin substrates including inflamed endothelial cells under fluid shear. Treatment of granulocytes with thioglycosides prior to infusion into mouse inhibited neutrophil homing to sites of acute inflammation and bone marrow by ～80%–90%. Overall, thioglycosides represent an easy to synthesize class of efficient metabolic inhibitors or decoys. They reduce N-/O-linked glycan biosynthesis and inflammatory leukocyte accumulation.
- Wang, Shuen-Shiuan,Gao, Xuefeng,Solar, Virginia del,Yu, Xinheng,Antonopoulos, Aristotelis,Friedman, Alan E.,Matich, Eryn K.,Atilla-Gokcumen, G. Ekin,Nasirikenari, Mehrab,Lau, Joseph T.,Dell, Anne,Haslam, Stuart M.,Laine, Roger A.,Matta, Khushi L.,Neelamegham, Sriram
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p. 1519 - 5,1532
(2018/10/24)
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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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- Characterization of the single-subunit oligosaccharyltransferase STT3A from Trypanosoma brucei using synthetic peptides and lipid-linked oligosaccharide analogs
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The initial transfer of a complex glycan in protein N-glycosylation is catalyzed by oligosaccharyltransferase (OST), which is generally a multisubunit membrane protein complex in the endoplasmic reticulum but a single-subunit enzyme (ssOST) in some protists. To investigate the reaction mechanism of ssOST, we recombinantly expressed, purified and characterized the STT3A protein from Trypanosoma brucei (TbSTT3A). We analyzed the in vitro activity of TbSTT3A by synthesizing fluorescently labeled acceptor peptides as well as lipid-linked oligosaccharide (LLO) analogs containing a chitobiose moiety coupled to oligoprenyl carriers of distinct lengths (C10, C15, C20 and C25) and with different double bond stereochemistry. We found that in addition to proline, charged residues at the +1 position of the sequon inhibited glycan transfer. An acidic residue at the -2 position significantly increased catalytic turnover but was not essential, in contrast to the bacterial OST. While all synthetic LLO analogs were processed by TbSTT3A, the length of the polyprenyl tail, but not the stereochemistry of the double bonds, determined their apparent affinity. We also synthesized phosphonate analogs of the LLOs, which were found to be competitive inhibitors of the reaction, although with lower apparent affinity to TbSTT3A than the active pyrophosphate analogs.
- Ramírez, Ana S.,Boilevin, Jérémy,Biswas, Rasomoy,Gan, Bee Ha,Janser, Daniel,Aebi, Markus,Darbre, Tamis,Reymond, Jean-Louis,Locher, Kaspar P.
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p. 525 - 535
(2017/06/09)
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- Nickel-Catalyzed Azide-Alkyne Cycloaddition to Access 1,5-Disubstituted 1,2,3-Triazoles in Air and Water
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Transition-metal-catalyzed or metal-free azide-alkyne cycloadditions are methods to access 1,4- or 1,5-disubstituted 1,2,3-triazoles. Although the copper-catalyzed cycloaddition to access 1,4-disubstituted products has been applied to biomolecular reaction systems, the azide-alkyne cycloaddition to access the complementary 1,5-regioisomers under aqueous and ambient conditions remains a challenge due to limited substrate scope or moisture-/air-sensitive catalysts. Herein, we report a method to access 1,5-disubstituted 1,2,3-triazoles using a Cp2Ni/Xantphos catalytic system. The reaction proceeds both in water and organic solvents at room temperature. This protocol is simple and scalable with a broad substrate scope including both aliphatic and aromatic substrates. Moreover, triazoles attached with carbohydrates or amino acids are prepared via this cycloaddition.
- Kim, Woo Gyum,Kang, Mi Eun,Lee, Jae Bin,Jeon, Min Ho,Lee, Sungmin,Lee, Jungha,Choi, Bongseo,Cal, Pedro M. S. D.,Kang, Sebyung,Kee, Jung-Min,Bernardes, Gon?alo J. L.,Rohde, Jan-Uwe,Choe, Wonyoung,Hong, Sung You
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p. 12121 - 12124
(2017/09/12)
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- Modulating Antimicrobial Activity and Mammalian Cell Biocompatibility with Glucosamine-Functionalized Star Polymers
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The development of novel reagents and antibiotics for combating multidrug resistance bacteria has received significant attention in recent years. In this study, new antimicrobial star polymers (14-26 nm in diameter) that consist of mixtures of polylysine and glycopolymer arms were developed and were shown to possess antimicrobial efficacy toward Gram positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) (with MIC values as low as 16 μ mL-1) while being non-hemolytic (HC50 > 10 000 μ mL-1) and exhibit excellent mammalian cell biocompatibility. Structure function analysis indicated that the antimicrobial activity and mammalian cell biocompatibility of the star nanoparticles could be optimized by modifying the molar ratio of polylysine to glycopolymers arms. The technology described herein thus represents an innovative approach that could be used to fight deadly infectious diseases.
- Wong, Edgar H. H.,Khin, Mya Mya,Ravikumar, Vikashini,Si, Zhangyong,Rice, Scott A.,Chan-Park, Mary B.
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p. 1170 - 1178
(2016/03/22)
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- Synthesis and biological evaluation of novel C1-glycosyl thiazole derivatives as acetylcholinesterase inhibitors
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A new series of C1-glycosyl thiazole derivatives was synthesised by the reaction of 1-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranos-2-yl)thiourea with 2-bromoacetophenone derivatives. Subsequent removal of the acetyl groups were conducted using NaOMe-MeOH. The structures of all new products were confirmed by IR, 1H NMR and HRMS (ESI). The acetylcholinesterase inhibitory activities of these new compounds were tested. Among them, N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl)-4-(4-nitrophenyl)-1,3-thiazole-2-amine showed the best activity with an inhibition rate of 43.21%.
- Yin, Long,Cheng, Feng-Chang,Li, Qu-Xiang,Liu, Wei-Wei,Liu, Xiu-Jian,Cao, Zhi-Ling,Shi, Da-Hua
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p. 545 - 548
(2016/10/05)
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- Synthesis and study of N-acetyl d-glucosamine triazole derivatives as effective low molecular weight gelators
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Sugar based low molecular weight gelators have many potential uses for the formation of advanced soft materials. Here we have synthesized a series of peracetylated d-glucosamine triazole derivatives via the Cu catalyzed azide/alkyne cycloaddition reaction (CuAAc) and studied their self-assembling properties in several organic solvents, aqueous solutions, and water. Among the sixteen compounds synthesized and studied, many were able to function as organogelators for multiple solvents. Also seven compounds were able to form hydrogels at low concentrations such as 0.2-1.0 wt %. These indicate that peracetylated d-glucosamine triazole analogs are effective small molecular gelators.
- Mangunuru, Hari P.R.,Yerabolu, Jayasudhan Reddy,Wang, Guijun
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supporting information
p. 3361 - 3364
(2015/03/30)
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- Synthesis, characterization, and biological evaluation of some novel glycosyl 1,3,4-thiadiazole derivatives as acetylcholinesterase inhibitors
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The corresponding 4-substituted glycosyl thiosemicarbazide derivatives (6a-6l) were obtained by the reaction of glycosyl isothiocyanate 4 with various hydrazides. Further cyclization with the system of p-TsCl/TEA led to the formation of N-glycosyl-5-substituted 1,3,4-thiadiazole-2-amine (7a-7l). Subsequent removal of the acetyl groups were conducted using the system of NaOMe/MeOH. The chemical structures of all new products were confirmed by IR, 1H NMR and ESI-HRMS. The acetylcholinesterase (AChE) inhibitory activities of those compounds were tested by Ellman's method. Among them, the compound 8h possessed the best acetylcholinesterase-inhibition activity with IC50 of 18.38 ± 0.89 μM.
- Liu, Wei-Wei,Li, Qu-Xiang,Shi, Da-Hua,Cao, Zhi-Ling,Cheng, Feng-Chang,Tao, Chuan-Zhou,Yin, Long,Wang, Xuan
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p. 275 - 286
(2015/03/04)
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- Synthesis of the antimicrobial S-Linked glycopeptide, glycocin F
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The first total synthesis of glycocin F, a uniquely diglycosylated antimicrobial peptide bearing a rare S-linked N-acetylglucosamine (GlcNAc) moiety in addition to an O-linked GlcNAc, has been accomplished using a native chemical ligation strategy. The synthetic and naturally occurring peptides were compared by HPLC, mass spectrometry, NMR and CD spectroscopy, and their stability towards chymotrypsin digestion and antimicrobial activity were measured. This is the first comprehensive structural and functional comparison of a naturally occurring glycocin with an active synthetic analogue.
- Brimble, Margaret A.,Edwards, Pat J.,Harris, Paul W. R.,Norris, Gillian E.,Patchett, Mark L.,Wright, Tom H.,Yang, Sung-Hyun,Carley, Sarah E.
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supporting information
p. 3556 - 3561
(2015/03/04)
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- N-GLYCOSYLATION OF PEPTIDES AND PROTEINS
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A process for the production of a glycoconjugate by N-glycosylation of a protein or peptide comprising the sequence D/E-X-N-X-S/T, wherein each X is the same or different and is any natural amino acid other than proline, wherein the process comprises reacting the protein or peptide with a polyisoprenyl pyrophosphate of formula (I), or a salt thereof, in the presence of PglB: (I) to produce the glycoconjugate comprising the protein or peptide having a saccharide [SI] linked to the asparagine in the sequence D/E-X-N-X-S/T. Polyisoprenylpyrophosphates used as substrates in the biocatalytic process are also provided, as well as certain glycoconjugates.
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Page/Page column 28
(2015/05/05)
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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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- Design of glycosyltransferase inhibitors targeting human O-GlcNAc transferase (OGT)
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Inhibition of glycosyltransferases requires the design of neutral inhibitors to allow cell permeation in contrast to their natural dianionic substrates. O-GlcNAc transferase (OGT) is a key enzyme involved in dynamic glycosylation of cytosolic and nuclear proteins in competition with phosphorylation. Designing OGT inhibitors is of prime interest for the better understanding of its biological implications. Introduction of a pyridine moiety as a pyrophosphate surrogate was evaluated, which provided moderate in vitro inhibition of OGT. Docking studies highlighted some key features for the binding of the designed inhibitors to the catalytic site of OGT where the carbohydrate moiety did not occupy its natural position but rather turned away and pointed to the solvent outside the catalytic pocket. Further investigation with cellular assays did not provide inhibition of OGT. This lack of OGT inhibition was rationalized with a permeation assay which revealed the sequestration of the inhibitors at the membrane. This journal is the Partner Organisations 2014.
- Wang, Shuai,Shen, David L.,Lafont, Dominique,Vercoutter-Edouart, Anne-Sophie,Mortuaire, Marlène,Shi, Yun,Maniti, Ofelia,Girard-Egrot, Agnès,Lefebvre, Tony,Pinto, B. Mario,Vocadlo, David,Vidal, Sébastien
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supporting information
p. 1172 - 1178
(2014/08/05)
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- Synthesis of and specific antibody generation for glycopeptides with arginine N-GlcNAcylation
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As a unique and unappreciated protein posttranslational modification, arginine N-glycosylation was recently discovered to play an important role in the process that bacteria counteract host defenses. To provide chemical tools for further proteomic and biochemical studies on arginine N-glycosylation, we report the first general strategy for a rapid and costeffective synthesis of glycopeptides carrying single or multiple arginine N-GlcNAcyl groups. These glycopeptides were successfully utilized to generate the first antibodies that can specifically recognize arginine N-GlcNAcylated peptides or proteins in a sequence-independent manner.
- Pan, Man,Li, Shan,Li, Xiang,Shao, Feng,Liu, Lei,Hu, Hong-Gang
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supporting information
p. 14517 - 14521
(2015/02/05)
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- A simplified procedure for gram-scale production of sialylglycopeptide (SGP) from egg yolks and subsequent semi-synthesis of Man3GlcNAc oxazoline
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Heterogeneity of glycan structures in native glycoconjugates always hampers precise studies on carbohydrate-involved biological functions. To construct homogeneous glycoconjugates from natural resource of homogeneous glycans is therefore a practical approach to solve this problem. We report here an optimized procedure for gram-scale production of sialylglycopeptide (SGP) containing a disialyl biantennary complex-type N-glycan from egg yolks. Our new procedure simplified the extraction process by treating the egg yolk powder with 40% acetone, avoiding massive emulsification, high-speed centrifugation, and sophisticated chromatography in reported methods. Subsequent semi-synthesis of the N-glycan core Man3GlcNAc oxazoline from SGP was accomplished for the first-time via glyco-trimming and successive oxazoline formation. This efficient semi-synthesis provides an alternative to the pure chemical approach that involves multi-step total synthesis and facilitates the application of endo-glycosidase-enabled chemoenzymatic synthesis of various homogeneous glycoconjugates.
- Sun, Bingyang,Bao, Wenzheng,Tian, Xiaobo,Li, Mingjing,Liu, Hong,Dong, Jinhua,Huang, Wei
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supporting information
p. 62 - 69
(2014/09/30)
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- Rationally designed short polyisoprenol-linked PglB substrates for engineered polypeptide and protein N-glycosylation
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The lipid carrier specificity of the protein N-glycosylation enzyme C. jejuni PglB was tested using a logical, synthetic array of natural and unnatural C10, C20, C30, and C40 polyisoprenol sugar pyrophosphates, including those bearing repeating cis-prenyl units. Unusual, short, synthetically accessible C20 prenols (nerylnerol 1d and geranylnerol 1e) were shown to be effective lipid carriers for PglB sugar substrates. Kinetic analyses for PglB revealed clear KM-only modulation with lipid chain length, thereby implicating successful in vitro application at appropriate concentrations. This was confirmed by optimized, efficient in vitro synthesis allowing >90% of Asn-linked β-N-GlcNAc-ylated peptide and proteins. This reveals a simple, flexible biocatalytic method for glycoconjugate synthesis using PglB N-glycosylation machinery and varied chemically synthesized glycosylation donor precursors.
- Liu, Feng,Vijayakrishnan, Balakumar,Faridmoayer, Amirreza,Taylor, Thomas A.,Parsons, Thomas B.,Bernardes, Goncalo J.L.,Kowarik, Michael,Davis, Benjamin G.
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supporting information
p. 566 - 569
(2014/02/14)
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- Synthesis of novel glycosyl 1,3,4-oxadiazole derivatives
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A convenient and practical protocol was developed to synthesize glycosyl 1,3,4-oxadiazoles from d-glucosamine with good to excellent yields. The key step involved p-TsCl/pyridine-mediated cyclization under mild conditions. Subsequent removal of the acetyl groups in the last step, conducted using the system of NaOMe/MeOH, gave the desired N-acetyl-d-glucosamine 1,3,4-oxadiazole derivatives.
- Liu, Weiwei,Li, Quxiang,Cheng, Fengchang,Shi, Dahua,Cao, Zhiling
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p. 333 - 338
(2015/02/05)
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- INFLAMMATION IMAGING AND THERAPY
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An imaging agent comprising a conjugate of an oligosaccharide moiety with an imaging moiety. The oligosaccharide is Lewis A or Lewis B or a mimetic thereof, or a pharmaceutically acceptable salt or PEGylated form of Lewis A or Lewis B or its mimetics. Lewis A and Lewis B and its mimetics are also provided for use in the therapeutic treatment of inflammatory diseases, autoimmune diseases and cancer.
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Page/Page column 19; 20
(2014/03/22)
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- Glycosynthase with broad substrate specificity-an efficient biocatalyst for the construction of oligosaccharide library
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A versatile glycosynthase (TnG-E338A) with strikingly broad substrate scope has been developed from Thermus nonproteolyticus β-glycosidase (TnG) by using site-directed mutagenesis. The practical utility of this biocatalyst has been demonstrated by the facile generation of a small library containing various oligosaccharides and a steroidal glycoside (total 25 compounds) in up to 100 % isolated yield. Moreover, an array of eight gluco-oligosaccharides has been readily synthesized by the enzyme in a one-pot, parallel reaction, which highlights its potential in the combinatorial construction of a carbohydrate library that will assist glycomic and glycotherapeutic research. Significantly, the enzyme provides a means by which glycosynthase technology may be extended to combinatorial chemistry.
- Wei, Jinhua,Lv, Xun,Lue, Yang,Yang, Gangzhu,Fu, Lifeng,Yang, Liu,Wang, Jianjun,Gao, Jianhui,Cheng, Shuihong,Duan, Qian,Jin, Cheng,Li, Xuebing
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supporting information
p. 2414 - 2419
(2013/05/23)
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- Conversion of cysteine into dehydroalanine enables access to synthetic histones bearing diverse post-translational modifications
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Six for the price of one: From a single precursor, dehydroalanine, six distinct post-translational modifications can be site-selectively installed on histone proteins (see figure), including the first site-selective phosphorylation and glycosylation of histones. Direct observation of histone deacetylase activity on a full-length modified histone as well as its interactions with both chromatin reader and writer/eraser proteins are reported.
- Chalker, Justin M.,Lercher, Lukas,Rose, Nathan R.,Schofield, Christopher J.,Davis, Benjamin G.
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supporting information; experimental part
p. 1835 - 1839
(2012/04/04)
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- Rapid-throughput competitive colorimetric assay based on monosaccharide-capped gold nanoparticles for detecting lectin-protein interactions
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Identification of protein binding partners is one of key challenges in proteomics. A rapid-throughput competitive colorimetric assay is presented that uses gold nanoparticles capped by sugars such as mannopyranoside (Man-GNPs), N-acetylglucosamine (GlcNAc-GNPs), glucose (Glc-GNPs), or N-acetylgalactosamine (GalNAc-GNPs). The assay expediently detects protein- protein interactions in solution, particularly protein-lectin interactions. The competitive assays were conducted in microtiter plates; ten proteins (two glycoproteins and eight lectins) and three sugar-binding lectins (concanavalin A (ConA), wheat germ agglutinin (WGA), and Ricinus communis agglutinin (RCA120)) were combinatorially arranged in a 30-well plate, and constant concentrations of the monosaccharide-capped GNPs (sugar-GNPs) were added to each well. If interactions occurred between the proteins, the sugar-GNPs retained their burgundy color. If no interactions occurred between the proteins, the sugar-GNPs were agglomerated by the corresponding binding lectin, thus producing a blue color. Several new binding pairs were identified for the first time by using this assay, and the binding constants and stoichiometric ratios were determined on the basis of the wavelength shifts. The results were further verified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and fluorescence resonance energy transfer (FRET) spectroscopy. The assay is very sensitive, requiring only nanomolar protein concentrations.
- Tsai, Charng-Sheng,Chen, Chao-Tsen
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p. 314 - 322
(2013/01/13)
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- Rapid-throughput competitive colorimetric assay based on monosaccharide-capped gold nanoparticles for detecting lectin-protein interactions
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Identification of protein binding partners is one of key challenges in proteomics. A rapid-throughput competitive colorimetric assay is presented that uses gold nanoparticles capped by sugars such as mannopyranoside (Man-GNPs), N-acetylglucosamine (GlcNAc-GNPs), glucose (Glc-GNPs), or N-acetylgalactosamine (GalNAc-GNPs). The assay expediently detects protein-protein interactions in solution, particularly protein-lectin interactions. The competitive assays were conducted in microtiter plates; ten proteins (two glycoproteins and eight lectins) and three sugar-binding lectins (concanavalin A (ConA), wheat germ agglutinin (WGA), and Ricinus communis agglutinin (RCA120)) were combinatorially arranged in a 30-well plate, and constant concentrations of the monosaccharide-capped GNPs (sugar-GNPs) were added to each well. If interactions occurred between the proteins, the sugar-GNPs retained their burgundy color. If no interactions occurred between the proteins, the sugar-GNPs were agglomerated by the corresponding binding lectin, thus producing a blue color. Several new binding pairs were identified for the first time by using this assay, and the binding constants and stoichiometric ratios were determined on the basis of the wavelength shifts. The results were further verified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and fluorescence resonance energy transfer (FRET) spectroscopy. The assay is very sensitive, requiring only nanomolar protein concentrations.
- Tsai, Charng-Sheng,Chen, Chao-Tsen
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p. 314 - 322
(2014/01/17)
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- Chemo-enzymatic synthesis of functionalized oligomers of N-acetyllactosamine glycan derivatives and their immobilization on biomaterial surfaces
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Poly-N-acetyllactosamines (poly-LacNAc, [-3Gal(β1-4)GlcNAc(β1-] n) are terminal glycan structures present in glycoproteins and glycolipids. Their biological functions as ligands for galectins and as carriers of glycan epitopes are well documented. In the present paper we have characterized six novel functionalized β-d-GlcNAc derivatives, including aglyca of varying hydrophobicity and molecular weight, as substrates for recombinant human β1,4 galactosyltransferase 1 (β4GalT-1). The sugar derivatives carry short or long amino- or azide-terminated linker molecules for further modification or immobilization. The linker chemistry had an impact on enzyme kinetics and enzymatic syntheses of N-acetyllactosamine derivatives (LacNAc, Gal(β1-4)GlcNAc(β1-R). The combination of β4GalT-1 with bacterial β1,3-N-acetylglucosaminyltransferase (β3GlcNAc-T) resulted in the preparative syntheses of LacNAc oligomers with up to three LacNAc repeating units. All products were characterized by NMR and MS. The obtained LacNAc glycans were immobilized onto microtiter plates and their efficiency of binding of fungal galectin CGL2 was determined.
- Adamiak, Kathrin,Anders, Thorsten,Henze, Manja,Keul, Helmut,Moeller, Martin,Elling, Lothar
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p. 108 - 114
(2012/10/30)
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- Selenenylsulfide-linked homogeneous glycopeptides and glycoproteins: Synthesis of human "hepatic Se MetaboliteA"
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Introducing selenium: The synthesis and full characterization of human hepatic Se metaboliteA has been accomplished by using a robust, efficient, and Cys-specific selenenylation protocol (see scheme; NaPi=sodium phosphate). The selenenylsulfide linkage is sufficiently stable to allow quantification of Se-containing glycoconjugates in biological fluids by using atomic detection methods. Copyright
- Boutureira, Omar,Bernardes, Gonacalo J. L.,Fernandez-Gonzalez, Marta,Anthony, Daniel C.,Davis, Benjamin G.
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supporting information; experimental part
p. 1432 - 1436
(2012/03/27)
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- Native N-glycopeptide thioester synthesis through N→S acyl transfer
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Peptide thioesters are important tools for the total synthesis of proteins using native chemical ligation (NCL). Preparation of glycopeptide thioesters, that enable the assembly of homogeneously glycosylated proteins, is complicated by the perceived fragile nature of the sugar moiety. Herein, we demonstrate the compatibility of thioester formation via N→S acyl transfer with native N-glycopeptides and report observations that will aid in their preparation.
- Premdjee, Bhavesh,Adams, Anna L.,MacMillan, Derek
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supporting information; experimental part
p. 4973 - 4975
(2011/10/09)
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- Design and synthesis of O-GlcNAcase inhibitors via 'click chemistry' and biological evaluations
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Protein O-GlcNAcylation has been shown to play an important role in a number of biological processes, including regulation of the cell cycle, DNA transcription and translation, signal transduction, and protein degradation. O-GlcNAcase (OGA) is responsible for the removal of O-linked β-N-acetylglucosamine (O-GlcNAc) from serine or threonine residues, and thus plays a key role in O-GlcNAc metabolism. Potent OGA inhibitors are useful tools for studying the cellular processes of O-GlcNAc, and may be developed as drugs for the treatment neurodegenerative diseases. In this study, Cu(I)-catalyzed 'Click' cycloaddition reactions between glycosyl azides and alkynes were exploited to generate inhibitory candidates of OGA. Enzymatic kinetic screening revealed that compound 7 was a potent competitive inhibitor of human O-GlcNAcase (Ki = 185.6 μM). Molecular docking simulations of compound 7 into CpOGA (Clostridium perfringens OGA) suggested that strong π-π stacking interaction between the compound and W490 considerably contributed to improving the inhibitory activity. Crown Copyright
- Li, Tiehai,Guo, Lina,Zhang, Yan,Wang, Jiajia,Li, Zhonghua,Lin, Lin,Zhang, Zhenxing,Li, Lei,Lin, Jianping,Zhao, Wei,Li, Jing,Wang, Peng George
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scheme or table
p. 1083 - 1092
(2011/06/22)
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- Synthesis and antiviral activity of new substituted pyrimidine glycosides
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A number of N-substituted pyrimidine glycosides were synthesized by coupling reaction of the pyrimidine base with acetobromosugars followed by deprotection. The synthesized compounds were tested for their antiviral activity against Hepatitis B Virus (HBV). Plaque reduction infectivity assay was used to determine virus count reduction as a result of treatment with tested compounds which showed moderate to high anti viral activities.
- Ramiz, Mahmoud M. M.,El-Sayed, Wael A.,Hagag, Ezzat,Abdel-Rahman, Adel A.-H.
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experimental part
p. 1028 - 1038
(2011/11/29)
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- Synthesis and evaluation of anti-tubercular activity of new dithiocarbamate sugar derivatives
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The present study was undertaken to optimize the anti-tubercular activity of 2-acetamido-2-deoxy-β-d-glucopyranosyl N,N-dimethyldithiocarbamate (OCT313, Glc-NAc-DMDC), a lead compound previously reported by us. Structural modifications of OCT313 included the replacements of the DMDC group at C-1 by pyrrolidine dithiocarbamate (PDTC) and the acetyl group at C-2 by either propyl, butyl, benzyl or oleic acid groups. The antimycobacterial activities of these derivatives were evaluated against Mycobacterium tuberculosis (MTB). Glc-NAc-pyrrolidine dithiocarbamate (OCT313HK, Glc-NAc-PDTC) exhibited the most potent anti-tubercular activity with the minimal inhibitory concentration (MIC) of 6.25-12.5 μg/ml. The antibacterial activity of OCT313HK was highly specific to MTB and Mycobacterium bovis BCG, but not against Mycobacterium avium, Mycobacterium smegmatis, Staphylococcus aureus or Escherichia coli. Importantly, OCT313HK was also effective against MTB clinical isolates, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Interestingly, OCT313HK was exerted the primary bactericidal activity, and it was also exhibited the bacteriolytic activity at high concentrations. We next investigated whether the mycobacterial monooxygenase EthA, a common activator of thiocarbamide-containing anti-tubercular drugs, also activated OCT313HK. Contrary to our expectations, the anti-tubercular activity of dithiocarbamate sugar derivatives and dithiocarbamates were not dependent on ethA expression, in contrast to thiocarbamide-containing drugs. Overall, this study presents OCT313HK as a novel and potent compound against MTB, particularly promising to overcome drug resistance.
- Horita, Yasuhiro,Takii, Takemasa,Kuroishi, Ryuji,Chiba, Taku,Ogawa, Kenji,Kremer, Laurent,Sato, Yasuo,Lee, Yoosa,Hasegawa, Tomohiro,Onozaki, Kikuo
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scheme or table
p. 899 - 903
(2011/03/21)
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- Olefin cross-metathesis on proteins: Investigation of allylic chalcogen effects and guiding principles in metathesis partner selection
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Olefin metathesis has recently emerged as a viable reaction for chemical protein modification. The scope and limitations of olefin metathesis in bioconjugation, however, remain unclear. Herein we report an assessment of various factors that contribute to productive cross-metathesis on protein substrates. Sterics, substrate scope, and linker selection are all considered. It was discovered during this investigation that allyl chalcogenides generally enhance the rate of alkene metathesis reactions. Allyl selenides were found to be exceptionally reactive olefin metathesis substrates, enabling a broad range of protein modifications not previously possible. The principles considered in this report are important not only for expanding the repertoire of bioconjugation but also for the application of olefin metathesis in general synthetic endeavors.
- Lin, Yuya A.,Chalker, Justin M.,Davis, Benjamin G.
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supporting information; experimental part
p. 16805 - 16811
(2011/02/17)
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