- OLIGONUCLEOTIDE CONJUGATE COMPOSITIONS AND METHODS OF USE
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The disclosure relates to GalNAc moieties comprising at least one GalNAc monomer. The disclosure also relates to GalNAc-oligonucleotide conjugates comprising GalNAc moieties and oligonucleotides, e.g., saRNAs or siRNAs useful in regulating the expression of a target gene. Methods of using the GalNAc- oligonucleotide conjugates are also provided.
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Paragraph 0395
(2021/02/26)
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- Glycosyl Aldehydes: New Scaffolds for the Synthesis of Neoglycoconjugates via Bioorthogonal Oxime Bond Formation
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The straightforward preparation of glycosyl neoconjugates by oxime (or hydrazone) bond formation represents a key bioorthogonal tool in chemical biology. However, when this strategy is employed by reacting the reducing end of the glycan moiety, the configuration and the stereochemical information is lost due to partial (or complete) opening of the glycan cyclic hemiacetal and the formation of the corresponding opened tautomers. We have completed the synthesis of a library of glycosyl aldehydes to be used as scaffold for the synthesis of neoglycoconjugates via oxime bond formation. These glycosyl aldehydes constitute a simple and accessible alternative to avoid loss of chiral information when conjugating, by oxime (or hydrazone) bonds, the aldehyde functionality present at the reducing end of natural carbohydrates.
- Reina, José J.,Rioboo, Alicia,Montenegro, Javier
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p. 831 - 845
(2018/01/11)
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- Synthesis and biological evaluation of novel mono- and bivalent ASGP-R-targeted drug-conjugates
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Asialoglycoprotein receptor (ASGP-R) is a promising biological target for drug delivery into hepatoma cells. Nevertheless, there are only few examples of small-molecule conjugates of ASGP-R selective ligand equipped by a therapeutic agent for the treatment of hepatocellular carcinoma (HCC). In the present work, we describe a convenient and versatile synthetic approach to novel mono- and multivalent drug-conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose and anticancer drug – paclitaxel (PTX). Several molecules have demonstrated high affinity towards ASGP-R and good stability under physiological conditions, significant in vitro anticancer activity comparable to PTX, as well as good internalization via ASGP-R-mediated endocytosis. Therefore, the conjugates with the highest potency can be regarded as a promising therapeutic option against HCC.
- Petrov, Rostislav A.,Maklakova, Svetlana Yu.,Ivanenkov, Yan A.,Petrov, Stanislav A.,Sergeeva, Olga V.,Yamansarov, Emil Yu.,Saltykova, Irina V.,Kireev, Igor I.,Alieva, Irina B.,Deyneka, Ekaterina V.,Sofronova, Alina A.,Aladinskaia, Anastasiia V.,Trofimenko, Alexandre V.,Yamidanov, Renat S.,Kovalev, Sergey V.,Kotelianski, Victor E.,Zatsepin, Timofey S.,Beloglazkina, Elena K.,Majouga, Alexander G.
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p. 382 - 387
(2017/12/26)
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- Synthesis and biological evaluation of novel doxorubicin-containing ASGP-R-targeted drug-conjugates
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Asialoglycoprotein receptor (ASGP-R) belongs to a wide family of C-type lectins and it is currently regarded as an attractive protein in the field of targeted drug delivery (TDD). It is abundantly expressed in hepatocytes and can be found predominantly on the sinusoidal surface especially of HepG2 cells. Therefore, ASGP-R can be used for the TDD of anticancer therapeutics against HCC and molecular diagnostic tools. To date, a variety of mono- and multivalent selective ASGP-R ligands have been discovered. Although many of these compounds have demonstrated a relatively high binding affinity towards the target, the reported synthetic schemes are not handled, complicated and include many non-trivial steps. In the current study, we describe a convenient and versatile synthetic approach to novel monovalent drug-conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose fragment as an ASGP-R-recognition “core-head” and well-known nonselective cytostatic – Doxorubicin (Dox). This is the first example of the direct conjugation of a drug molecule to the ASGP-targeted warhead by a really convenient manner via a simple linker sequence. The performed MTS-based biological evaluation in HepG2 cells revealed the novel conjugates as having anticancer activity. Confocal microscopy showed that the molecules readily penetrated HepG2 membrane and were mainly localized within the cytoplasm instead of the nucleus. Per contra, Dox under the same conditions demonstrated good anticancer activity and was predominantly concentrated in the nucleus. Therefore, we speculate that the amide “trigger” that we have used in this study for linker attachment is a sufficiently stable inside the cells to be enzymatically or spontaneously degraded. As a consequence, we did not observe the release of the drug. Ligands containing triggers that are more liable towards endogenous hydrolysis within the tissue of targeting are strongly required.
- Ivanenkov, Yan A.,Majouga, Alexander G.,Petrov, Rostislav A.,Petrov, Stanislav A.,Kovalev, Sergey V.,Maklakova, Svetlana Yu.,Yamansarov, Emil Yu.,Saltykova, Irina V.,Deyneka, Ekaterina V.,Filkov, Gleb I.,Kotelianski, Victor E.,Zatsepin, Timofey S.,Beloglazkina, Elena K.
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p. 503 - 508
(2018/01/02)
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- Exploring the Structural Space of the Galectin-1–Ligand Interaction
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Galectin-1 is a tumor-associated protein recognizing the Galβ1-4GlcNAc motif of cell-surface glycoconjugates. Herein, we report the stepwise expansion of a multifunctional natural scaffold based on N-acetyllactosamine (LacNAc). We obtained a LacNAc mimeti
- Bertleff-Zieschang, Nadja,Bechold, Julian,Grimm, Clemens,Reutlinger, Michael,Schneider, Petra,Schneider, Gisbert,Seibel, Jürgen
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p. 1477 - 1481
(2017/08/10)
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- Stereoselective dihydroxylation reaction of alkenyl β- D -hexopyranosides: A methodology for the synthesis of glycosylglycerol derivatives and 1-O-Acyl-3-O-β- D -glycosyl-sn-glycerol analogues
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A variety of new glycosylglycerol derivatives have been prepared by stereoselective dihydroxylation of a range of alkenyl β-D-hexopyanosides under Donohoe's conditions. We have studied the relationship between the diastereoisomeric excess and the structural features of the precursor (sugar and alkenyl moieties). The stereochemical yields demonstrated that the presence of a hydrogen-bond donor group (OH, NHAc) at the 2-position of the sugar moiety is required to obtain high levels of stereofacial discrimination. New 1-O-acyl-3-O-β-D-glycosyl-sn-glycerol analogues were obtained by functionalisation of the primary hydroxy group with a fatty acid. Preliminary cytotoxic activity assays of both glycosylglycerol and glycoglycerolipid analogues are also presented. An efficient asymmetric dihydroxylation reaction of alkenyl β-D-hexopyranoside derivatives is described. New glycosylglycerol and glycoglycerolipid analogues have been synthesised by this methodology. Preliminary cytotoxic activity assays are presented. Copyright
- Vega-Perez, Jose M.,Palo-Nieto, Carlos,Perinan, Ignacio,Vega-Holm, Margarita,Calderon-Montano, Jose M.,Lopez-Lazaro, Miguel,Iglesias-Guerra, Fernando
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experimental part
p. 1237 - 1252
(2012/04/10)
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- Structurally diverse disaccharide analogs of antifreeze glycoproteins and their ability to inhibit ice recrystallization
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The β-D-galactosyl-(1,3)-α-N-acetyl-D-galactosamine disaccharide is present in antifreeze glycoproteins (AFGPs). Analogs of this disaccharide including the β-linked (1,3)-, (1,4)-, and (1,6)-galactosyl-N-acetyl galactosamine and the β-(1,3)-galactosyl-galactoside were synthesized and evaluated for ice recrystallization inhibition (IRI) activity. The results from this study demonstrate that the b-linked-(1,4) disaccharide exhibits more potent IRI activity than the native b-linked-(1,3) disaccharide. The C2 N-acetyl group of the disaccharide does not affect IRI activity but in monosaccharides, the presence of the C2 N-acetyl group decreases IRI activity. The current study will facilitate the design of potent small-molecule ice recrystallization inhibitors.
- Balcerzak, Anna K.,Ferreira, Sandra S.,Trant, John F.,Ben, Robert N.
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p. 1719 - 1721
(2012/04/04)
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- Synthesis of benzaldehyde-functionalized glycans: A novel approach towards glyco-SAMs as a tool for surface plasmon resonance studies
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In recent years the interest in tools for investigating carbohydrateprotein (CPI) and carbohydrate-carbohydrate interactions (CCI) has increased significantly. For the investigation of CPI and CCI, several techniques employing different linking methods are available. Surface plasmon resonance (SPR) imaging is a most appropriate tool for analyzing the formation of self-assembled monolayers (SAM) of carbohydrate derivatives, which can mimic the glycocalyx. In contrast to the SPR imaging methods used previously to analyze CPI and CCI, the novel approach reported herein allows a facile and rapid synthesis of linker spacers and carbohydrate derivatives and enhances the binding event by controlling the amount and orientation of ligand. For immobilization on biorepulsive amino-functionalized SPR chips by reductive amination, diverse aldehyde-functionalized glycan structures (glucose, galactose, mannose, glucosamine, cellobiose, lactose, and lactosamine) have been synthesized in several facile steps that include olefin metathesis. Effective immobilization and the first binding studies are presented for the lectin concanavalin A.
- Kopitzki, Sebastian,Jensen, Knud J.,Thiem, Joachim
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supporting information; experimental part
p. 7017 - 7029
(2010/09/10)
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- SYNTHESIS OF CORE SUGAR CHAIN STRUCTURE OF ASPARGINE-LINKED GLYCOPROTEIN
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It is intended to chemically synthesize the trisaccharide moiety at the reducing end in the core sugar chain structure of an asparagine-linked glycoprotein. By using a highly inexpensive natural polysaccharide having a mannose β-1,4-bond as the starting m
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Page/Page column 15-16
(2008/06/13)
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- Parallel solid phase synthesis of tricomponent bisubstrate analogues as potential fucosyltransferase inhibitors
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A combinatorial library of 32 tricomponent bisubstrate fucosyltransferase analogs has been generated using solid-phase peptide synthesis with orthogonally protected lysine as a scaffold.
- Filippov, Dmitri V.,Van Den Elst, Hans,Tromp, Cornelia M.,Van Der Marel, Gijs A.,Van Boeckel, Constant A. A.,Overkleeft, Herman S.,Van Boom, Jacques H.
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p. 773 - 778
(2007/10/03)
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- Design of N-acetyl-6-sulfo-β-D-glucosaminide-based inhibitors of influenza virus sialidase
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Biological activity of N-acetyl-6-sulfo-β-D-glucosaminides (6-sulfo-GlcNAc 1) having a structural homology to N-acetylneuraminic acid (Neu5Ac 2) and 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en 3) was examined in terms of inhibitory activity against influenza virus sialidase (influenza, A/Memphis/1/71 H3N2). pNP 6-Sulfo-GlcNAc 1a was proved to show substantial activity to inhibit the virus sialidase (IC50=2.8 mM), though p-nitrophenyl (pNP) GlcNAc without 6-sulfo group and pNP 6-sulfo-GlcNH3+ 1b without 2-NHAc showed little activity (IC50 >50 mM). The activity was enhanced nearly 100-fold when the pNP group of 1a was converted to p-acetamidophenyl one 5 (IC50=30 μM) or replaced with 1-naphthyl 6 (IC50=10 μM) or n-propyl one 8 (IC50=11 μM).
- Sasaki, Kenji,Nishida, Yoshihiro,Kambara, Mikie,Uzawa, Hirotaka,Takahashi, Tadanobu,Suzuki, Takashi,Suzuki, Yasuo,Kobayashi, Kazukiyo
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p. 1367 - 1375
(2007/10/03)
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- The isolation and synthesis of two novel N-acetyl glucosamine derivatives from Dictyostelium cellular slime molds which exhibit neurite outgrowth activity
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To clarify the diversity of secondary metabolites of Dictyostelium cellular slime molds and explore any biologically active substances which they may hold, constituents of two species were investigated. From a methanol extract of their fruit bodies, two novel acylated amino sugars were isolated, dictyoglucosamine A (1) from D. purpureum and dictyoglucosamine B (2) from D. discoideum. For further analysis, these compounds were then synthesized from N-acetyl-D-glucosamine. Biological evaluation of 1 and 2 showed they induce neuronal differentiation of rat pheochromocytoma (PC-12) cells.
- Kikuchi, Haruhisa,Komiya, Jun,Saito, Yoshinori,Sekiya, Jun-Ichi,Honma, Shigeyoshi,Nakahata, Norimichi,Oshima, Yoshiteru
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p. 1477 - 1480
(2007/10/03)
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- Stereoselective synthesis of epoxyalkyl glycoside precursors of glycosyl glycerol analogues from alkenyl glycosides of N-acetyl-D-glucosamine derivatives
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The synthesis of epoxyalkyl glycoside derivatives of N-acetyl-D-glucosamine is described. Epoxidation of the corresponding alkenyl glycosides with m-CPBA took place with different stereoselectivity depending on the nature of the unsaturated system and the protecting groups on the sugar moiety. The configuration of the newly formed stereogenic centres has been confirmed unequivocally by chemical correlation.
- Vega-Perez, Jose M.,Candela, Jose I.,Blanco, Eugenia,Iglesias-Guerra, Fernando
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p. 2471 - 2483
(2007/10/03)
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- Synthesis and conjugation of oligosaccharide fragments related to the immunologically reactive part of the circulating anodic antigen of the parasite Schistosoma mansoni
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The immunoreactive part of the circulating anodic antigen (CAA) from the parasite Schistosoma mansoni is a threonine-linked polysaccharide consisting of →6)-[β-D-GlcpA-(1→3)]-β-D-GalpNAc-(1→ repeating disaccharides. In the framework of an immunochemical p
- Vermeer, Henricus J.,Halkes, Koen M.,Van Kuik, J. Albert,Kamerling, Johannis P.,Vliegenthart, Johannes F.G.
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p. 2249 - 2263
(2007/10/03)
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- New α-selective thermal glycosylation of acetyl-protected 2-acetamido-2-deoxy-β-D-glucopyranosyl diphenylphosphinate
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This paper describes new α-selective thermal glycosylation using acetyl-protected 2-acetamido-2-deoxy-β-D-glucopyranosyl diphenylphosphinate (4) as a glycosyl donor. When the glycosylation of 4 with 1-hexanol was carried out under various conditions, the conditions using trimethylsilyl trifluoromethanesulfonate as a promoter in nitromethane at reflux temperature were most suitable for the formation of the α anomer. The glycosylation of 4 with the other common alcohols gave corresponding α-glycosides in relatively high yields under the conditions. When cholesterol, a very steric hindered alcohol, was used as a glycosyl acceptor, α-glycoside was also produced predominantly. Copyright (C) 2000 Elsevier Science Ltd.
- Kadokawa, Jun-ichi,Nagaoka, Takeshi,Ebana, Jun,Tagaya, Hideyuki,Chiba, Koji
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p. 341 - 344
(2007/10/03)
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- Chemical synthesis of N-acetylglucosamine derivatives and their use as glycosyl acceptors by the Mesorhizobium loti chitin oligosaccharide synthase NodC
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Rhizobial bacteria synthesize lipo-chitin oligosaccharide signal molecules (Nod factors) that are essential for the formation of symbiotic organs on the roots of host plants, a process known as nodulation. Biosynthesis of the chitin oligosaccharide moiety
- Kamst, Eric,Zegelaar-Jaarsveld, Korien,Van Der Marel, Gijs A.,Van Boom, Jacques H.,Lugtenberg, Ben J.J.,Spaink, Herman P.
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p. 176 - 189
(2007/10/03)
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- Conformational differences between Fuc(α1-3)GlcNAc and its thioglycoside analogue
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NOE measurements and molecular mechanics calculations have been performed to study the conformational behaviour of Fuc(α1-3)GlcNAc and its thioglycoside analogue in solution. Experimental data show that, in contrast with the natural O-disaccharide, which
- Aguilera, Begona,Jimenez-Barbero, Jesus,Fernandez-Mayoralas, Alfonso
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- The asymmetric dihydroxylation of some alkenyl 2-acetylamino-2-deoxy-β-d-glucopyranosides: The preparation of optically pure epoxides as putative inhibitors of chitinases
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Various alkenyl 2-acetylamino-2-deoxy-β-D-glucopyranosides have been subjected to the Sharpless asymmetric dihydroxylation protocol to yield the corresponding diols, albeit with somewhat disappointing stereoselectivity. An alternative, more traditional ap
- Fairweather, Jon K.,Stick, Robert V.,Tilbrook, D. Matthew G.
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p. 471 - 482
(2007/10/03)
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- Stereselectivity control in anomeric O-alkylation. Application to the synthesis of C2 symmetric glycoconjugates
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Tetrbutylammonium salts strongly influence the stereoselectivity of O-anomeric alkylation and allows to shift from β to α selectivity. Allyl glucosaminide 7 prepared in this way, was used to synthesize die new type of C2 symmetric neoglycoconju
- Lubineau,Escher,Alais,Bonnaffe
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p. 4087 - 4090
(2007/10/03)
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- New procedure for the preparation of 2-(trimethylsilyl)ethyl 2-acetamido-2-deoxy-3,4,6-tri-O-acetyl-β-D-glucopyranoside and other alkyl β-glycosides
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The title compound and other alkyl β-glycosides 1a-g can be prepared in one step from commercially available 2-acetamido-2-deoxy-1,3,4,6-tetra-O-acetyl-β-D-glucopyranose (3) and simple alcohols using camphorsulfonic acid as a promoter together with azeotr
- Sowell, C. Gregory,Livesay, Mark T.,Johnson, David A.
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p. 609 - 610
(2007/10/02)
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- Preparation and characterization of N-chitosan derivatives
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Allyl glycosides of 8 simple sugars have been prepared and characterized, including 1H-and 13C-NMR assignments.Formylmethyl glycosides, obtained by reductive ozonolysis of the allyl glycosides, have been reductively N-alkylated to chitosan with typical yields of 80percent.The glycosides of α- and β-D-glucopyranose, α- and β-D-galactopyranose, 2-acetamido-2-deoxy-α- and β-D-glucopyranose, β-D-glucuronic acid, and β-lactose have been incorporated by this method.The degree of substitution (d.s.) of the products was controlled by varying the molar ratio of glycoside to free amine groups of chitosan by between 0.5 and 3.0.Derivatives of degree of substitution >0.3 were typically water soluble, and compounds of higher d.s. generally gave less-viscous aqueous solutions.Assignment of 13C-NMR chemical shifts verified the structure of these derivatives.The linewidths of the branch resonances (5-100 Hz) provided qualitative information about the relationship between d.s. and branch mobility.The resonances of high-d.s. products were narrower and more intense than analogous low-d.s. derivatives.The chitosan resonances of the backbone were generally broader (50-200 Hz) and less intense, and as a result were difficult to assign fully.
- Holme, Kevin R.,Hall, Laurance D.
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p. 291 - 306
(2007/10/02)
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- Synthesis of N-acetylsugar-β-trans-glycosides: Facile one-pot transglycosylation of epoxypentyl tri-0-acetyl-N-acetylglucosamine
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Glycosides 10 and 11 were prepared from epoxypentyl β-D-N-acetylglucosamine 8 under mild conditions, using TMS triflate as the promotor. Presumably, this novel reaction proceeds via in situ activation of the intermediate oxazoline 9.
- Boldt,Schumacher-Wandersleb,Peter
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p. 1413 - 1416
(2007/10/02)
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- A NEW SYNTHESIS OF 1,2-TRANS-2-ACETAMIDO-2-DEOXYGLYCOPYRANOSIDES VIA 1,2-TRANS-2-DEOXY-2-IODOGLYCOSYL AZIDES
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Trans-addition of iodoazide to the double bond of 3,4,6-tri-O-acetyl-1,5-anhydro-D-arabino-hex-1-enitol yielded 2-deoxy-2-iodoglycosyl azides, which are percursors of 1,2-trans-2-amino-2-deoxyglycopyranosides when treated by an alcohol in the presence of triphenylphosphine.
- Lafont, Dominique,Guilloux, Pascal,Descotes, Gerard
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- Synthesis of D-galactosamine derivatives and binding studies using isolated rat hepatocytes.
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Derivatives of glycosides of D-galactosamine were prepared in order to study further the binding requirement of the Gal/GalNAc receptor in mammalian hepatocytes. These structures included N-propanoyl, N-benzoyl, and N,N-phthaloyl derivatives of 2-hydroxye
- Wong,Townsend,Lee
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- Protected glycosides and disaccharides of 2-amino-2-deoxy-D-glucopyranose by ferric chloride-catalyzed coupling.
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The ferric chloride-catalyzed glycosylation of hydroxy compounds by protected 2-acylamino-2-deoxy-beta-D-glucopyranose 1-acetates is described. In addition to known glycosides from the reaction of alcohols with 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-beta-D-glucopyranose (3), ally (and other alkyl) beta-glycosides were obtained from the N-benzoyl, N-phenoxyacetyl, N-methoxyacetyl, N-chloroacetyl, and N-phthaloyl congeners of 3. The latter compounds, except for the N-phthaloyl derivative, gave oxazolines in the absence of an alcoholic reactant. Compound 3 and the related N-benzoyl, N-chloroacetyl, N-acetyl-3,4,6-tri-O-benzyl, and N-acetyl-4-O-acetyl-3,6-di-O-benzyl derivatives were coupled to one or more protected sugars to form protected, beta-linked disaccharides. Coupling at the 6-positions of acceptors proceeded smoothly and gave 67-80% yields. For successful coupling at positions 3 and 4, long reaction times and multiple additions of glycosyl donor were required, and yields ranged from 60% to as low as 30%. 1,3,4,6-Tetra-O-acetyl-2-(chloroacetamido)-2-deoxy-beta-D- glucopyranose appeared to be the most reactive glycosyl donor in this series. The reaction of 2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-alpha-D-glucopyrano)[2,1- d]-2-oxazoline (derived from 3) with allyl alcohol was catalyzed by ferric chloride, and oxazolines were detected as intermediates in some of the glycosylations of protected sugars.
- Kiso,Anderson
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p. 309 - 323
(2007/10/02)
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