79360-05-7Relevant articles and documents
Synthesis of glycodendrimers by modification of poly(propylene imine) dendrimers
Ashton, Peter R.,Boyd, Sue E.,Brown, Christopher L.,Nepogodiev, Sergey A.,Meijer,Peerlings,Stoddart, J. Fraser
, p. 974 - 984 (1997)
The use of preformed poly-(propylene imine) dendrimers (DAB-dendr- (NH2)(x)) for the rapid and facile construction of high molecular weight carbohydrate-coated dendrimers (glycodendrimers) is presented. An efficient attachment of spacer-armed derivatives of D-galactose and lactose to the primary amino end groups of DAB-dendr (NH2)(x) has been achieved by means of amide bond formation, using the N-hydroxysuccinimide coupling procedure. Acetate protecting groups have been employed in order to avoid side reactions at the coupling stage. Deacetylation leads to the target glycodendrimers. The reactivity of all the available DAB dendr-(NH2)(x) (generations 1-5) has been investigated and a series of homologous carbohydratecoated dendrimers have been synthesized. In addition, the attachment of larger saccharide moieties has been demonstrated by the condensation of a trisgalactoside cluster with DAB-dendr-(NH2)(x) carrying both four and eight primary amino groups. The regularity of the glycodendrimers has been proven by NMR spectroscopy, and the molecular weights of the low-generation carbohydrate-coated dendrimers have been determined by mass spectrometry. Modifications of DAB dendr (NH2)(x) with biologically active carbohydrates affords a new and simple approach to high molecular weight tom pounds that may be considered as neoglycoconjugates with perfectly symmetrical structures and that offer much promise as multivalent ligands involved in carbohydrate protein interactions.
Synthesis of cell-penetrating S-galactosyl-oligoarginine peptides as inducers of recombinant protein expression under the control of lac operator/repressor systems
Mizuta, Yukina,Takasu, Akinori,Higuchi, Masahiro
, p. 677 - 683 (2013)
The synthesis of glycodendrimers and glycopoly(oxazoline)s as inducers of recombinant protein expression has recently been reported; however, these compounds induced the expression of only small amounts of the green fluorescence protein (GFP), which was used as the model recombinant protein, because of their poor ability to penetrate the Escherichia coli cell membrane. Therefore, S-galactosyl-oligo(Arg) conjugates have now been synthesized to overcome this problem. Following in vivo expression of GFP induced by each of the S-galactosyl (Arg)n constructs (n=5, 6, 8) at the T5 promoter in E. coli for 18 hours, we visually observed that the cultures fluoresced green light when excited with UV light. The fluorescent intensities for these cultures were greater than that found for a control culture, which indicates that the peptides had induced GFP expression. Quantitative fluorescent measurements also supported the observations that the peptides were better inducers of GFP expression than the galactosyl dendrimers and the poly(oxazoline)s and the natural inducer lactose. Because the level of GFP expression was directly related to the number of arginine moieties in each peptide, we propose that the number of arginine moieties is responsible for how well each peptide passes through the E. coli membrane, which affects the expression level. A similar tendency was observed when the T7 promoter was placed upstream from the gene for an artificial extracellular matrix protein and the S-Gal-oligo(Arg) peptides were used as inducers. To assess how the distance between two galactosyl moieties as well as how the multivalent effect (cluster effect) in an oligo(Arg) inducer affects the expression level of GFP, we synthesized a conjugate of Lys(Arg)8 (Lys=lysine) and two S-galactosyls, which enhanced the expression of GFP in comparison with that obtained for S-Gal(Arg)8. Copyright
Design and synthesis of bis-biotin-containing reagents for applications utilizing monoclonal antibody-based pretargeting systems with streptavidin mutants
Wilbur, D. Scott,Park, Steven I.,Chyan, Ming-Kuan,Wan, Feng,Hamlin, Donald K.,Shenoi, Jaideep,Lin, Yukang,Wilbur, Shani M.,Buchegger, Franz,Pantelias, Anastasia,Pagel, John M.,Press, Oliver W.
experimental part, p. 1225 - 1238 (2011/04/24)
Previous studies have shown that pretargeting protocols, using cancer-targeting fusion proteins, composed of 4 anti-CD20 single chain Fv (scFv) fragments and streptavidin (scFv4-SAv), followed by a biotinylated dendrimeric N-acetyl-galactosamine blood clearing agent (CA), 1, then a radiolabeled DOTA-biotin derivative (a monobiotin), 3a, can provide effective therapy for lymphoma xenografts in mouse models. A shortcoming in this pretargeting system is that endogenous biotin may affect its efficacy in patients. To circumvent this potential problem, we investigated a pretargeting system that employs anti-CD20 scFv4-SAv mutant fusion proteins with radioiodinated bis-biotin derivatives. With that combination of reagents, good localization of the radiolabel to lymphoma tumor xenografts was obtained in the presence of endogenous biotin. However, the blood clearance reagents employed in the studies were ineffective, resulting in abnormally high levels of radioactivity in other tissues. Thus, in the present investigation a bis-biotin-trigalactose blood clearance reagent, 2, was designed, synthesized, and evaluated in vivo. Additionally, another DOTA-biotin derivative (a bis-biotin), 4a, was designed and synthesized, such that radiometals (e.g., 111In, 90Y, 177Lu) could be used in the pretargeting protocols employing scFv4-SAv mutant fusion proteins. Studies in mice demonstrated that the CA 2 was more effective than CA 1 at removing [125I]scFv4-SAv-S45A mutant fusion proteins from blood. Another in vivo study compared tumor targeting and normal tissue concentrations of the new reagents (2 and [111In]4b) with standard reagents (1 and [111In]3b) used in pretargeting protocols. The study showed that lymphoma xenografts could be targeted in the presence of endogenous biotin when anti-CD20 fusion proteins containing SAv mutants (scFv 4-SAv-S45A or scFv4-SAv-Y43A) were employed in combination with CA 2 and [111In]4b. Importantly, normal tissue concentrations of [111In]4b were similar to those obtained using the standard reagents (1 and [111In]3b), except that the blood and liver concentrations were slightly higher with the new reagents. While the reasons for the higher blood and liver concentrations are unknown, the differences in the galactose structures of the clearance agents 1 and 2 may play a role.
N-terminal sugar conjugation and C-terminal Thr-for-Thr(ol) exchange in radioiodinated Tyr3-octreotide: Effect on cellular ligand trafficking in vitro and tumor accumulation in vivo
Schottelius, Margret,Reubi, Jean Claude,Eltschinger, Veronique,Schwaiger, Markus,Wester, Hans-Jürgen
, p. 2778 - 2789 (2007/10/03)
For effective targeting of somatostatin receptor (sst) expressing tumors by radiolabeled octreotide analogues, high ligand uptake into sst-positive cells is mandatory. To optimize it, two modifications have been introduced into [ 125I]Tyr3
Use of multivalent glycodendrimers to inhibit the activity of human immunodeficiency virus
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Page 11-12, (2010/02/08)
The present invention relates to compositions and methods for inhibiting the interaction of a ligand and receptor. In particular, compositions are methods are provided for inhibition of interaction between a virus, especially HIV, and a receptor. Inhibition of such ligand/receptor interaction is advantageous in inhibiting infection of a cell with a virus. Further, an inhibitor of ligand/receptor interaction serves as a standard in assays of inhibition in vitro or in vivo. In a particular embodiment, a composition according to the invention includes a compound having the formula: [(X)—(Y)]p-Z where X is and where Q1 and Q2 are each independently H, a bond to Y, or a bond to Z, where at least one of Q1 or Q2 is a bond to Y or a bond to Z; where R1, R4, R6 and R8 are each H; R2, R3, and R5 are each independently OH, OSO3D, or OPO3D, and R7 is CH20H, CH2OSO3D or CH2OPO3D; where D is H or a cation selected from the group consisting of: alkali metal cations, alkaline earth metal cations, ammonium cations, quaternary ammonium cations and amine cations; and where at least one of R2, R3, R5 and R7 is a sulfur or phosphate containing group; where Y is an optional linker, Z is a multivalent support, and p is an integer in the range of 1-2000 inclusive.
The effect of glycosylation on the structure of designed four-helix bundle motifs
Andersson, Linda K.,Dolphin, Gunnar T.,Kihlberg, Jan,Baltzer, Lars
, p. 459 - 464 (2007/10/03)
A galactose-, 1, and a cellobiose derivative, 2, have been site selectively, post-translationally, incorporated into a folded helix-loop-helix dimer LA-42b in a one step reaction at room temperature. The structural effects on the folded peptide upon glycosylation have been studied by CD and NMR spectroscopy. The negative value of the mean residue ellipticity of the folded peptide, LA-42b, was raised from -19000 ± 1000 to -21200 ± 1000 deg cm2 dmol-1 upon introduction of the galactose derivative and to -19500 ± 1000 deg cm2 dmol-1 upon introduction of the cellobiose derivative, showing that the helical content was increased. The dissociation constant of the dimer decreased from 120 to 30 μM upon glycosylation. The introduction of 1 into GTD-C, a folded helix-loop-helix dimer with a well defined tertiary structure, had little structural impact. Glycosylation stabilises the folded structure of proteins with partially exposed hydrophobic cores but has little effect on well-packed proteins.
Building blocks for glycopeptide synthesis: Glycosylation of 3-Mercaptopropionic acid and Fmoc amino acids with unprotected carboxyl groups
Elofsson,Walse,Kihlberg
, p. 7613 - 7616 (2007/10/02)
3-Mercaptopropionic acid and Fmoc amino acids, having unprotected carboxyl groups, were glycosylated with sugar 1,2-trans-acetates in 90 and 53-65% yields, respectively, under lewis acid promotion. The synthesis of a neoglycopeptide illustrates the use of the building blocks in solid phase peptide synthesis.
Cell-specific glycopeptide ligands
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, (2008/06/13)
Cell-specific ligands comprising conjugates of saccharides and amino acids or peptides are synthesized from amino acids such as ornithine, lysine, peptides such as dilysine, diornithine or oligolysine and selected saccharides having reactive functional groups protected by appropriate blocking groups. Such glycopeptides are useful as tissue specific substances, which when coupled with bioactive materials through metabolizable or hydrolyzable linkages, deliver such bioactive materials to the selected site. In this manner, antiinflammatory drugs such as dexamethasone are linked through a metabolizable or hydrolyzable linkage and on administration to an animal suffering from inflammatory disease carries the drug to the site of inflammation for intracellular release. Other examples include the macrophage ligand N2 -N2, N6 -Bis-[3-(α-D-mannopyranosylthio)propionyl]-6-lysyl-N6 -[3-(α-D-mannopyranosylthio)propionyl]-L-lysine, 5, which when coupled to β-glucocerebrosidase, can deliver the enzyme selectively to kupffer cells. This is useful in the enzyme replacement therapy of Gaucher's disease.
Cell-Specific Ligands for Selective Drug Delivery to Tissues and Organs
Ponpipom, Mitree M.,Bugianesi, Robert L.,Robbins, James C.,Doebber, T. W.,Shen, T. Y.
, p. 1388 - 1395 (2007/10/02)
Various numbers of D-mannose residues have been attached via spacer arms to lysine, dilysine, and oligolysine backbones.These D-mannosyl peptide analogues were found to be potent competitive inhibitors of the uptake of 125I-labelled D-mannose-bovine serum
