- Synthesis of malformin-A1, C, a glycan, and an aglycon analog: Potential scaffolds for targeted cancer therapy
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Improvement in therapeutic efficacy while reducing chemotherapeutic side effects remains a vital objective in synthetic design for cancer treatment. In keeping with the ethos of therapeutic development and inspired by the Warburg effect for augmenting biological activities of the malformin family of cyclic-peptide natural products, specifically anti-tumor activity, a β-glucoside of malformin C has been designed and synthesized utilizing precise glycosylation and solution phase peptide synthesis. We optimized several glycosylation procedures utilizing different donors and acceptors. The overarching goal of this study was to ensure a targeted delivery of a glyco-malformin C analog through the coupling of D-glucose moiety; selective transport via glucose transporters (GLUTs) into tumor cells, followed by hydrolysis in the tumor microenvironment releasing the active malformin C a glycon analog. Furthermore, total synthesis of malformin C was carried out with overall improved strategies avoiding unwanted side reactions thus increasing easier purification. We also report on an improved solid phase peptide synthesis protocol for malformin A1.
- Andreana, Peter R.,Hossain, Farzana,Nishat, Sharmeen
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- Amino acid derivative and preparation method thereof
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The invention discloses an amino acid derivative and a preparation method thereof. The amino acid comprises - SH and/or - OH groups, wherein the sugar chain comprises one mannose or more than two mannose in series, and the linker comprises S or o, the method of the invention can synthesize the required polysaccharide compound in one step, thereby not only saving a large amount of manpower and time, but also enabling a large amount of preparation of the target compound to be smooth. , The synthesis yield of the product is improved, a large amount of synthetic raw materials are saved, the production cost is greatly reduced, meanwhile, the environmental protection is facilitated, and the research of amino acid glycosylation is broken through and the application barrier is applied.
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Paragraph 0056; 0070-0072
(2021/10/11)
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- Nanodisk-based glioma-targeted drug delivery enabled by a stable glycopeptide
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Heptapeptide ATWLPPR (A7R) binds specifically to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) overexpressed in glioma cells, exhibiting high potential to achieve glioma targeted drug delivery. However, in vivo application of A7R peptide remains challenging due to the poor proteolytic stability and inaccessibility of A7R to the brain. To tackle these problems, we identified a glycosylated A7R derivative to enhance in vivo stability and brain transport efficacy. Our results showed that glycosylation of peptide could efficiently improve stability in serum, traverse the blood-brain barrier (BBB) and be uptaken by glioma cells. Furthermore, a novel glioma-targeted drug delivery system was constructed successfully employing glycopeptide as the targeting moiety and nanodisk as the carrier of paclitaxel (PTX). Physicochemical characterization showed that the nanodisk presented suitable size of 50 nm and adequate loading capacity of PTX. Compared to non-glycosylated nanodisk, glycopeptide modification could significantly enhance the uptake of disks by brain capillary endothelial cells through glucose transporter 1 (GLUT1). In vivo imaging and glioma fluorescence section results also indicated that nanodisks modified with glycopeptide showed a higher accumulation in glioma. The glycopeptide-enabled PTX delivery system exhibited superior anti-glioma efficacy in intracranial glioma xenograft model. These results suggested that glycosylation of peptides provided an efficient pathway to design multifunctional and stable brain targeting ligands.
- Wang, Huan,Wang, Xiaoyi,Xie, Cao,Zhang, Mingfei,Ruan, Huitong,Wang, Songli,Jiang, Kuan,Wang, Fei,Zhan, Changyou,Lu, Weiyue,Wang, Hao
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- A convenient and efficient synthetic approach to mono-, di-, and tri-O-mannosylated Fmoc amino acids
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A convenient and highly efficient synthesis of mono-, di-, and tri-O-mannosylated Fmoc-Ser and Thr is described. The short synthetic route and high overall yield highlight the synthetic utility of this unified approach.
- Chen, Liqun,Tan, Zhongping
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supporting information
p. 2190 - 2193
(2013/04/24)
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- Glycosylation of α-amino acids by sugar acetate donors with InBr 3. Minimally competent Lewis acids
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A simplified method for the preparation of Fmoc-serine and Fmoc-threonine glycosides for use in O-linked glycopeptide synthesis is described. Lewis acids promote glycoside formation, but also promote undesired reactions of the glycoside products. Use of 'minimally competent' Lewis acids such as InBr 3 promotes the desired activation catalytically, and with greatly reduced side products from sugar peracetates.
- Lefever, Mark R.,Szab, Lajos Z.,Anglin, Bobbi,Ferracane, Michael,Hogan, Joanna,Cooney, Lauren,Polt, Robin
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body text
p. 121 - 125
(2012/05/20)
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- Glycosylated analogs of formaecin I and drosocin exhibit differential pattern of antibacterial activity
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The synthetic glycopeptides are interesting model systems to study the effect of O-glycosylation in modulating their function and structure. A series of glycosylated analogs of two antibacterial peptides, formaecin I and drosocin, were synthesized by varying the nature of sugar and its linkage with bioactive peptides to understand the influence of structure variation of glycosylation on their antibacterial activities. Higher antibacterial activities of all glycopeptides compared to their respective non-glycosylated counterparts emphasize in part the importance of sugar moieties in functional implications of these peptides. The consequences of the unique differences among the analogs were apparent on their antibacterial activities but not evident structurally by circular dichroism studies. We have shown that differently glycosylated peptides exhibit differential effect among each other when tested against several Gram-negative bacterial strains. The change of monosaccharide moiety and/or its anomeric configuration in formaecin I and drosocin resulted into decrease in the antibacterial activity in comparison to that of the native glycopeptide, but the extent of decrease in antibacterial activity of glycosylated drosocin analogs was less. Probably, the variation in peptide conformation arising due to topological dissimilarities among different sugars in the same peptide resulting in possible modulation in binding properties appears to be responsible for differences in their antibacterial activities. Indeed, these effects of glycosylation are found to be sequence-specific and depend in the milieu of amino acid residues. Interestingly, none of the carbohydrate variants affected the basic property of these peptides, which is non-hemolytic and non-toxicity to eukaryotic cells. The Author(s) 2011.
- Talat, Sariya,Thiruvikraman, Menithalakshmi,Kumari, Saroj,Kaur, Kanwal J.
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p. 537 - 555
(2014/02/14)
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- Facile synthesis of glycosylated Fmoc amino acid building blocks assisted by microwave irradiation
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The synthesis of glycosylated Fmoc amino acids by reaction of mono- and disaccharide peracetates with Fmoc amino acids having free carboxyl groups was rapidly promoted by Lewis acids (SnCl4, BF3·Et 2O) under microwave irradiation. The products are useful building blocks for the synthesis of glycopeptides.
- Yao, Nianhuan,Fung, Gabriel,Malekan, Hamed,Ye, Long,Kurth, Mark J.,Lam, Kit S.
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experimental part
p. 2277 - 2281
(2010/11/19)
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- Oxytocin analogues with O-glycosylated serine and threonine in position 4
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Oxytocin structure was modified in position 4 using glycoamino acids. Procedure for transformation of Fmoc-protected serine and threonine derivatives into appropriate O-glycosylated precursors suitable for solid phase peptide synthesis (SPPS) was worked o
- Marcinkowska,Borovickova,Slaninova,Grzonka
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p. 1335 - 1344
(2008/09/19)
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- Synthesis of mannosyl and oligomannosyl threonine building blocks found on the mycobacterium tuberculosis 45 kDa MPT 32 glycoprotein
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Mycobacterium tuberculosis secretes a 45 kDa glycoprotein (MPT 32) carrying mannosylated threonine residues. A general strategy was developed to couple peracetylated mannose, α-(1,2)-linked mannobiose or mannotriose to Fmoc-threonine-benzyl ester. Activation of mannosyl acetates or fluorides by borontrifluoride etherate gave the desired Fmoc-glycosyl amino acid building blocks in good yields. The synthesis leads to stable compounds and can easily be scaled up.
- Varon, Daniel,Lioy, Eduardo,Patarroyo, Manuel E.,Schratt, Xaver,Unverzagt, Carlo
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p. 161 - 165
(2007/10/03)
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- Solid-phase synthesis of O-linked glycopeptide analogues of enkephalin
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The synthesis of 18 N-α-FMOC-amino acid glycosides for solid-phase glycopeptide assembly is reported. The glycosides were synthesized either from the corresponding O'Donnell Schiff bases or from N-α-FMOC-amino protected serine or threonine and the appropriate glycosyl bromide using Hanessian's modification of the Koenigs-Knorr reaction. Reaction rates of D-glycosyl bromides (e.g., acetobromoglucose) with the L- and D-forms of serine and threonine are distinctly different and can be rationalized in terms of the steric interactions within the two types of diastereomeric transition states for the D/L and D/D reactant pairs. The N-α-FMOC-protected glycosides [monosaccharides Xyl, Glc, Gal, Man, GlcNAc, and GalNAc; disaccharides Gal-β(1-4)-Glc (lactose), Glc-β(1-4)-Glc (cellobiose), and Gal-α(1-6)-Glc (melibiose)] were incorporated into 22 enkephalin glycopeptide analogues. These peptide opiates bearing the pharmacophore H-Tyr-c[DCys-Gly-Phe-DCys]- were designed to probe the significance of the glycoside moiety and the carbohydrate-peptide linkage region in blood-brain barrier (BBB) transport, opiate receptor binding, and analgesia.
- Mitchell,Pratt,Hruby,Polt
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p. 2327 - 2342
(2007/10/03)
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- Solid phase synthesis of O-glycoopioid peptides related to dermorphin
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Glycosylation of Fmoc-hydroxyamino acids with β-D-glucose pentaacetate has been carried out in the presence of several Lewis acids and BF3.Et2O has been found to be the most suitable one. Thus, 2,3,4,6-tetra-O-acetyl-β-D-glycopyranosyl derivatives of Fmoc-Ser/Thr/Tyr are prepared in a single step in reasonably good yields and high purity. The O-glycosylated derivatives are then converted to their corresponding trichlorophenyl esters for use in the solid phase synthesis of five glycoopioid peptides related to dermorphin. The effect of glycosylation on biological activity of dermorphin has been studied. Among the peptides synthesized, [Tyr(β-D-Glc)5]dermorphin and [Ser(β-D-Glc)5, Tyr7)]dermorphin exhibit considerable analgesic activity of about 80-90% compared to morphine and antidiarrhoeal activity of about 50% compared to dermorphin.
- Sivanandaiah,Suresh Babu,Shankaramma
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p. 760 - 767
(2007/10/03)
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- Glycosylation of Fmoc amino acids: Preparation of mono- and di-glycosylated derivatives and their incorporation into Arg-Gly-Asp (RGD)-containing glycopeptides
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Compounds containing O-glycosidic linkages between carbohydrate species (D-glucopyranose, D-mannopyranose and L-rhamnopyranose) and hydroxy-containing amino acid components (L-threonine, L-serine and L-hydroxyproline) have been synthesized. Significant qu
- Vegad, Hiran,Gray, Charles J.,Somers, Peter J.,Dutta, Anand S.
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p. 1429 - 1441
(2007/10/03)
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- Preparation of Building Blocks for Glycopeptide Synthesis by Glycosylation of Fmoc Amino Acids Having Unprotected Carboxyl Groups
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Nα-Fmoc amino acids with an unprotected α-carboxyl group have been glycosylated with carbohydrate 1,2-trans peracetates using Lewis acids as promoters.Aliphatic and phenolic O- and S-glycosides of amino acids, with a 1,2-trans anomeric configuration, were obtained as products in 34-65percent yields.The glycosylated building blocks have the protective groups of choice (i.e.O-acetyl and Nα-Fmoc) for direct use in stepwise synthesis of glycopeptides.The starting materials are readily available and the method does not require an extensive experience in synthetic carbohydrate chemistry.
- Salvador, Lourdes A.,Eloffson, Mikael,Kihlberg, Jan
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p. 5643 - 5656
(2007/10/02)
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- Building blocks for glycopeptide synthesis: Glycosylation of 3-Mercaptopropionic acid and Fmoc amino acids with unprotected carboxyl groups
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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.
- Elofsson,Walse,Kihlberg
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p. 7613 - 7616
(2007/10/02)
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- Improved method for the synthesis of o-glycosylated fmoc amino acids to be used in solid-phase glycopeptide synthesis (Fmoc = fluoren-9-ylmethoxycarbonyl)
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The building blocks O1-(2,3,4,6-tetra-O-acetyl-β-D- galactopyranosyl)-Nα(fluoren-9-ylmethoxycarbonyl)serine (5)and O 1-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -Nα-(fluoren-9-ylmethoxycarbonyl)threonine (6) for use in solid-phase glycopeptide synthesis can be obtained via their ally esters by mild treatment with tetrakis(triphenylphosphine)palladium(0) and tributyltin hydride with no Fmoc elimination or sugar cleavage or anomerization.
- De La Torre, Beatriz G.,Torres, Josep L.,Bardaji, Eduard,Clapes, Pere,Xaus, Nuria,Jorba, Xavier,Calvet, Silvia,Albericio, Fernando,Valencia, Gregorio
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p. 965 - 967
(2007/10/02)
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