Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
Org Lett ; 26(9): 1891-1895, 2024 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-38408024

RESUMEN

Pseudocyclic arylbenziodoxaboroles are unique aryne precursors under neutral aqueous conditions that selectively react with organic sulfides, forming the corresponding sulfonium salts. This reaction is compatible with various substituents (alkyl, halogen, CN, NO2, CHO, and cyclopropyl) in the aromatic ring or alkyl group of the sulfide. Similar reactions of sulfoxides afford o-hydroxy-substituted sulfonium salts. The structures of key products were confirmed by X-ray analysis.

2.
Front Immunol ; 9: 820, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29725338

RESUMEN

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are expressed in various immune cells and most of them carry signaling functions. High-affinity synthetic sialoside ligands have been developed for various Siglecs. Therapeutic potentials of the nanoparticles and compounds that contain multiple numbers of these sialosides and other reagents such as toxins and antigens have been demonstrated. However, whether immune responses can be regulated by monomeric sialoside ligands has not yet been known. CD22 (also known as Siglec-2) is an inhibitory molecule preferentially expressed in B lymphocytes (B cells) and is constitutively bound and functionally regulated by α2,6 sialic acids expressed on the same cell (cis-ligands). Here, we developed synthetic sialosides GSC718 and GSC839 that bind to CD22 with high affinity (IC50 ~100 nM), and inhibit ligand binding of CD22. When B cells are activated by B cell antigen receptor (BCR) ligation, both GSC718 and GSC839 downregulate proliferation of B cells, and this regulation requires both CD22 and α2,6 sialic acids. This result suggests that these sialosides regulate BCR ligation-induced B cell activation by reversing endogenous ligand-mediated regulation of CD22. By contrast, GSC718 and GSC839 augment B cell proliferation induced by TLR ligands or CD40 ligation, and this augmentation requires CD22 but not α2,6 sialic acids. Thus, these sialosides appear to enhance B cell activation by directly suppressing the inhibitory function of CD22 independently of endogenous ligand-mediated regulation. Moreover, GSC839 augments B cell proliferation that depends on both BCR ligation and CD40 ligation as is the case for in vivo B cell responses to antigens, and enhanced antibody production to the extent comparable to CpG oligonuleotides or a small amount of alum. Although these known adjuvants induce production of the inflammatory cytokines or accumulation of inflammatory cells, CD22-binding sialosides do not. Thus, synthetic sialosides that bind to CD22 with high-affinity modulate B cell activation through endogenous ligand-dependent and independent pathways, and carry an adjuvant activity without inducing inflammation.


Asunto(s)
Formación de Anticuerpos , Linfocitos B/inmunología , Proliferación Celular/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Lectina 2 Similar a Ig de Unión al Ácido Siálico/metabolismo , Ácidos Siálicos/metabolismo , Adyuvantes Inmunológicos , Animales , Linfocitos B/efectos de los fármacos , Ligandos , Ratones , Ratones Endogámicos C57BL , Polisacáridos/inmunología , Unión Proteica , Receptores de Antígenos de Linfocitos B/inmunología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunología , Transducción de Señal
3.
Mol Pharm ; 14(5): 1528-1537, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28191842

RESUMEN

Sialyl LewisX (sLeX) is a natural ligand of E-selectin that is overexpressed by inflamed and tumor endothelium. Although sLeX is a potential ligand for drug targeting, synthesis of the tetrasaccharide is complicated with many reaction steps. In this study, structurally simplified novel sLeX analogues were designed and linked with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000 (DSPE-PEG) for E-selectin-mediated liposomal delivery. The sLeX structural simplification strategies include (1) replacement of the Gal-GlcNAc disaccharide unit with lactose to reduce many initial steps and (2) substitution of neuraminic acid with a negatively charged group, i.e., 3'-sulfo, 3'-carboxymethyl (3'-CM), or 3'-(1-carboxy)ethyl (3'-CE). While all the liposomes developed were similar in particle size and charge, the 3'-CE sLeX mimic liposome demonstrated the highest uptake in inflammatory cytokine-treated human umbilical vein endothelial cells (HUVECs), being even more potent than native sLeX-decorated liposomes. Inhibition studies using antiselectin antibodies revealed that their uptake was mediated primarily by overexpressed E-selectin on inflamed HUVECs. Molecular dynamics simulations were performed to gain mechanistic insight into the E-selectin binding differences among native and mimic sLeX. The terminally branched methyl group of the 3'-CE sLeX mimic oriented and faced the bulk hydrophilic solution during E-selectin binding. Since this state is entropically unfavorable, the 3'-CE sLeX mimic molecule might be pushed toward the binding pocket of E-selectin by a hydrophobic effect, leading to a higher probability of hydrogen-bond formation than native sLeX and the 3'-CM sLeX mimic. This corresponded with the fact that the 3'-CE sLeX mimic liposome exhibited much greater uptake than the 3'-CM sLeX mimic liposome.


Asunto(s)
Selectina E/química , Células Endoteliales/metabolismo , Liposomas/química , Células Endoteliales de la Vena Umbilical Humana , Humanos , Liposomas/metabolismo , Simulación de Dinámica Molecular
4.
Molecules ; 21(5)2016 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-27187324

RESUMEN

The convergent synthesis of the Lewis A (Le(a)) tandem repeat is described. The Le(a) tandem repeat is a carbohydrate ligand for a mannose binding protein that shows potent inhibitory activity against carcinoma growth. The Le(a) unit, {ß-d-Gal-(1→3)-[α-l-Fuc-(1→4)]-ß-d-GlcNAc}, was synthesized by stereoselective nitrile-assisted ß-galactosylation with the phenyl 3-O-allyl-2,4,6-tri-O-benzyl-1-thio-ß-galactoside, and ether-assisted α-fucosylation with fucosyl (N-phenyl)trifluoroacetimidate. This common Le(a) unit was easily converted to an acceptor and donor in high yields, and the stereoselective assembly of the hexasaccharide and dodecasaccharide as the Le(a) tandem repeat framework was achieved by 2-trichloroacetamido-assisted ß-glycosylation and the (N-phenyl)trifluoroacetimidate method.


Asunto(s)
Oligosacáridos/síntesis química , Secuencia de Carbohidratos , Espectroscopía de Resonancia Magnética con Carbono-13 , Galactosa/química , Antígenos del Grupo Sanguíneo de Lewis , Oligosacáridos/química , Oligosacáridos/farmacología , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa por Ionización de Electrospray , Secuencias Repetidas en Tándem
5.
Carbohydr Res ; 405: 78-86, 2015 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-25500195

RESUMEN

Novel sugar-conjugated cholesterols, ß-Gal-, α-Man-, ß-Man-, α-Fuc-, and ß-Man-6P-S-ß-Ala-Chol, were synthesized and incorporated into liposomes. In vitro experiments using the glyco-coated liposomes showed that the glyco-coated liposomes are efficiently taken up by cells expressing carbohydrate-binding receptors selectively. Glyco-coated liposomes are promising candidates for drug delivery vehicles.


Asunto(s)
Carbohidratos/química , Colesterol/química , Liposomas/química , Liposomas/síntesis química , Animales , Transporte Biológico , Técnicas de Química Sintética , Células Hep G2 , Humanos , Liposomas/metabolismo , Melanoma Experimental , Ratones
6.
J Org Chem ; 77(21): 9437-46, 2012 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-22800502

RESUMEN

The complex-type N-linked octasaccharide oxazoline having LacNAc as the nonreducing end sugar was efficiently synthesized using the benzyl-protected LacNAc, mannose, and ß-mannosyl GlcNAc units as key building blocks. To achieve a highly ß-selective glycosylation with the LacNAc unit, the N-trichloroacetyl group was used for the protection of the amino group in the LacNAc unit. After complete assembly of these units and deprotection, the obtained free sugar was successfully derivatized into the corresponding sugar oxazoline. On the other hand, the N-acetylglucosaminylated saposin C, a hydrophobic lipid-binding protein, was chemically synthesized by the native chemical ligation reaction. On the basis of the previous results related to the synthesis of the nonglycosylated saposin C, the O-acyl isopeptide structure was introduced to the N-terminal peptide thioester carrying GlcNAc to improve its solubility toward aqueous organic solvents. The ligation reaction efficiently proceeded with the simultaneous O- to N-acyl shift at the O-acyl isopeptide moiety. After the removal of the cysteine-protecting group and folding, saposin C carrying GlcNAc was successfully obtained. The synthetic sugar oxazoline was then transferred to this glycoprotein using the mutant of endo-ß-N-acetylglucosaminidase from Mucor hiemalis (Endo-M) (glycosynthase), and the saposin C carrying the complex-type nonasaccharide was successfully obtained.


Asunto(s)
Acetilglucosaminidasa/química , Acetilglucosaminidasa/metabolismo , Carbohidratos/química , Glicopéptidos/química , Glicoproteínas/química , Glicoproteínas/síntesis química , Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidasa/química , Saposinas/química , Saposinas/síntesis química , Proteínas Portadoras , Glicopéptidos/metabolismo , Glicoproteínas/metabolismo , Glicosilación , Interacciones Hidrofóbicas e Hidrofílicas , Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidasa/metabolismo , Datos de Secuencia Molecular , Saposinas/metabolismo
7.
J Org Chem ; 76(13): 5229-39, 2011 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-21612260

RESUMEN

The biantennary complex-type N-glycans bearing LacNAc and LacdiNAc as the nonreducing end motif were synthesized in a protected form suitable to use in the Fmoc solid-phase peptide synthesis studies. Two approaches for the nonasaccharide synthesis were examined by taking advantage of the highly ß-selective glycosylation with GlcNTCA (N-phenyl)trifluoroacetimidate. An earlier approach, which involved the reaction of the trisaccharide donor (Gal-GlcNTCA-Man) and trisaccharide acceptor (Man-GlcNPhth(2)-N(3)), produced a mixture of nonasaccharide isomers. On the other hand, mannosylation of the trisaccharide acceptor (Man-GlcNPhth(2)-N(3)) stereoselectively afforded the known pentasaccharide (Man(3)-GlcNPhth(2)-N(3)), which was reacted with the disaccharyl glycosyl donor (Gal-GlcNTCA or GalNTCA-GlcNTCA) to produce the desired nonasaccharide as a single stereoisomer. Selective dephthaloylation followed by N-acetylation furnished the GlcNAc(2) functionality. The resulting nonasaccharyl azides were condensed with Fmoc-Asp(OPfp)-OBu(t) or Fmoc-Asp(OPfp)-OPac in the presence of Ph(CH(3))(2)P and HOOBt. Finally, the Zn reduction and cleavage of the tert-butyl ester or Zn reduction alone produced the targeted nonasaccharyl Asn building blocks.


Asunto(s)
Glicopéptidos/síntesis química , Polisacáridos/síntesis química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Glicopéptidos/química , Datos de Secuencia Molecular , Polisacáridos/química , Estereoisomerismo
9.
Chem Commun (Camb) ; (35): 3673-5, 2007 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-17728890

RESUMEN

Polymer-supported oligosaccharide synthesis was carried out using an ultrafiltration technique in which the synthesized polymer-bound oligosaccharides were separated from the other reagents by ultrafiltration though membranes with specifically sized pores.


Asunto(s)
Oligosacáridos/síntesis química , Polímeros/química , Secuencia de Carbohidratos , Estructura Molecular , Ultrafiltración
10.
Biochem Pharmacol ; 73(7): 981-9, 2007 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-17214973

RESUMEN

d-Eritadenine (DEA) is a potent inhibitor of S-adenosyl-l-homocysteine hydrolase (SAHH) and has hypocholesterolemic activity. We have hypothesized that 3-deaza-DEA (C3-DEA) and its analogues retain high level of SAHH inhibitory activity and have resistance to deamination and glycosidic bond hydrolysis in vivo. Such C3-DEA analogues would have much higher hypocholesterolemic activity. C3-DEA, and its methyl ester (C3-OMeDEA) and its methyl amido (C3-NMeDEA) were synthesized to examine their SAHH inhibitory and hypocholesterolemic activities. A crystal structure of SAHH containing C3-DEA was determined and confirmed that DEA and C3-DEA bound to the same site of SAHH with the same binding mode. The SAHH inhibitory activities of C3-DEA (K(I)=1.5 microM) and C3-OMeDEA (K(I)=1.5 microM) are significantly lower than that of DEA (K(I)=30 nM), while rats fed by C3-DEA and C3-OMeDEA decrease the total plasma cholesterol and phospholipids by 36-40% and 23%, respectively, which is similar to the level of reductions (42% and 27%) by DEA. C3-NMeDEA lost most of the SAHH inhibitory activity (K(I)=30 microM) and dietary C3-NMeDEA does not decrease cholesterol and phospholipid in plasma but decreases the triacylglycerol level by 16%. DEA and C3-DEA analogues are neither substrates nor inhibitors of adenosine deaminase.


Asunto(s)
Adenina/análogos & derivados , Adenosilhomocisteinasa/antagonistas & inhibidores , Anticolesterolemiantes/farmacología , Adenina/farmacología , Animales , Ratas , S-Adenosilhomocisteína/metabolismo , Especificidad por Sustrato
11.
Org Lett ; 8(20): 4465-8, 2006 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-16986926

RESUMEN

A peptide carrying a mercaptomethylated proline derivative at the C-terminus was prepared by solid-phase peptide synthesis (SPPS) and converted to the thioester of 3-mercaptopropionic acid (MPA) by aqueous MPA under microwave irradiation conditions. This post-SPPS thioesterification reaction was successfully applied to the synthesis of a glycopeptide thioester composed of 25 amino acid (AA) residues, which was then used for the preparation of a 61-AA glycopeptide by the thioester condensation method.


Asunto(s)
Ésteres/química , Microondas , Péptidos/síntesis química , Ácido 3-Mercaptopropiónico/química , Cromatografía Líquida de Alta Presión , Glicosilación , Oxidación-Reducción , Péptidos/química , Compuestos de Sulfhidrilo
12.
Org Lett ; 6(13): 2133-6, 2004 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-15200303

RESUMEN

[reaction: see text] Palladium(0)-catalyzed one-atom ring-expansion of 1-hydroxy-2,2-dialkyl-1-propenoylindan derivatives has been achieved in the presence of P(o-tolyl)(3) giving 2-hydroxy-3,3-dialkyl-2-vinyl-1-tetralone derivatives in excellent yields. This ring-expansion reaction was applied to a 17-(1-oxo-2-propenyl)-beta-estradiol derivative and furnished a similar ring-expanded product in an excellent yield.

13.
Org Lett ; 4(3): 455-7, 2002 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-11820903

RESUMEN

Palladium(0)-catalyzed one-atom ring expansion of various hydroxy methoxyallenyl compounds has been achieved in excellent yields without the use of aryl halides. Hydroxy methoxyallenylisoindolinones, -indanones, and -phthalans have been readily converted to the corresponding isoquinolones, naphthoquinones, and isochromanones in the presence of P(o-tolyl)(3).

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA