RESUMEN
Computer modelling of the antithrombin III-heparin-thrombin complex inspired the synthesis of novel glycoconjugates, whose factor Xa and thrombin inhibitory activities can be adjusted in a rational way, leading to anticoagulants with unprecedented characteristics.
Asunto(s)
Anticoagulantes/química , Heparina/análogos & derivados , Heparina/química , Anticoagulantes/metabolismo , Anticoagulantes/farmacología , Antitrombina III/química , Secuencia de Carbohidratos , Diseño de Fármacos , Inhibidores del Factor Xa , Datos de Secuencia Molecular , Polisacáridos/química , Polisacáridos/metabolismo , Conformación Proteica , Relación Estructura-Actividad , Trombina/antagonistas & inhibidores , Trombina/metabolismoRESUMEN
In this paper, we report the synthesis of 'non-glycosamino' glycan analogues 5-10 of the antithrombin III binding pentasaccharide 1. Pentasaccharides 5-10 feature a pseudo-alternating EFGH tetrasaccharide sequence, that is, the disaccharide fragments EF and GH have the same substitution pattern. In the synthetic strategy applied for the synthesis of pentasaccharides 5-10, the properly protected EF disaccharide fragments 19 and 20 are obtained from their GH counterparts 17 and 18 by base-catalyzed epimerization. Series I, comprising pentasaccharides 5-7, has an invariable EFGH tetrasaccharide containing 2-O-sulfate 3-O-methyl uronic acid moieties. Series II, on the other hand, contains pentasaccharides 8-10 and has an invariable EFGH tetrasaccharide containing 2,3-di-O-methyl uronic acid moieties. Coupling disaccharides 17 with 25 and 18 with 26 exclusively afforded the alpha-coupled tetrasaccharides 27 and 28, respectively. Glycosylation of acceptor tetrasaccharides 29 and 30 with glucosyl donors 35, 36 and 39 provided, after deprotection and sulfation, the title-compounds 5-10. Biological data obtained with series I and II indicate that the in vivo half-life but not the intrinsic anti-Xa activity depends on the substitution pattern of the D-unit. In addition, the applicability of reversed UV capillary electrophoresis as an analytical tool to determine the purity of these 'non-glycosamino' glycans is demonstrated.
Asunto(s)
Antitrombina III/metabolismo , Heparina/química , Oligosacáridos/síntesis química , Secuencia de Aminoácidos , Animales , Antitrombina III/farmacología , Sitios de Unión , Secuencia de Carbohidratos , Electroforesis , Glucosamina/metabolismo , Heparina/análogos & derivados , Espectroscopía de Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Estructura Molecular , Oligosacáridos/metabolismo , Ratas , Ratas WistarRESUMEN
The syntheses are described of four isosteric racemic myo-inositol 1,4,5-trisphosphate (1) analogues with the phosphate groups replaced by sulfonamide (2), sulfate (3), methylphosphonate (4), and carboxymethyl (5). None of these compounds had any affinity for the IP3 receptor or induced platelet aggregation.
