RESUMO
The synthesis of three heparin analogues (i.e. compounds VI-VIII) having perphosphorylated thrombin binding domains (TBDs) is reported. These compounds were tested in vitro for their antithrombin III (ATIII)-mediated anti-Xa and antithrombin activities. Conjugates VI and VIII show a remarkable increase in antithrombin activity compared to the structurally related conjugates with persulfated TBDs (i.e. compounds IV and V), whereas compound VII displays a diminished activity.
Assuntos
Antitrombinas/síntese química , Heparina/análogos & derivados , Trombina/metabolismo , Antitrombinas/química , Antitrombinas/metabolismo , Sítios de Ligação , Configuração de Carboidratos , Sequência de Carboidratos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Dados de Sequência Molecular , FosforilaçãoRESUMO
The synthesis of a novel antithrombotic consisting of a heparin pentasaccharide conjugated to the active site inhibitor N-(2-naphtalenesulfonyl)-glycyl-(D)-4-aminophenyl-alanyl-piperidin e (NAPAP) (i.e. compound I) is reported. This conjugate shows a unique pharmacological profile both in vitro and in vivo having direct anti-thrombin and ATIII-mediated anti-Xa activity. Furthermore, conjugate I has a prolonged in vivo half-life compared to NAPAP (1.5 h vs 9 min.).
Assuntos
Antitrombinas/síntese química , Antitrombinas/farmacologia , Dipeptídeos/química , Oligossacarídeos/síntese química , Piperidinas/química , Animais , Sequência de Carboidratos , Desenho de Fármacos , Inibidores do Fator Xa , Meia-Vida , Heparina/química , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Dados de Sequência Molecular , Ratos , Solubilidade , Trombina/antagonistas & inibidoresRESUMO
The syntheses of several heparin-like glycoconjugates (i.e., 16a-f) containing identical AT III binding domains (ABD) and spacers but different thrombin binding domains (TBDs) are described. Biological activities of conjugates 16a-f indicate that the thrombin inhibitory activity is mainly determined by the charge density of the TBD moiety.
Assuntos
Glicoconjugados/síntese química , Glicoconjugados/farmacologia , Heparina/análogos & derivados , Heparina/farmacologia , Oligossacarídeos/síntese química , Trombina/metabolismo , Angiotensina III/metabolismo , Sítios de Ligação , Configuração de Carboidratos , Sequência de Carboidratos , Dermatan Sulfato/química , Desenho de Fármacos , Glicoconjugados/química , Modelos Moleculares , Dados de Sequência Molecular , Oligossacarídeos/química , Oligossacarídeos/farmacologia , Relação Estrutura-AtividadeRESUMO
The in vitro antithrombotic activity of synthetic glycoconjugates I and II, comprising a flexible polyethylene glycol type and a rigid polyglucose type spacer, respectively, are compared to heparin.
Assuntos
Anticoagulantes/farmacologia , Glicoconjugados/farmacologia , Heparina/análogos & derivados , Heparina/farmacologia , Polietilenoglicóis/farmacologia , Trombina/antagonistas & inibidores , Anticoagulantes/síntese química , Anticoagulantes/química , Configuração de Carboidratos , Sequência de Carboidratos , Inibidores do Fator Xa , Glicoconjugados/síntese química , Glicoconjugados/química , Heparina/síntese química , Heparina/química , Humanos , Dados de Sequência Molecular , Fator Plaquetário 4/antagonistas & inibidores , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Relação Estrutura-AtividadeRESUMO
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.