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1.
Bioorg Med Chem ; 98: 117553, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38128297

RESUMO

Neutrophil binding to vascular P- and E-selectin is the rate-limiting step in the recruitment of immune cells to sites of inflammation. Many diseases, including sickle cell anemia, post-myocardial infarction reperfusion injury, and acute respiratory distress syndrome are characterized by dysregulated inflammation. We have recently reported sialyl Lewisx analogues as potent antagonists of P- and E-selectin and demonstrated their in vivo immunosuppressive activity. A key component of these molecules is a tartrate diester that serves as an acyclic tether to orient the fucoside and the galactoside moiety in the required gauche conformation for optimal binding. The next stage of our study involved attaching an extended carbon chain onto one of the esters. This chain could be utilized to tether other pharmacophores, lipids, and contrast agents in the context of enhancing pharmacological applications through the sialyl Lewisx / receptor-mediated mechanism. Herein, we report our preliminary studies to generate a small library of tartrate based sialyl Lewisx analogues bearing extended carbon chains. Anionic charged chemical entities are attached to take advantage of proximal charged amino acids in the carbohydrate recognition domain of the selectin receptors. Starting with a common azido intermediate, synthesized using copper-catalyzed Huisgen 1,3-dipolar cycloadditions, these molecules demonstrate E- and P-selectin binding properties.


Assuntos
Selectina E , Selectina-P , Humanos , Selectina-P/metabolismo , Selectina E/metabolismo , Tartaratos , Antígeno Sialil Lewis X , Oligossacarídeos/química , Sítios de Ligação , Carbono , Inflamação , Adesão Celular
2.
J Org Chem ; 81(1): 256-64, 2016 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-26624806

RESUMO

Intramolecular Pd-catalyzed functionalization of cyclopropyl α-amino acid-derived benzamides proceeds without silver or pivalate additives. Both electronically and sterically diverse ethyl 1,2,3,4-tetrahydroisoquinolone-3-carboxylates were accessible in good to excellent yields.

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