Synthesis, structural characterization and NO-donor evaluation of hybrid compounds useful to treat sickle cell disease symptoms

Abstract

Sickle cell anemia (SCA) is a hereditary hemoglobinopathy characterized by a pumctual mutation at sixth codon of beta-globin gene, resulting in the replacement of a glutamic acid for valine at beta-globin chain. This modification promotes, at low oxygen concentrations, polymerization of hemoglobin molecules that alters the structure of the erythrocyte cytoskeleton (sickling) or cause erythrocyte hemolysis. Sickle cells exhibit increased adhesion to vascular endothelial cells promoting vaso-occlusive processes, major cause of symptomatic manifestations of the disease. It is known that the inflammatory process associated with disease contributes to a number of complications. Patients with SCA exhibit increased levels of tumor necrosis factor (TNF-alpha) and other pro-inflammatory cytokines. Currently, hydroxyurea (HU) is the only drug available for the treatment and its beneficial effects are associated with its biotransformation in vivo to nitric oxide (NO). NO plays beneficial effects such as vasodilation, inhibition of platelet aggregation and production of fetal hemoglobin (HbF), the latter serves to assist in the transport of oxygen in the patient's disease. The increase in HbF is associated with a decrease of vaso-occlusive processes. Continuing with our line of research, we intend to extend this proposed series of hybrid compounds with multiple activities: inhibiton of TNF-± andability to donor nitric oxide. This proposed is based on preliminary verification that higher NO donation by furoxan derivatives increase antiplatelet effects and induce gamma-globin gene expression and HbF, without altering TNF-± inhibition. Thus, for better understanding the pharmacological results obtained and partial enrichment of the work it will be synthesized a series of hybrid compounds (3a-b and 4a-b) according to the structural planning (Scheme 1). (AU)