Synthesis and pharmacological evaluation of new pomalidomide derivatives to treat sickle cell disease symptoms

Abstract

The Sickle Cell Anemia (SCD) is a genetic blood disease characterized by a mutation in the ² -hemoglobin gene. This mutation promotes polymerization of hemoglobin molecules, in situations of low oxygen tension, which alter the structure of the erythrocyte cytoskeleton promoting changes in its physical structure (sickling). Furthermore, there is an increased adhesion of cells to the blood vessel promoting vaso-occlusive process, the main characteristic of the disease. The disease promotes chronic inflammation and increase several proinflammatory cytokines, such as TNF-alpha, this is therefore an important target for therapeutic intervention. Currently, hydroxyurea (HU) is the only drug available for the treatment and its beneficial effects are associated with nitric oxide (NO) released after metabolism. Nitric oxide (NO) plays beneficial effects such as vasodilation, inhibition of platelet aggregation and the production of fetal hemoglobin (HbF). HbF reduces the polymerization of hemoglobin S (HbS) and assists in transporting oxygen from the patient with disease. In our previous studies we found that the strategy of inhibition of TNF- ± associated with the NO release is an important approach for the treatment of symptoms associated with sickle cell disease, such molecules are capable of inducing the synthesis of HbF, inhibiting platelet aggregation and also reducing pain and inflammation associated with the disease. Thus, intending to optimize the activity of precursor molecules, this project proposes the synthesis and evaluation of a new series of hybrid molecules (3a-c and 4a- f) containing an inhibitory subunit of TNF-±, derived from pomalidomida, associated with furoxan derivatives with higher NO release profile in accordance with the structural engineering (Scheme 1) in order to characterize the best drug candidates for the treatment of symptoms of sickle cell disease. (AU)