Hybrids of thalidomide and furoxan derivatives: evaluation of anti-inflammatory

Author(s)

Cristiane Maria de Souza

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2018-01-31

Examining board members

Fernando Ferreira Costa; André Fattori; Mário Angelo Claudino

• Advisor: Fernando Ferreira Costa

Abstract

Sickle cell anemia (SCA) occurs due to molecular alterations in the beta globin gene leading to the formation of HbS. The key event in the pathogenesis of sickle cell anemia is the polymerization of HbS. The rate of HbS polymerization depends on some factors such as: oxygen concentration, pH, concentration, temperature, pressure, ionic strength, and the presence of normal hemoglobin. The consequences of HbS polymerization are: deformation, stiffness and loss of flexibility of the red blood cells, resulting in hemolytic anemia, vaso-occlusive events and splenic function impairment causing an increase in susceptibility to infection. Sickle cell anemia, despite having its origin in the mutation of the beta globin gene, presents a variety of disorders such as, a state of chronic inflammation that is associated with vascular injury, increased production of reactive oxygen species (ROS), hemolysis, decreased bioavailability of NO, and increased production of inflammatory molecules (TNF-alpha, GM-SCF, IL-1², IL-3, M-CSF, IL-6, IL-8). Strong evidence suggests that the significant increase of fetal hemoglobin (HbF) levels provide an improvement in the clinical picture of the disease. Currently, Hydroxyurea (HU) is the only well tested drug approved by the Food and Drug administration (FDA) for the treatment of sickle cell anemia. The mechanism of action of this drug is based on the ability to increase HbF levels and thus reduce clinical complications of the disease. However, new drugs are being studied in order to improve the prognosis of patients with sickle cell anemia. The objective of this study was to assess the anti-inflammatory ability and induction of gamma globin, constituent of HbF of the candidates derived from Thalidomide + furoxan derivatives. The compounds SCD2013.1, SCD2013.2 and SCD2013.3 were not able to induce significantly the production of ?A and ?G chains; The compounds SCD2013.1 and SCD2013.3 were able to decrease the control neutrophil adhesion to FN (***p<0.0001, n=10) and of patients with SC hemoglobinopathy (***p<0.0001, n=9). SCD2013.1 demonstrated anti-inflammatory activity by decreasing TNF-? production in human macrophages (1?M *p<0.05, 2.5?M **p<0.0033, n=5), while the SCD2013.3 compound did not show the same effect at the concentrations tested. In conclusion, SCD2013.1 was able to decrease the neutrophil adhesion to FN and also showed anti-inflammatory activity, thus making it the most promising among the three compounds tested (AU)

• FAPESP's process: 15/16188-4 - Hybrids of thalidomide + furoxan derivatives: evaluation of anti-inflammatory properties and induction of gamma globin in vitro
• Grantee: Cristiane Maria de Souza
• Support Opportunities: Scholarships in Brazil - Master