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Design, synthesis and pharmacological evaluation of hydroxyurea derivatives designed as histone deacetylase inhibitors for Sickle Cell Anemia

Grant number: 18/19523-7
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): January 01, 2019
Effective date (End): July 31, 2021
Field of knowledge:Health Sciences - Pharmacy - Medicines Analysis and Control
Principal Investigator:Jean Leandro dos Santos
Grantee:Aline Renata Pavan
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Sickle Cell Anemia (SCA) is the most prevalent genetic disease in world. The lack of new drugs and the low life expectancy are the cruel aspects of the disease. Nowadays, the therapeutic resource include hydroxyurea (HU) and supplementation with glutamine. In vivo, HU is bioconverted in nitric oxide which results in beneficial effects, being the increase in fetal hemoglobin production one of the most importants. However, myelosuppression and genotoxicity are adverse effects of HU treatment, besides the rate of non-responsive patients to the drug. All these data justifies the search for new treatment strategies. On this approach, the gene reactivaton of gama-globin and as consequence the increase in fetal hemoglobin production by genetic mechanisms are valuable therapeutic intervention. Studies have demonstrated histone deacetylases (HDAC) inhibition, especially HDAC-1 and 2, to be a promising strategy to perform an increasement of gama-globin expression and HbF production without cycle cell alteration. In this project we have proposed synthesis and pharmacological evaluation of new HU analogues design to be also HDAC 1 and 2 inhibitors. Thus, NO donation from HU associated with HDAC 1 and 2 inhibition might result in sinergic effect of HbF production, being a new therapeutic approach for Sickle Cell Anemia. (AU)