Sickle cell disease (SCD) is a one of the most prevalent genetic and hematologic disease worldwide, which has the hydroxyurea (HU) as the only available drug to the treatment. Despite the beneficial effects of HU in reducing morbidity and mortality associated with the disease, some undesirable features limits its clinical use. Moreover, some individuals do not respond to HU-treatment, justifying the search for new drugs. In this aspect, the reactivation of gamma-globin gene expression, and consequent increase in fetal hemoglobin (HbF) production, by epigenetic mechanisms is a valuable therapeutic intervention. The drugs thalidomide and pomalidomida are known to be able to increase gamma-globin gene expression and fetal hemoglobin levels; however, the exact molecular mechanisms related to these effects are still being investigated. Recent studies show that inhibition of histone deacetylase (HDAC), mainly HDAC-1 and HDAC-2, was shown to be a promising strategy to promote increased gene expression of gamma-globin and HbF production without causing change in the cycle and proliferation cell. In this proposal, using a molecular hybridization approach, we describe the synthesis and pharmacological evaluation of new thalidomide and pomalidomide analogs within HADC inhibitory properties useful as new therapies for SCD treatment.
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