Synthesis and pharmacological evaluation of Bromodomain inhibitors (BRD-3) designed as fetal hemoglobin inducers

Abstract

Sickle cell anemia (SCA) is one of the most prevalent genetic blood diseases in the world. Currently, therapeutic strategies aiming to increase the levels of fetal hemoglobin (HbF) contribute significantly in reducing morbidity and mortality associated with the disease. The comprehension of the molecular mechanisms involved in fetal hemoglobin gene silencing may allow the development of drugs able to induce HbF more effective and safe. During erythropoiesis, the gamma-globin gene expression is silenced, in part, by the binding of a complex containing the protein GATA-1, which binds at sites near to the promoter of gamma-globin gene preventing transcription. Specifically, GATA-1 recruitment is accomplished by bromodomain-3 (BRD-3). In this project, our hypothesis is that the inhibition of BRD-3 may be a new therapeutic approach capable of promoting HbF levels increasing. Therefore, we conducted a preliminary study of virtual screening with 2.2 million of molecules in order to identify some prototypes with potential inhibition of bromodomain-3 (BRD-3). From these, and by using tools of molecular modification, we propose herein the synthesis and pharmacological evaluation of a series of phthalimide derivatives as BRD-3 inhibitors (I) useful to treat the symptoms of sickle cell disease. (AU)