Design, synthesis and pharmacological evaluation of new phthalimide derivatives as histone deacetylase inhibitors for sickle cell anemia

Author(s)

Aline Renata Pavan

• Document type: Master's Dissertation
• Press: Araraquara. 2018-08-27.
• Institution: Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara
• Defense date: 2018-07-24
• Advisor: Jean Leandro dos Santos

Abstract

Reactivation of gamma-globin gene expression and fetal hemoglobin (HbF) production through epigenetic mechanisms are valuable strategy to sickle cell anemia treatment. Early studies have demonstrated that histone deacetylase inhibition, especially HDAC-1 and HDAC-2, is a promising strategy to increase gamma-globin gene expression and HbF production without alteration in cell cycle or cell proliferation. At this work it was designed, by molecular modeling, new compounds HDAc 1 and 2 inhibitors. The molecular modeling studies has demonstrated how these compounds interacts with HDAC-2, being the subunit N-(2-aminophenyl)benzamide responsible for interact with the zinc atom of active site. During the optimization process, the docking score values hava changed from -9,8 to -12,3, which indicates better interactions with the receptor. It was synthesized and characterized eleven new compounds. Enzimatic assays have demonstrated that the enzymatic inhibition of the compounds varied from 83 to 96% against HDAC 1, 83-94% against HDAC 2 and 82-89% of HDAC 3. Compound (22) (4-(4-aminophenetyl)-N-(2-aminophenyl) benzamide was one of the most promisor among all compounds. At 10uM it was able to inhibit HDAC 1 and 2 more than 90%. These data has demonstrated that the design compounds in this work are potencial inhibitors of HDAC, being molecule (22) the most promisor and uselful as an alternative fo HbF induction. (AU)

• FAPESP's process: 15/21252-3 - Synthesis and Pharmacological evaluation of new thalidomide/pomalidomide analogues regulators of epigenetic mechanisms
• Grantee: Aline Renata Pavan
• Support Opportunities: Scholarships in Brazil - Master