Sickle Cell Disease (SCD) is a hematological disease characterized by a punctual mutation at the sixth codon of the β-globin gene leading to the substitution of glutamic acid for valine residue in the globin beta chain. It has been reported that histone deacetylase inhibitors are able to increase fetal hemoglobin levels and its reactivation ameliorates clinical symptoms in SCD patients. Based on that, herein we describe the synthesis of 7 novel molecules (compounds 1-7) obtained through molecular hybridization approach using as templates resveratrol and NO donor groups, represented by furoxan derivatives. All compounds have shown NO donor properties at different levels ranging from 1.8 – 26.3%. In vitro, compound (E)-4-(4-(3,5-dimethoxystyryl)phenoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide (2) was the most active NO-donor. Static adhesion assay demonstrated that compound (E)-4-(4-(4-methoxystyryl)phenoxy)-3-phenyl-1,2,5-oxadiazole 2-oxide (3), at 10 μM and 20 µM, reduced the cellular adhesion to fibronectin compared with control. All compounds have demonstrated analgesic activity by inhibiting the number of abdominal writhes induced by acetic acid in mice at values ranging from 7.7 – 37.3%. It was found that the most active TNF-α inhibitors were compounds (E)-4-(4-(3,5-dimethoxystyryl)phenoxy)-3-phenyl-1,2,5-oxadiazole 2-oxide (4), (E)-4-(4-(4-methoxystyryl)phenoxy)-3-methyl-1,2,5-oxadiazole 2-oxide (5) and (E)-4-(4-(3,5-dimethoxystyryl)phenoxy)-3-methyl-1,2,5-oxadiazole 2-oxide (6). All compounds were able to inhibit histone deacetylase (HDAC 1, 2 and 8). Compound 5 exhibited IC50 value of 0.78 μM against HDAC-8. Using in vitro chemotaxis assay it was not possible to observe inhibition of neutrophil chemotaxis after treatment with compounds (3) and (5). In addition, compounds (1-6) were not able to induce membrane perturbation at all concentrations evaluated, while the control resveratrol caused this alteration. Moreover, the compound (5) was able to increase by approximately twice the levels of gamma-globin chains (γG+γA) at 25 µM using CD34+ cells. The in vivo evaluation of mutagenicity using a micronucleus test showed that compounds (1-6) did not induce genotoxicity. In summary, these hybrid compounds have shown to be a promising drug candidates for the treatment of SCD symptoms.

Synthesis and pharmacological evaluation of histone deacetylase inhibitors as fetal hemoglobin inducers

255th National Meeting (2018)

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