Sickle Cell Disease (SCD) is one of the most prevalent genetic hemoglobinopathies worldwide. Currently, hydroxyurea is the only drug approved by Food and Drug Administration for the treatment, however, adverse effects limit its use during long-term therapy. Mechanisms involved into gamma-globin gene silencing in adult erythroid cells are promising targets to increase fetal hemoglobin. Here, a series of nine furoxan derivatives were synthesized and evaluated as new fetal hemoglobin inducers acting through histone acetylation. All compounds exhibited anti-inflammatory activity by inhibiting the TNF-α levels in the supernatants of monocyte cultures. Four compounds (4-8) demonstrated analgesic effect <i>in vivo</i> through acetic acid induced abdominal constrictions model using mice. The most active compound (6) has protected 50% of abdominal constrictions, while the reference drug dypirone only protected 35%. <i>In vitro</i> all compounds reduced the platelet aggregation induced by ADP at levels ranging from 32 - 84%. Phenylsulfonylfuroxan derivatives (compounds 5 and 6) have inhibited ADP-induced platelet aggregation by 84% and 76.1%, respectively. Interestingly, both compounds (5 and 6) at 100 μM, have increased the gamma-globin gene expression using human erythroleukemic cell line K562 cells. The mechanisms involved in gamma-globin increase are related to acetylation of histone H3 and H4 induced by these compounds. Compounds 5 and 6 have exhibited multiple beneficial effects in SCD, including: a) analgesic effect; b) inhibition of platelet aggregation; and c) potential to increase gamma-globin and further fetal hemoglobin due to epigenetic mechanisms. Therefore, these compounds constitute new prototypes to treat SCD and an alternative to hydroxyurea.

Histone H3 and H4 acetylation of gamma-globin gene induced by phenylsulfonylfuroxan

255th National Meeting (2018)

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