Discovery of phenylsulfonylfuroxan derivatives as gamma globin inducers by histone acetylation

• Published in: European journal of medicinal chemistry 2018-06, Vol.154, p.341-353
• Main Authors: Melo, Thais Regina Ferreira de, Kumkhaek, Chutima, Fernandes, Guilherme Felipe dos Santos, Lopes Pires, Maria Elisa, Chelucci, Rafael Consolin, Barbieri, Karina Pereira, Coelho, Fernanda, Capote, Ticiana Sidorenko de Oliveira, Lanaro, Carolina, Carlos, Iracilda Zeppone, Marcondes, Sisi, Chegaev, Konstantin, Guglielmo, Stefano, Fruttero, Roberta, Chung, Man Chin, Costa, Fernando Ferreira, Rodgers, Griffin P., dos Santos, Jean Leandro
• Format: Article
• Language: English
• Subjects: Analgesic activity; Antiplatelet activity; Epigenetic; Fetal hemoglobin; Furoxan; Sickle cell disease
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.05.008

N-oxide derivatives 5(a–b), 8(a–b), and 11(a–c) were designed, synthesized and evaluated in vitro and in vivo as potential drugs that are able to ameliorate sickle cell disease (SCD) symptoms. All of the compounds demonstrated the capacity to releasing nitric oxide at different levels ranging from 0.8 to 30.1%, in vivo analgesic activity and ability to reduce TNF-α levels in the supernatants of monocyte cultures. The most active compound (8b) protected 50.1% against acetic acid-induced abdominal constrictions, while dipyrone, which was used as a control only protected 35%. Compounds 8a and 8b inhibited ADP-induced platelet aggregation by 84% and 76.1%, respectively. Both compounds increased γ-globin in K562 cells at 100 μM. The mechanisms involved in the γ-globin increase are related to the acetylation of histones H3 and H4 that is induced by these compounds. In vitro, the most promising compound (8b) was not cytotoxic, mutagenic and genotoxic. [Display omitted] •Phenylsulfonylfuroxan 8a and 8b derivatives as gamma globin inducers in K562 cells.•The mechanisms involved in the γ-globin increase are related to the acetylation of histones H3 and H4 that is induced by these compounds.•Compounds 8a and 8b exhibited analgesic activity in vivo and inhibited platelet aggregation in vitro.