Synthesis and evaluation of resveratrol derivatives as fetal hemoglobin inducers

• Autor(a) principal: Bosquesi, Priscila Longhin [UNESP]
• Data de Publicação: 2020
• Outros Autores: Melchior, Aylime Castanho Bolognesi [UNESP], Pavan, Aline Renata [UNESP], Lanaro, Carolina, de Souza, Cristiane Maria, Rusinova, Radda, Chelucci, Rafael Consolin [UNESP], Barbieri, Karina Pereira [UNESP], Fernandes, Guilherme Felipe dos Santos [UNESP], Carlos, Iracilda Zepone [UNESP], Andersen, Olaf Sparre, Costa, Fernando Ferreira, Dos Santos, Jean Leandro [UNESP]
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNESP
• Texto Completo: http://dx.doi.org/10.1016/j.bioorg.2020.103948; http://hdl.handle.net/11449/198853
• topic: Epigenetic; Fetal hemoglobin inducers; Gamma-globin inducers; Nitric oxide; Resveratrol; Sickle Cell Disease

Resveratrol (RVT) derivatives (10a-i) were designed, synthesized, and evaluated for their potential as gamma-globin inducers in treating Sickle Cell Disease (SCD) symptoms. All compounds were able to release NO at different levels ranging from 0 to 26.3%, while RVT did not demonstrate this effect. In vivo, the antinociceptive effect was characterized using an acetic acid-induced abdominal contortion model. All compounds exhibited different levels of protection, ranging from 5.9 to 37.3%; the compound 10a was the most potent among the series. At concentrations between 3.13 and 12.5 µM, the derivative 10a resulted in a reduction of 41.1–64.3% in the TNF-α levels in the supernatants of macrophages that were previously LPS-stimulated. This inhibitory effect was higher than that of RVT used as the control. In addition, the compound 10a and RVT induced double the production of the gamma-globin chains (γG + γA), compared to the vehicle, using CD34+ cells. Compound 10a also did not induce membrane perturbation and it was not mutagenic in the in vivo assay. Thus, compound 10a emerged as a new prototype of the gamma-globin-inducer group with additional analgesic and anti-inflammatory activities and proving to be a useful alternative to treat SCD symptoms.