Synthesis and evaluation of resveratrol derivatives as fetal hemoglobin inducers

• Published in: Bioorganic chemistry Vol. 100; p. 103948
• Main Authors: Bosquesi, Priscila Longhin, Melchior, Aylime Castanho Bolognesi, Pavan, Aline Renata, Lanaro, Carolina, de Souza, Cristiane Maria, Rusinova, Radda, Chelucci, Rafael Consolin, Barbieri, Karina Pereira, Fernandes, Guilherme Felipe dos Santos, Carlos, Iracilda Zepone, Andersen, Olaf Sparre, Costa, Fernando Ferreira, Dos Santos, Jean Leandro
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.07.2020; Elsevier
• Subjects: Analgesics - chemical synthesis; Analgesics - therapeutic use; Animals; Biochemistry & Molecular Biology; Cells, Cultured; Chemistry; Chemistry, Organic; Constriction, Pathologic - chemically induced; Constriction, Pathologic - drug therapy; Disease Models, Animal; Epigenetic; Fetal hemoglobin inducers; Gamma-globin inducers; Humans; Interleukin-1beta - metabolism; Life Sciences & Biomedicine; Lipopolysaccharides - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Nitric oxide; Nitric Oxide - metabolism; Physical Sciences; Resveratrol; Resveratrol - analogs & derivatives; Resveratrol - pharmacology; Resveratrol - therapeutic use; Science & Technology; Sickle Cell Disease; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - metabolism; NO; FDA; DNS; DIP; Epigenetic; HPFH; IL-1β; NGF; HbF; HU; Fetal hemoglobin inducers; LPS; sGC; RVT; RBC; TNF-α; SCD; Nitric oxide; DBU; Resveratrol; Sickle Cell Disease; DMAP; HbS; Gamma-globin inducers; HYBRID COMPOUNDS; ANALGESIC DRUGS; SICKLE; SIGNALING PATHWAYS; PAIN; FUROXAN DERIVATIVES; NITRIC-OXIDE; GENE-EXPRESSION; TNF-ALPHA; PHARMACOLOGICAL EVALUATION
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103948

[Display omitted] •New resveratrol derivatives (10a-i) with NO-donor properties.•All compounds exhibited in vivo analgesic effect.•All compounds did not induce membrane perturbation.•Compound 10a inhibited the production of the pro-inflammatory TNF-α and it was not mutagenic in the in vivo assay.•Compound 10a induced production of the gamma-globin chains (γG + γA) in CD34+ cells. 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.