Synthesis, structural characterization and NO-donor evaluation of hybrid compounds useful to treat sickle cell disease symptoms

• Grant number: 13/04244-1
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: September 20, 2013
• End date: December 19, 2013
• Field of knowledge: Health Sciences - Pharmacy - Medicines Analysis and Control
• Principal Investigator: Jean Leandro dos Santos
• Grantee: Thaís Regina Ferreira de Melo
• Supervisor: Roberta Fruttero
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Institution abroad: Università degli Studi di Torino (UNITO), Italy
• Associated to the scholarship: 11/15204-5 - Synthesis and Pharmacological Evaluation of new hybrid compounds useful to treat sickle cell disease symptoms, BP.MS

Abstract

Sickle cell anemia (SCA) is a hereditary hemoglobinopathy characterized by a pumctual mutation at sixth codon of beta-globin gene, resulting in the replacement of a glutamic acid for valine at beta-globin chain. This modification promotes, at low oxygen concentrations, polymerization of hemoglobin molecules that alters the structure of the erythrocyte cytoskeleton (sickling) or cause erythrocyte hemolysis. Sickle cells exhibit increased adhesion to vascular endothelial cells promoting vaso-occlusive processes, major cause of symptomatic manifestations of the disease. It is known that the inflammatory process associated with disease contributes to a number of complications. Patients with SCA exhibit increased levels of tumor necrosis factor (TNF-alpha) and other pro-inflammatory cytokines. Currently, hydroxyurea (HU) is the only drug available for the treatment and its beneficial effects are associated with its biotransformation in vivo to nitric oxide (NO). NO plays beneficial effects such as vasodilation, inhibition of platelet aggregation and production of fetal hemoglobin (HbF), the latter serves to assist in the transport of oxygen in the patient's disease. The increase in HbF is associated with a decrease of vaso-occlusive processes. Continuing with our line of research, we intend to extend this proposed series of hybrid compounds with multiple activities: inhibiton of TNF-± andability to donor nitric oxide. This proposed is based on preliminary verification that higher NO donation by furoxan derivatives increase antiplatelet effects and induce gamma-globin gene expression and HbF, without altering TNF-± inhibition. Thus, for better understanding the pharmacological results obtained and partial enrichment of the work it will be synthesized a series of hybrid compounds (3a-b and 4a-b) according to the structural planning (Scheme 1). (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

FERREIRA DE MELO, THAIS REGINA; KUMKHAEK, CHUTIMA; DOS SANTOS FERNANDES, GUILHERME FELIPE; LOPES PIRES, MARIA ELISA; CHELUCCI, RAFAEL CONSOLIN; BARBIERI, KARINA PEREIRA; COELHO, FERNANDA; DE OLIVEIRA CAPOTE, TICIANA SIDORENKO; LANARO, CAROLINA; CARLOS, IRACILDA ZEPPONE; et al. Discovery of phenylsulfonylfuroxan derivatives as gamma globin inducers by histone acetylation. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 154, p. 341-353, JUN 25 2018. (10/12495-6, 14/00984-3, 16/09502-7, 13/04244-1, 14/06755-6)

FERREIRA DE MELO, THAIS REGINA; DULMOVITS, BRIAN M.; DOS SANTOS FERNANDES, GUILHERME FELIPE; DE SOUZA, CRISTIANE M.; LANARO, CAROLINA; HE, MINGHZU; AL ABED, YOUSEF; CHUNG, MAN CHIN; BLANC, LIONEL; COSTA, FERNANDO FERREIRA; et al. Synthesis and pharmacological evaluation of pomalidomide derivatives useful for sickle cell disease treatment. BIOORGANIC CHEMISTRY, v. 114, SEP 2021. (16/09502-7, 15/19531-1, 13/04244-1, 10/12495-6, 14/00984-3, 14/06755-6)