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Targeting histone deacetylase (HDAC-1 and HDAC-2) as mechanisms to induce fetal hemoglobin in sickle cell disease

Abstract

Sickle cell disease (SCD) is one of the most prevalent chronic hereditary hemoglobinopathies worldwide. Currently, the only drug available for its treatment is hydroxyurea, responsible among other actions, to increase the levels of fetal hemoglobin (HbF). Gamma-globin gene regulation is complex and involves various proteins and enzymes, such as histone deacetylase (HDAC). HADC inhibitors, like the butyrate has shown effect to induce HbF levels both in vitro and in vivo. Class I HDAC inhibition, specifically HDAC-1 and HDAC-2, proved to be a promising strategy to promote increased gene expression of gamma-globin and production of HbF without causing changes in the cell cycle and proliferation.In this proposal, in continuity with our research aiming to identify new drugs to treat SCD symptoms, we describe herein the synthesis and pharmacological evaluation of new compounds designed as HDAC-1 and HDAC-2 inhibitors obtained by molecular hybridization approach. (AU)

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Scientific publications (10)
(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; 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, . (16/09502-7, 15/19531-1, 13/04244-1, 10/12495-6, 14/00984-3, 14/06755-6)
DOS SANTOS FERNANDES, GUILHERME FELIPE; PAVAN, ALINE RENATA; DOS SANTOS, JEAN LEANDRO. Heterocyclic N-oxides - A Promising Class of Agents against Tuberculosis, Malaria and Neglected Tropical Diseases. CURRENT PHARMACEUTICAL DESIGN, v. 24, n. 12, p. 1325-1340, . (15/21252-3, 16/09502-7, 15/19531-1)
DUTRA, LUIZ ANTONIO; GUANAES, JESSICA FRADE O.; JOHMANN, NADINE; LOPES PIRES, MARIA ELISA; CHIN, CHUNG MAN; MARCONDES, SISI; DOS SANTOS, JEAN LEANDRO. Synthesis, antiplatelet and antithrombotic activities of resveratrol derivatives with NO-donor properties. Bioorganic & Medicinal Chemistry Letters, v. 27, n. 11, p. 2450-2453, . (15/19531-1, 11/15520-4, 15/21271-8, 14/03945-9)
CHELUCCI, RAFAEL C.; DE OLIVEIRA, ISABELA J.; BARBIERI, KARINA P.; LOPES-PIRES, MARIA E.; POLESI, MARISA C.; CHIBA, DIEGO E.; CARLOS, IRACILDA Z.; MARCONDES, SISI; DOS SANTOS, JEAN L.; CHUNG, MANCHIN. Antiplatelet activity and TNF- release inhibition of phthalimide derivatives useful to treat sickle cell anemia. MEDICINAL CHEMISTRY RESEARCH, v. 28, n. 8, p. 1264-1271, . (15/19531-1, 13/23461-3)
SANTOS FERNANDES, GUILHERME FELIPE; BERNARDES SILVA, GABRIEL DALIO; PAVAN, ALINE RENATA; CHIBA, DIEGO EIDY; CHIN, CHUNG MAN; DOS SANTOS, JEAN LEANDRO. Epigenetic Regulatory Mechanisms Induced by Resveratrol. NUTRIENTS, v. 9, n. 11, . (16/08880-8, 15/19531-1, 16/09502-7, 16/08470-4)
DOS SANTOS FERNANDES, GUILHERME FELIPE; DE SOUZA, PAULA CAROLINA; MORENO-VIGURI, ELSA; SANTIVANEZ-VELIZ, MERY; PAUCAR, ROCIO; PEREZ-SILANES, SILVIA; CHEGAEV, KONSTANTIN; GUGLIELMO, STEFANO; LAZZARATO, LORETTA; FRUTTERO, ROBERTA; et al. Design, Synthesis, and Characterization of N-Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity. Journal of Medicinal Chemistry, v. 60, n. 20, p. 8647-8660, . (15/19531-1, 14/24811-0, 16/09502-7, 14/03920-6, 14/02240-1, 16/02860-5, 13/14957-5, 14/11586-9)
DUTRA, LUIZ ANTONIO; HEIDENREICH, DAVID; BERNARDES DA SILVA, GABRIEL DALIO; CHIN, CHUNG MAN; KNAPP, STEFAN; DOS SANTOS, JEAN LEANDRO. Dietary Compound Resveratrol Is a Pan-BET Bromodomain Inhibitor. NUTRIENTS, v. 9, n. 11, . (16/08880-8, 15/19531-1, 14/03945-9)
PAVAN, ALINE RENATA; BERNARDES DA SILVA, GABRIEL DALIO; JORNADA, DANIELA HARTMANN; CHIBA, DIEGO EIDY; DOS SANTOS FERNANDES, GUILHERME FELIPE; CHIN, CHUNG MAN; DOS SANTOS, JEAN LEANDRO. Unraveling the Anticancer Effect of Curcumin and Resveratrol. NUTRIENTS, v. 8, n. 11, . (14/14980-0, 15/19531-1, 14/24811-0, 14/02240-1, 16/08470-4, 15/21252-3)
DE SOUZA, P. C.; FERNANDES, G. F. S.; MARINO, L. B.; RIBEIRO, C. M.; DA SILVA, P. B.; CHORILLI, M.; SILVA, C. S. P.; RESENDE, F. A.; SOLCIA, M. C.; DE GRANDIS, R. A.; et al. Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection. BIOMEDICINE & PHARMACOTHERAPY, v. 130, . (18/11079-0, 18/00163-0, 14/03920-6, 17/12419-7, 16/09502-7, 14/02240-1, 13/14957-5, 16/02860-5, 14/24811-0, 16/24633-0, 18/17739-2, 15/19531-1, 16/22429-7, 14/11586-9)
PAVAN, ALINE RENATA; DOS SANTOS, JEAN LEANDRO. Advances in Sickle Cell Disease Treatments. Current Medicinal Chemistry, v. 28, n. 10, p. 2008-2032, . (18/19523-7, 15/19531-1)

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