Design, synthesis and pharmacological evaluation of hydroxyurea derivatives designed as histone deacetylase inhibitors for Sickle Cell Anemia

• Grant number: 18/19523-7
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): January 01, 2019
• Effective date (End): June 30, 2023
• Field of knowledge: Health Sciences - Pharmacy - Medicines Analysis and Control
• Principal Investigator: Jean Leandro dos Santos
• Grantee: Aline Renata Pavan
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated scholarship(s): 21/10059-9 - Synthesis and pharmacological evaluation of PROTAC-HDAC inhibitors-based compounds for sickle cell disease, BE.EP.DR

Abstract

Sickle Cell Anemia (SCA) is the most prevalent genetic disease in world. The lack of new drugs and the low life expectancy are the cruel aspects of the disease. Nowadays, the therapeutic resource include hydroxyurea (HU) and supplementation with glutamine. In vivo, HU is bioconverted in nitric oxide which results in beneficial effects, being the increase in fetal hemoglobin production one of the most importants. However, myelosuppression and genotoxicity are adverse effects of HU treatment, besides the rate of non-responsive patients to the drug. All these data justifies the search for new treatment strategies. On this approach, the gene reactivaton of gama-globin and as consequence the increase in fetal hemoglobin production by genetic mechanisms are valuable therapeutic intervention. Studies have demonstrated histone deacetylases (HDAC) inhibition, especially HDAC-1 and 2, to be a promising strategy to perform an increasement of gama-globin expression and HbF production without cycle cell alteration. In this project we have proposed synthesis and pharmacological evaluation of new HU analogues design to be also HDAC 1 and 2 inhibitors. Thus, NO donation from HU associated with HDAC 1 and 2 inhibition might result in sinergic effect of HbF production, being a new therapeutic approach for Sickle Cell Anemia. (AU)

Scientific publications

(5)

(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)

PAVAN, ALINE RENATA; DOS SANTOS, JEAN LEANDRO. Advances in Sickle Cell Disease Treatments. Current Medicinal Chemistry, v. 28, n. 10, p. 2008-2032, 2021. (18/19523-7, 15/19531-1)

URIAS, BEATRIZ SILVA; PAVAN, ALINE RENATA; ALBUQUERQUE, GABRIELA RIBEIRO; PROKOPCZYK, IGOR MUCCILO; FERREIRA ALVES, TANIA MARA; FERREIRA DE MELO, THAIS REGINA; RODRIGUES SARTORI, GERALDO; MARTINS DA SILVA, JOAO HERMINIO; CHIN, CHUNG MAN; DOS SANTOS, JEAN LEANDRO. Optimization of Resveratrol Used as a Scaffold to Design Histone Deacetylase (HDAC-1 and HDAC-2) Inhibitors. PHARMACEUTICALS, v. 15, n. 10, p. 18-pg., 2022-10-01. (18/11079-0, 17/07789-0, 18/19523-7, 15/19531-1, 15/21252-3, 19/09456-3)

PAVAN, ALINE RENATA; LOPES, JULIANA ROMANO; LIMA IMPERADOR, CARLOS HENRIQUE; CHIN, CHUNG MAN; DOS SANTOS, JEAN LEANDRO. Perspectives and challenges to discovering hemoglobin-inducing agents in Sickle Cell Disease. FRONTIERS IN MEDICINE, v. 9, p. 4-pg., 2022-09-08. (19/10746-6, 18/19523-7, 20/13279-7)

TERRONI, BARBARA; OLIVEIRA DE MORAES, LUIS HENRIQUE; PAVAN, ALINE RENATA; RODRIGUES, GERSON JHONATAN; DOS SANTOS, JEAN LEANDRO. Vascular Effects of the Fetal Hemoglobin Inducer Agent 3-(1,3-Dioxoisoindolin-2-yl) Benzyl Nitrate. PHARMACEUTICALS, v. 15, n. 11, p. 12-pg., 2022-11-01. (20/13279-7, 18/19523-7)

PAVAN, ALINE RENATA; LOPES, JULIANA ROMANO; DOS SANTOS, JEAN LEANDRO. The state of the art of fetal hemoglobin-inducing agents. EXPERT OPINION ON DRUG DISCOVERY, v. 17, n. 11, p. 15-pg., 2022-11-07. (18/19523-7, 21/10059-9, 20/13279-7, 15/19531-1, 10/12495-6, 12/50359-2, 15/21252-3)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

PAVAN, Aline Renata. Design and synthesis of new inhibitors and degraders (PROteolysis TArgeting Chimera - PROTAC) of histone deacetylases (HDACs) 1 and 2 for sickle cell anemia. 2023. Doctoral Thesis - Universidade Estadual Paulista (Unesp). Instituto de Química. Araraquara Araraquara.