Optimization, synthesis and pharmacological evaluation of new drug candidates to treat the symptoms of sickle cell disease

• Grant number: 10/12495-6
• Support Opportunities: Regular Research Grants
• Duration: January 01, 2011 - March 31, 2013
• Field of knowledge: Health Sciences - Pharmacy - Medicines Analysis and Control
• Principal Investigator: Jean Leandro dos Santos
• Grantee: Jean Leandro dos Santos
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Sickle cell disease (SCD) is an hereditary chronic hemolytic anemia due to the inheritance of hemoglobin S gene from each parent, and is characterized by the presence of red blood cells that when deprived of oxygen, take the form of sickle. It has been reported that patients with SCD have increased circulating levels of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha). Hydroxyurea (HU) is the most widely drug used for treatment and its beneficial effects are related in part to the ability of HU after in vivo biotransformation converted to nitric oxide (NO). Among the beneficial effects of NO include: vasodilation, inhibition of platelet aggregation and induction of gamma globin gene expression - constituent of fetal hemoglobin. In this context, in continuity with a research aimed at planned, synthesized and evaluated through pharmacological assays new drug candidates to treat the symptoms of sickle cell disease will be synthesized, for optimization purposes, a series of hybrid compounds (3a-h) according to the structural planning (Figure 1). The strategy of NO donation associated with TNF-alpha inhibition represents a new therapeutic approach to treat the symptoms of sickle cell disease, and showed promise in accordance with previously data obtained in our laboratory. (AU)

Scientific publications

(12)

(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)

DOS SANTOS, JEAN LEANDRO; LANARO, CAROLINA; LIMA, LIDIA MOREIRA; GAMBERO, SHELEY; FRANCO-PENTEADO, CARLA FERNANDA; AEXANDRE-MOREIRA, MAGNA SUZANA; WADE, MARLENE; YERIGENAHALLY, SHOBHA; KUTLAR, ABDULLAH; MEILER, STEFFEN E.; et al. Design, Synthesis, and Pharmacological Evaluation of Novel Hybrid Compounds To Treat Sickle Cell Disease Symptoms. Journal of Medicinal Chemistry, v. 54, n. 16, p. 5811-5819, AUG 25 2011. (07/56115-0, 10/12495-6)

DOS SANTOS, JEAN LEANDRO; BOSQUESI, PRISCILA LONGHIN; VARANDA, ELIANA APARECIDA; LIMA, LIDIA MOREIRA; CHUNG, MAN CHIN. Assessment of the In Vivo Genotoxicity of New Lead Compounds to Treat Sickle Cell Disease. Molecules, v. 16, n. 4, p. 2982-2989, APR 2011. (10/12495-6)

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)

SILVA, FABIO H.; KARAKUS, SERKAN; MUSICKI, BILJANA; MATSUI, HOTAKA; BIVALACQUA, TRINITY J.; DOS SANTOS, JEAN L.; COSTA, FERNANDO F.; BURNETT, ARTHUR L.. Beneficial Effect of the Nitric Oxide Donor Compound 3-(1,3-Dioxoisoindolin-2-yl)Benzyl Nitrate on Dysregulated Phosphodiesterase 5, NADPH Oxidase, and Nitrosative Stress in the Sickle Cell Mouse Penis: Implication for Priapism Treatment. Journal of Pharmacology and Experimental Therapeutics, v. 359, n. 2, p. 230-237, NOV 1 2016. (14/00984-3, 10/12495-6, 13/19781-2, 14/21965-7)

DOS SANTOS, JEAN LEANDRO; LANARO, CAROLINA; CHELUCCI, RAFAEL CONSOLIN; GAMBERO, SHELEY; BOSQUESI, PRISCILA LONGHIN; REIS, JULIANA SANTANA; LIMA, LIDIA MOREIRA; CERECETTO, HUGO; GONZALEZ, MERCEDES; COSTA, FERNANDO FERREIRA; et al. Design, Synthesis, and Pharmacological Evaluation of Novel Hybrid Compounds to Treat Sickle Cell Disease Symptoms. Part II: Furoxan Derivatives. Journal of Medicinal Chemistry, v. 55, n. 17, p. 7583-7592, SEP 13 2012. (07/56115-0, 10/12495-6)

JEAN LEANDRO DOS SANTOS; CHUNG MAN CHIN. Anemia falciforme: desafios e avanços na busca de novos fármacos. Química Nova, v. 35, n. 4, p. 783-790, 2012-00-00. (10/12495-6)

DOS SANTOS, JEAN LEANDRO; MOREIRA, VANESSA; CAMPOS, MICHEL LEANDRO; CHELUCCI, RAFAEL CONSOLIN; BARBIERI, KARINA PEREIRA; MAGGIO DE CASTRO SOUTO, POLLYANA CRISTINA; MATSUBARA, MARCIO HIDEKI; TEIXEIRA, CATARINA; BOSQUESI, PRISCILA LONGHIN; PECCININI, ROSANGELA GONCALVES; et al. Pharmacological Evaluation and Preliminary Pharmacokinetics Studies of a New Diclofenac Prodrug without Gastric Ulceration Effect. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 13, n. 11, p. 16-pg., 2012-11-01. (10/12495-6, 09/12664-5)

BOSQUESI, PRISCILA LONGHIN; FERREIRA MELO, THAIS REGINA; VIZIOLI, EDNIR OLIVEIRA; DOS SANTOS, JEAN LEANDRO; CHUNG, MAN CHIN. Anti-Inflammatory Drug Design Using a Molecular Hybridization Approach. PHARMACEUTICALS, v. 4, n. 11, p. 25-pg., 2011-11-01. (10/12495-6)

DOS SANTOS, JEAN LEANDRO; MOREIRA, VANESSA; CAMPOS, MICHEL LEANDRO; CHELUCCI, RAFAEL CONSOLIN; BARBIERI, KARINA PEREIRA; MAGGIO DE CASTRO SOUTO, POLLYANA CRISTINA; MATSUBARA, MARCIO HIDEKI; TEIXEIRA, CATARINA; BOSQUESI, PRISCILA LONGHIN; PECCININI, ROSANGELA GONCALVES; et al. Pharmacological Evaluation and Preliminary Pharmacokinetics Studies of a New Diclofenac Prodrug without Gastric Ulceration Effect. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 13, n. 11, p. 15305-15320, NOV 2012. (10/12495-6, 09/12664-5)

DOS SANTOS, J. L.; CHIN, C. M.. Recent Insights on the Medicinal Chemistry of Sickle Cell Disease. Current Medicinal Chemistry, v. 18, n. 15, p. 2339-2358, MAY 2011. (10/12495-6)

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)

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)