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Design, synthesis and pharmacological evaluation of new hybrid drugs useful to treat hematological disorders

Grant number: 12/50359-2
Support Opportunities:Research Grants - Research Partnership for Technological Innovation - PITE
Duration: September 01, 2013 - December 31, 2015
Field of knowledge:Health Sciences - Pharmacy - Medicines Analysis and Control
Convênio/Acordo: GlaxoSmithKline
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
Host Company: Glaxosmithkline Brasil Ltda
City: Araraquara

Abstract

Sickle Cell Disease (SCD) is characterized by a punctual mutation (GTG to GAG) at the sixth codon of the β-globin gene what leads to the substitution of glutamic acid to valine residue in the gene for β-globin chain. Nowadays, hydroxyurea (HU) is the only drug approved to treat the disease. However, the drug has several adverse effects such as mielosuppression and genotoxicity in long term therapy. AH these factors together justify the discovery of new drugs to treat SCD symptoms. Resveratrol, a stilbenoid, is a phytoaiexin produced naturally by several plants and it is present in large quantity in red wine. It has been reported that this compound demonstrated potent antioxidant, antiinflamatory and analgesic effect useful to treat SCD symptoms. In addition, some studies have shown that resveratrol is able to induce gamma-globin gene expression. Nitric oxide has an important role in SCD. The beneficial effects of NO include: vasodilation, inhibition of platelet aggregation and induction of gamma globin gene expression. We have previously reported that nitric oxide donor compounds are also able to induce gamma-globin gene expression and fetal hemoglobin. In a continuing effort to develop new candidate drugs to treat hemoglobinophaties symptoms (such as SCD) with improved pharmacodynamic profile, we propose here the design, synthesis, and pharmacological evaluation of new resveratrol derivatives (compounds 1-12), obtained by molecular hybridization of the prototypes resveratrol (1) and NO donors subunits represented by furoxan and organic nitrate esters. (AU)

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Scientific publications (8)
(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)
BOSQUESI, PRISCILA LONGHIN; BOLOGNESI MELCHIOR, AYLIME CASTANHO; PAVAN, ALINE RENATA; LANARO, CAROLINA; DE SOUZA, CRISTIANE MARIA; RUSINOVA, RADDA; CHELUCCI, RAFAEL CONSOLIN; BARBIERI, KARINA PEREIRA; DOS SANTOS FERNANDES, GUILHERME FELIPE; CARLOS, IRACILDA ZEPONE; et al. Synthesis and evaluation of resveratrol derivatives as fetal hemoglobin inducers. BIOORGANIC CHEMISTRY, v. 100, . (14/00984-3, 12/50359-2)
FERREIRA DE MELO, THAIS REGINA; CHELUCCI, RAFAEL CONSOLIN; LOPES PIRES, MARIA ELISA; DUTRA, LUIZ ANTONIO; BARBIERI, KARINA PEREIRA; BOSQUESI, PRISCILA LONGHIN; GOULART TROSSINI, GUSTAVO HENRIQUE; CHUNG, MAN CHIN; DOS SANTOS, JEAN LEANDRO. Pharmacological Evaluation and Preparation of Nonsteroidal Anti-Inflammatory Drugs Containing an N-Acyl Hydrazone Subunit. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 15, n. 4, p. 5821-5837, . (12/50359-2, 11/15204-5)
CHELUCCI, RAFAEL CONSOLIN; DUTRA, LUIZ ANTONIO; LOPES PIRES, MARIA ELISA; FERREIRA DE MELO, THAIS REGINA; BOSQUESI, PRISCILA LONGHIN; CHUNG, MAN CHIN; DOS SANTOS, JEAN LEANDRO. Antiplatelet and Antithrombotic Activities of Non-Steroidal Anti-Inflammatory Drugs Containing an N-Acyl Hydrazone Subunit. Molecules, v. 19, n. 2, p. 2089-2099, . (12/50359-2, 11/15204-5)
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., . (18/19523-7, 21/10059-9, 20/13279-7, 15/19531-1, 10/12495-6, 12/50359-2, 15/21252-3)
PINHEIRO, ANDRESSA KELY; PEREIRA, DALILA ANDRADE; DOS SANTOS, JEAN LEANDRO; CALMASINI, FABIANO BERALDI; ALEXANDRE, EDUARDO COSTA; REIS, LEONARDO OLIVEIRA; BURNETT, ARTHUR L.; COSTA, FERNANDO FERREIRA; SILVA, FABIO HENRIQUE. Resveratrol-nitric oxide donor hybrid effect on priapism in sickle cell and nitric oxide-deficient mouse. PLoS One, v. 17, n. 6, p. 13-pg., . (12/50359-2, 14/00984-3)
DUTRA, LUIZ ANTONIO; DE ALMEIDA, LETICIA; PASSALACQUA, THAIS G.; REIS, JULIANA SANTANA; TORRES, FABIO A. E.; MARTINEZ, ISABEL; PECCININI, ROSANGELA GONCALVES; CHIN, CHUNG MAN; CHEGAEV, KONSTANTIN; GUGLIELMO, STEFANO; et al. Leishmanicidal Activities of Novel Synthetic Furoxan and Benzofuroxan Derivatives. Antimicrobial Agents and Chemotherapy, v. 58, n. 8, p. 4837-4847, . (11/15520-4, 12/50359-2)
YAMASAKI, PAULO RENATO; DO NASCIMENTO, DEJAIR CAETANO; CHELUCCI, RAFAEL CONSOLIN; FERNANDES BELONE, ANDREA DE FARIA; ROSA, PATRICIA SAMMARCO; DIORIO, SUZANA MADEIRA; FERREIRA DE MELO, THAIS REGINA; BARBIERI, KARINA PEREIRA; POLESI PLACERES, MARISA CAMPOS; CARLOS, IRACILDA ZEPONE; et al. Synthesis and evaluation of novel dapsone-thalidomide hybrids for the treatment of type 2 leprosy reactions. Bioorganic & Medicinal Chemistry Letters, v. 24, n. 14, p. 3084-3087, . (12/50359-2)
FERREIRA DE MELO, THAIS REGINA; CHELUCCI, RAFAEL CONSOLIN; LOPES PIRES, MARIA ELISA; DUTRA, LUIZ ANTONIO; BARBIERI, KARINA PEREIRA; BOSQUESI, PRISCILA LONGHIN; GOULART TROSSINI, GUSTAVO HENRIQUE; CHUNG, MAN CHIN; DOS SANTOS, JEAN LEANDRO. Pharmacological Evaluation and Preparation of Nonsteroidal Anti-Inflammatory Drugs Containing an N-Acyl Hydrazone Subunit. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 15, n. 4, p. 17-pg., . (11/15204-5, 12/50359-2)

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Filed patent(s) as a result of this research project

PROCESSO DE OBTENÇÃO DE COMPOSTOS DERIVADOS ESTILBÊNICOS, COMPOSTOS DERIVADOS ESTILBÊNICOS E SEUS USOS BR1020160172438 - Universidade Estadual de Campinas (UNICAMP) ; Universidade Estadual Paulista (UNESP) . Jean Leandro Dos Santos ; Aylime Castanho Bolognesi Merchior Jesuíno ; Priscila Longhin Bosquesi De Oliveira ; Aline Renata Pavan ; Carolina Lanaro ; Chung Man Chin ; Fernando Ferreira Costa - July 2016, 25