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

Grant number: 12/50359-2
Support type:Research Grants - Research Partnership for Technological Innovation - PITE
Duration: September 01, 2013 - December 31, 2015
Field of knowledge:Health Sciences - Pharmacy
Cooperation agreement: GlaxoSmithKline
Principal Investigator:Jean Leandro dos Santos
Grantee:Jean Leandro dos Santos
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
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)

Articles published in Agência FAPESP Newsletter about the research grant
Brazilian drug shows good results against sickle cell anemia 

Scientific publications (4)
(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)
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; FRUTTERO, ROBERTA; GRAMINHA, MARCIA A. S.; DOS SANTOS, JEAN LEANDRO. Leishmanicidal Activities of Novel Synthetic Furoxan and Benzofuroxan Derivatives. Antimicrobial Agents and Chemotherapy, v. 58, n. 8, p. 4837-4847, AUG 2014. Web of Science Citations: 25.
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; CHUNG, MAN CHIN; DOS SANTOS, JEAN LEANDRO. 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, JUL 15 2014. Web of Science Citations: 6.
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, APR 2014. Web of Science Citations: 11.
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, FEB 2014. Web of Science Citations: 17.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.
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