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Biorreductive Quinazolines: synthesis and biological evaluation for PET diagnostic and treatment of hypoxic tumors

Grant number: 13/27186-7
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): September 01, 2014
Effective date (End): October 01, 2018
Field of knowledge:Health Sciences - Pharmacy
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Ivone Carvalho
Grantee:Paulo Sérgio Gonçalves Nunes
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):17/04599-5 - Novel fluoro-quinazoline derivatives bearing a bioreductive group for tumoral hypoxia diagnosis, BE.EP.DR


The hypoxia observed in tumors is characterized by a decrease in oxygen supply to a particular tissue or cell due to decreased blood supply, and is associated with resistance to conventional chemotherapy and radiotherapy. The tumors hypoxia treatment and diagnosis with biorreductível compounds, such as nitro- derivatives and hydroquinones, exploits the potential of reducing differentiated cells in the region of hypoxia due to the presence of reductase enzymes. However, some limitations are observed in relation to the compounds currently used for both the treatment performed with biorreductivel prodrugs, as for diagnosis by positron emission tomography (PET using 18F. Thus, this study aims to synthesize and evaluate the biological activity of compounds containing the quinazoline privileged structure, substituted at C - 5, C - 6 and C - 8, by methoxyl, fluoro - ethyl and nitro - aromatic or heteroaromatic, respectively, useful in the treatment and diagnosis of tumors hypoxia. The compounds are synthesized from 4,5- dimetoxiantranílico acid, using classical for obtaining 8-chloro- quinazoline intermediate methods which have chlorine - substituted aromatic nitro group such as 2 - ([4- nitrobenzyl]oxy) ethaneamine or nitroimidazole followed by selective deacetylation replacement with fluoro- ethyl at C- 6. The addition of fluoride - ethyl group will be held in the last stages of the synthetic route to allow obtaining the derivative labeled with radioactive 18F. Compounds are initially obtained with the cold fluorine (19F), and have evaluated their cytotoxic activity in vitro models. Compounds that show the best performance will be synthesized with the addition of 18F and subjected to the test for uptake into cells in hypoxia, and finally evaluating the in vivo biodistribution. (AU)

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Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
NUNES, Paulo Sérgio Gonçalves. Synthesis of novel quinazolines for the treatment of tumors under hypoxia and nitroimidazole for diagnosis by PET. 2018. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) Ribeirão Preto.

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