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Master's Dissertation
DOI
Document
Author
Full name
Marcelo Thaad Fernandes Soares
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Bernardes, Emerson Soares (President)
Abdalla, Dulcineia Saes Parra
Quaglio, Luciana Malavolta
Title in Portuguese
Síntese e caracterização da fluoroetil melatonina
Keywords in Portuguese
fluoração
fluoroetil
melatonina
Abstract in Portuguese
A melatonina é um neurohormônio presente em vários processos biológicos no organismo, apresentando receptores MT1 e / ou MT2, mesmo em células cancerígenas. A melatonina começou a ser receitada a pacientes com câncer desde o final do século XIX na forma de estrato de pineal, porém somente no final do século XX começou a se entender que a melatonina apresenta um efeito de restrição no crescimento descontrolado de alguns tipos de células cancerígenas, sendo que sua ausência completa no organismo está ligado ao crescimento de tumores e tendências de metastização. Essa molécula também interage com medicamentos utilizados na terapia oncológica, apresentando bons resultados e reforçando a terapia empregada. A expressão dos receptores MT1 em células de câncer de mama (ER+) é um fator de prognóstico independente, o que indica um potencial para diagnósticos e tratamento de tumores de mama. O objetivo deste trabalho foi desenvolver uma molécula análoga da melatonina marcada com flúor com o intuito de criar uma nova ferramenta para o diagnóstico de tumores que expressam os receptores MT1/MT2, utilizando a técnica de tomografia por emissão de pósitrons (PET). Para gerar a molécula da fluoroetil melatonina foi empregado uma fluoração indireta, utilizando o grupo prostético fluoroetil, proveniente da molécula fluoroetil tosilato preparada para posterior síntese com a melatonina. A reação utilizou hidreto de sódio como base forte, dimetilformamida (DMF) como solvente, melatonina e o fluoroetil tosilato, sendo o tosilato um bom grupo abandonador. Esta reação de substituição nucleofílica bimolecular (SN2), foi feita em temperatura ambiente com duração de 20 horas. O produto obtido foi purificado e caracterizado usando técnicas de espectrometria de massas e espectroscopia por ressonância magnética nuclear (RMN) de hidrogênio, carbono e flúor confirmando a formação da molécula da fluoroetil melatonina, com um rendimento de 35%. Com a fluoroetil melatonina caracterizada, ela servirá de padrão e ponto partida para síntese da melatonina com flúor -18, o que permitirá que a molécula seja avaliada como um potencial novo traçador de tumores que expressam os receptores MT1/MT2 da melatonina.
Title in English
Synthesis and characterization of fluoroethyl melatonin
Keywords in English
fluorination
fluoroethyl
melatonin
Abstract in English
Melatonin is a neurohormone that regulates several biological processes in the body, including cancer, mainly through MT1 and / or MT2 receptors. Melatonin was first prescribed to cancer patients in the late 19th century as a pineal stratum. Still, it was only in the late 20th century that the molecular mechanism by which melatonin reduces the growth of some cancer cells began to be understood. Moreover, it was found that the complete absence of melatonin in the body was linked to tumor growth and increased metastatic potential. Melatonin was found to interact with several cytotoxic drugs used in cancer therapy, presenting good results and reinforcing the therapy employed. The expression of MT1 receptors in breast cancer cells (ER +) was found to be an independent prognostic factor, indicating a potential for melatonin to be used in the diagnose and treatment of breast cancer. The aim of this study was to develop a fluorine-labeled melatonin analog molecule to create a new diagnostic tool for MT1/MT2-expressing tumors by Positron Emission Tomography (PET). To generate the fluoroethyl melatonin molecule an indirect fluorination was employed using the prosthetic group fluoroethyl from the fluoroethyl tosylate molecule prepared for subsequent synthesis with melatonin. The synthesis was prepared uing sodium hydride as a strong base, dimethylformamide (DMF) as solvent, melatonin and fluoroethyl tosylate (tosylate is a good leaving group). The bimolecular nucleophilic substitution reaction (SN2) was performed at room temperature, for 20 hours. The reaction product was purified and characterized using mass spectrometry and hydrogen, carbon and fluorine nuclear magnetic resonance (NMR) spectroscopy techniques, confirming the formation of the fluoroethyl melatonin molecule with a 35% yield. The fluoroethyl melatonin obtained from this study will serve as the standard and starting point for the synthesis of fluorine-18 melatonin, which will allow the molecule to be evaluated as a potential new tumor tracer for MT1 / MT2-expressing tumors.
 
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Publishing Date
2019-11-07
 
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