S?ntese e avalia??o farmacol?gica de novas imidazolonas planejadas como inibidoras de ciste?no proteases para o tratamento da leucemia

• Ano de defesa: 2013
• Autor(a) principal: Azevedo, Luciana Luiz de
• Orientador(a): K?mmerle, Arthur Eugen
• Banca de defesa: Souza, Rodrigo Octavio Mendon?a Alves, Lacerda, Renata Barbosa, Romeiro, Nelilma Correia
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal Rural do Rio de Janeiro
• Programa de Pós-Graduação: Programa de P?s-Gradua??o em Qu?mica
• Departamento: Instituto de Ci?ncias Exatas
• País: Brasil
• Palavras-chave em Português: Leucemia; imidazolonas; atividade antitumoral
• Palavras-chave em Inglês: Leukemia; imidazolones; antitumor activity
• Área do conhecimento CNPq: Qu?mica
• Link de acesso: https://tede.ufrrj.br/jspui/handle/jspui/2747

Cancer is described as a set of more than 100 different diseases that have in common the uncontrolled growth of abnormal cells that invade tissues and organs, been considered by the World Health Organization as one of the biggest health problems facing humanity at this century. Deubiquitinases (cysteine proteases) are potential therapeutic targets in cancer treatment. These enzymes are responsible for the regulation of many cellular processes, among them, the cell multiplication one. Thus, this work proposes the design and synthesis of molecules that could modulate the action of these enzymes, aiming at preventing tumor cell proliferation. The molecules described herein belong to the class of imidazolones and were planned from the class of tyrphostins, which are remarkably active inhibiting cell lines from chronic myelogenous leukemia. For this purpose we synthesized 3 series of correlated imidazolone compounds planned as inhibitors of deubiquitinases and evaluated their biological activities against different leukemic cell lines. The imidazolones were synthesized by means of an Erlenmeyer reaction, followed by reaction with aniline or benzylamine in a pyridine and acetic acid medium, which was essential to our synthesis. It was observed the formation of diastereoisomeric mixture for some products synthesized, and their isomeric ratios were determined by analysis of 1H NMR spectra, ranging from 85-100% for the Z isomer, which was experimentally characterized by 13C NMR coupled to hydrogen over long distances. Some imidazolones were selected for antitumor activity evaluation by MTT colorimetric assay. The effectiveness of the compounds was determined by observation of cell viability at the highest concentration (50?M) in culture of two different leukemic cell lines, K562 and Lucena-1. The viability of these cells ranged from 61.4 to 6.1%. Their potencies were determined and the results ranged from 57.8 to 20.4?M. The products with the best antitumor activity were 39h and 41a, which showed cell viability of 16.7% and 19.7% for K562, respectively, and 6.1% and 13.7% for the Lucena-1. Compounds also presented CE50 of 20.4?M to 39h and 24.1?M for 41a in K562, and 22.7?M for 39h and 25?M for 41a in Lucena-1. The results of antitumor activity for both cell lines were similar both in potency and in maximum effectiveness. This fact was not expected, since the Lucena-1 cell presents multidrug resistance. Thus, the results obtained for our series of proposed imidazolones make them interesting as new lead compounds for the treatment of leukemia. The results supported the design of this work, once until now, the tested imidazolones presented greater antitumor activity compared to prototypes that inspired the design.