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Doctoral Thesis
DOI
https://doi.org/10.11606/T.82.2019.tde-29102021-175606
Document
Author
Full name
Daiane Yukie Tezuka
Institute/School/College
Knowledge Area
Date of Defense
Published
São Carlos, 2019
Supervisor
Committee
Leitão, Andrei (President)
Prado Junior, Jose Clovis do
Albuquerque, Sérgio de
Anibal, Fernanda de Freitas
Machado Neto, João Agostinho
Pinto, Mara Cristina
Title in Portuguese
Caracterização in vitro da atividade de inibidores de cisteíno proteases em parasitos (Trypanosoma cruzi e Leishmania infantum) e células de câncer de próstata (DU-145 e a PC-3)
Keywords in Portuguese
Atividade antineoplásica
Derivados de dipeptidil nitrila
Doença de Chagas
Ensaios celulares
Leishmaniose
Abstract in Portuguese
As cisteíno proteases (CP) compõem uma classe de enzimas presentes em vários organismos e sua importância está bem definida em algumas doenças como câncer (catepsina L), doença de Chagas (cruzaína) e leishmaniose (CPB). Considerando a similaridade entre as CPs presentes nessas patologias, foi investigada a importância dessas enzimas para o desenvolvimento dessas doenças a partir da atividade biológica in vitro de novas dipeptidil nitrilas reversíveis de CP. A atividade dessas substâncias foi avaliada através de ensaios celulares nessas três doenças, na busca por novas alternativas terapêuticas. No estudo realizado com as linhagens de câncer de próstata DU-145 e PC-3, os compostos NEQ0677 e NEQ0681 foram os mais promissores, com maior potência citotóxica tanto quanto citostática nessas células. Além disso, foram eficazes em inibir a migração e a formação de colônias, processos importantes para o processo metastático. Em T. cruzi, o teste com as três formas do parasito levou a distintas respostas biológicas para Neq0677 e Neq0690. Além disso, estudos de terapia combinada das substâncias Neq0827 e Neq0831 combinadas com o Benznidazol levaram a um efeito sinérgico na forma amastigota. Essa série de substâncias foram seletivas para a forma amastigota de Leishmania spp. De maneira geral, os resultados obtidos mostraram respostas distintas para as diferentes doenças abordadas neste trabalho.
Title in English
In vitro characterization of cysteine protease inhibitor activity on parasites (Trypanosoma cruzi and Leishmania infantum) and prostate cancer cells (DU-145 and PC-3).
Keywords in English
Antineoplastic activity
Cell assays
Chagas disease
Dipeptidyl nitrile derivatives
Leishmaniasis
Abstract in English
Cysteine proteases (CP) are a class of enzymes present in many organisms and their importance is well defined in some diseases such as cancer (cathepsin L), Chagas disease (cruzain) and leishmaniasis (CPB). Considering the similarity between the PC's present in these pathologies, the importance of these enzymes for the development of these diseases was investigated from the in vitro biological activity of new reversible PC dipeptidyl nitriles. The activity of these substances was evaluated through cellular assays in these three diseases, searching for new therapeutic alternatives. In the study performed with prostate cancer strains DU-145 and PC-3, the compounds NEQ0677 and NEQ0681 were the most promising, with higher cytotoxic and cytostatic potency in these cells. In addition, they were effective in inhibiting migration and colony formation, important processes for the metastatic process. In T. cruzi, testing with the three parasite forms led to distinct biological responses to Neq0677 and Neq0690. In addition, combined therapy studies of Neq0827 and Neq0831 combined with Benznidazole have led to a synergistic effect on amastigote form. This series of substances were selective for the amastigote form of Leishmania spp. In general, the results obtained showed different responses to the different diseases addressed in this paper.
 
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Publishing Date
2021-11-26
 
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