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Abstract(s)
A química medicinal moderna tem-se mostrado fundamental no processo de descoberta e desenvolvimento de novos fármacos. Neste contexto, os N-óxidos de quinolina e as quinolinas têm despertado cada vez mais interesse aos químicos medicinais, uma vez que estes núcleos estão presentes em compostos bioativos, nomeadamente antibacterianos, antiparasitários, antimaláricos e anticancerígenos.
No decorrer da investigação laboratorial conducente a esta dissertação, em que se pretendia generalizar a obtenção de novos benzoisoxazol-3-ilidenos anteriormente descrita para 5-(benzoisoxazol-3-ilideno)pirimidinas, verificou-se a formação inesperada de N-óxidos de quinolina durante a redução de 2-nitrobenzilidenos (cíclicos e acíclicos) e de 2-nitrofenilmetilenos. Neste contexto, é aqui proposta e desenvolvida uma nova via sintética que permite a formação seletiva de N-óxidos de quinolina. Assim, na presença de um agente redutor (SnCl2·2H2O), o grupo nitro é parcialmente reduzido, formando-se uma hidroxilamina intermediária, a qual permite uma ciclização intramolecular com posterior eliminação de água, originando assim o N-óxido de quinolina correspondente.
Adicionalmente, 5-(benzoisoxazol-3-ilideno)pirimidinas, os N-óxidos e os precursores sintetizados foram testados in vitro como inibidores da xantina oxidase e foi avaliada a sua citotoxicidade numa linha celular do cancro da mama (MCF-7) e em fibroblastos normais da derme humana (NHDF). Dos resultados obtidos, destaca-se um dos precursores, 5,5'-((2-nitrofenil)metileno)bis(1,3-dietil-2-tioxodihidropirimidina-4,6(1H,5H)-diona) (7g), o qual apresenta um elevado potencial como inibidor da xantina oxidase (concentração inibitória a 50% = 6,1 µM). Assim, é necessária uma avaliação futura dos parâmetros cinéticos e mecanísticos de inibição desta enzima por parte deste composto, bem como a preparação de novos análogos para um melhor entendimento da respetiva relação estrutura-atividade. Relativamente aos estudos de citotoxicidade, destaca-se o (E)-3-(2-nitrofenil)-1-fenilprop-2-en-1-ona (6j) o qual levou a uma baixa proliferação (2,4%) das células MCF-7 a 30 µM. A este dado acresce o facto de não apresentar marcada citotoxicidade em NHDF, mostrando-se seletivo para a linha tumoral estudada. Aos ensaios de avaliação in vitro acresceram estudos complementares in silico, nomeadamente estudos de docking molecular e de ADMET.
Modern medicinal chemistry has been fundamental in the discovery and development of new drugs. In this context, quinoline N-oxides and quinolines have increasingly aroused interest for medicinal chemists, since these nuclei are present in bioactive compounds, namely antibacterial, antiparasitic, antimalarial and anticancer drugs. In the course of the laboratory investigation conducing to this dissertation, in which it was intended to generalize the application of the previously described preparation of new benzisoxazoles, it was observed the unexpected formation of quinoline N-oxides during the reduction of 2-nitrobenzylidenes (cyclic and acyclic) and 2-nitrophenylmethylenes. In this context, a new synthetic route is proposed and developed here, allowing the selective formation of quinoline N-oxides. Thus, in the presence of a reducing agent (SnCl2·2H2O), the nitro group is partially reduced, forming an intermediate hydroxylamine, which allows an intramolecular cyclization with subsequent elimination of water, affording the corresponding quinoline N-oxide. In addition, the synthesized 5- (benzoisoxazol-3-ylidene) pyrimidines, N-oxides and precursors were tested in vitro as xanthine oxidase inhibitors of and their cytotoxicity was assessed in a breast cancer cell line (MCF-7) and normal human dermal fibroblasts (NHDF). From the results obtained, it can be stated that one of the precursors, 5,5'-((2-nitrophenyl)methylene)bis(1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H, 5H)-dione) (7g), has a high potential as a xanthine oxidase inhibitor (half-maximal inhibitory concentration = 6.1 µM). Thus, it is necessary a future evaluation of the kinetic and mechanistic parameters of the inhibition of this enzyme by this compound, as well as the preparation of new analogues for a better understanding of the respective structure-activity relationships. In the cytotoxicity studies it was observed that (E)-3-(2-nitrophenyl)-1-phenylprop-2-en-1-one (6j) led to a low relative cell proliferation (2.4%) of MCF-7 cells at 30µM. As this compound does not presented marked cytotoxicity in NHDF its seem to be selective for the studied tumor line. Additional in silico studies, in particular molecular docking and ADMET previsions, were added to the in vitro evaluation assays.
Modern medicinal chemistry has been fundamental in the discovery and development of new drugs. In this context, quinoline N-oxides and quinolines have increasingly aroused interest for medicinal chemists, since these nuclei are present in bioactive compounds, namely antibacterial, antiparasitic, antimalarial and anticancer drugs. In the course of the laboratory investigation conducing to this dissertation, in which it was intended to generalize the application of the previously described preparation of new benzisoxazoles, it was observed the unexpected formation of quinoline N-oxides during the reduction of 2-nitrobenzylidenes (cyclic and acyclic) and 2-nitrophenylmethylenes. In this context, a new synthetic route is proposed and developed here, allowing the selective formation of quinoline N-oxides. Thus, in the presence of a reducing agent (SnCl2·2H2O), the nitro group is partially reduced, forming an intermediate hydroxylamine, which allows an intramolecular cyclization with subsequent elimination of water, affording the corresponding quinoline N-oxide. In addition, the synthesized 5- (benzoisoxazol-3-ylidene) pyrimidines, N-oxides and precursors were tested in vitro as xanthine oxidase inhibitors of and their cytotoxicity was assessed in a breast cancer cell line (MCF-7) and normal human dermal fibroblasts (NHDF). From the results obtained, it can be stated that one of the precursors, 5,5'-((2-nitrophenyl)methylene)bis(1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H, 5H)-dione) (7g), has a high potential as a xanthine oxidase inhibitor (half-maximal inhibitory concentration = 6.1 µM). Thus, it is necessary a future evaluation of the kinetic and mechanistic parameters of the inhibition of this enzyme by this compound, as well as the preparation of new analogues for a better understanding of the respective structure-activity relationships. In the cytotoxicity studies it was observed that (E)-3-(2-nitrophenyl)-1-phenylprop-2-en-1-one (6j) led to a low relative cell proliferation (2.4%) of MCF-7 cells at 30µM. As this compound does not presented marked cytotoxicity in NHDF its seem to be selective for the studied tumor line. Additional in silico studies, in particular molecular docking and ADMET previsions, were added to the in vitro evaluation assays.
Description
Keywords
2-Nitrobenzilidenos Ação Anti Proliferativa Inibição da Xantina Oxidase. N-Óxidos de Quinolina Nova Via Sintética