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Previous issue date: 2017-07-21 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) / O estudo dos compostos heteroc?clicos nitrogenados compreende um dos ramos mais interessantes da qu?mica org?nica. Dentre as diversas classes de heterociclos nitrogenados relatados, as quinoxalinas possuem papel de destaque por suas relevantes aplica??es, notavelmente em ?reas biol?gicas e tecnol?gicas. Existem diversos protocolos de s?ntese de derivados quinoxal?nicos relatados na literatura, dentre os quais se destacam as rea??es a partir do precursor sint?tico 2,3-dicloroquinoxalina (1). O presente trabalho tem como enfoque a atua??o do composto 1 como precursor sint?tico para mol?culas relevantes, estando os resultados dividido em duas partes principais. Primeiramente, ? apresentado um estudo preparativo focado nas rea??es da quinoxalina 1 com aminoalco?is, al?m de outras transforma??es sint?ticas. Foram obtidos produtos tais como 2,3-dietanolaminoquinoxalina (2), 2-(2,3-diidro-]1,4]oxazino[3,2-b]quinoxal-4-il)etanol (3) a partir de dupla substitui??o do cloro, al?m do produto 3-[bis-(2-hidroxi-etil)-amino]-1H-quinoxalin-2-ona (4) como fruto da hidr?lise do composto (3), dentre outros. Um fator de destaque ? que enquanto etanolamina reage via duplo N-ataque nucleof?lico, dietanolamina reage via processo de cicliza??o intramolecular atrav?s de N- e O-ataques. Todos os produtos foram devidamente caracterizados por resson?ncia magn?tica nuclear de 1H e 13C. Os produtos 2 e 3 apresentaram atividade antic?ncer atrav?s de estudos citot?xicos em c?lulas HT29 (c?ncer colorretal), a qual pode estar relacionada com a inibi??o da enzima PI3K?. Ambas as quinoxalinas impactaram significativamente a viabilidade celular, na menor concentra??o (3,125?g/mL) j? ? poss?vel vermos que o crescimento foi retardado. O que p?de tamb?m ser constatado por meio de um estudo de docking dos compostos no s?tio ativo da enzima PI3K?, o qual mostrou que a intera??o acontece fundamentalmente atrav?s de liga??es de hidrog?nio entre as hidroxilas dos ligantes e os amino?cidos valina (Val851) e serina (Ser854), conhecidos por serem cruciais nesse processo inibit?rio provocado por f?rmacos. Na ?ltima parte do trabalho, foi avaliada a capacidade do composto 2 como agente redutor e estabilizante de nanopart?culas de prata (NanoAg), utilizando um planejamento fatorial 22, e tamb?m sua atua??o apenas como estabilizante em sua concentra??o m?nima conseguida (0,2mmol-1) utilizando o sistema glicerol/NaOH, na qual o derivado 2 foi capaz de estabilizar (NanoAg) em meio b?sico e neutro (fisiol?gico). Os resultados apontaram que a referida quinoxalina apresenta capacidade de redu??o de prata (I) em meio b?sico, por?m em cin?tica mais lenta, comparado ao seu uso apenas como agente estabilizante. E as an?lises por espectroscopia na regi?o do ultravioleta/vis?vel (UV-Vis) indicaram forma??o de NanoAg esf?ricas, assim como o c?lculo da largura ? meia altura da banda (LMAB) indicaram a forma??o de nanopart?culas mais uniformes para estes ensaios. Portanto, em ambos os testes a atua??o do composto 2 frente ? forma??o de NanoAg deixa a possibilidade de aplica??es futuras dos sistemas nanoestruturados para terapia do c?ncer. / The study of nitrogen heterocyclic compounds comprises one of the most interesting branch of the organic chemistry. Among several nitrogen heterocycles reported in literature, quinoxaline derivatives have been attracted great attention due their relevant applications, notably in biological and technological fields. There are several synthetic protocols reported in literature for the synthesis of quinoxaline derivatives, in which calls attention the use of compound 2,3-dichloroquinoxaline (1) as synthetic precursor. The present work focus on the synthesis of relevant quinoxaline from compound 1, with the results being divided in two main parts. Many of the presented reactions lead to quinoxaline derivatives with relevance in several areas, especially due their relevant activities against several pathologies. The second part of the work is focused in the obtainment of quinoxaline derivatives from reactions of building block 1 with aminoalcohol, besides other synthetic transformations. They were obtained interesting quinoxaline derivatives, such as compounds 2,3-diethanolaminoquinoxaline (2), 2-(2,3-dihydro-1-oxa-4,9,10-triaza-anthracen-4-yl)-ethanol (3), from the double substitution by the nucleophilic species, compound 3-[bis-(2-hydroxy-ethyl)-amino]-1H-quinoxalin-2-one (4) originated from the hydrolysis of compound 3, among others. An important factor is that while ethanolamine reacts via double nucleophilic N-attack, diethanolamine reacts via intramolecular cyclization process through N- and O-attacks. All products were adequately characterized by 1H and 13C nuclear magnetic resonance spectroscopies. Compounds 2 and 3 had presented interesting activity against colon rectal HT29 cancer cells, in which the activity may be associated to the inhibition of enzyme PI3K?. Both quinoxalines significantly affected cell viability depending on the lower concentration (3.125 ?g / mL), it is possible to see that the growth was delayed. This could also be verified by means of a docking study of the compounds in the active site of the enzyme PI3K?, which showed that the interaction occurs mainly through hydrogen bonds between the hydroxyls of the ligands and the amino acids valine (Val851) and serine ( Ser854), known to be crucial in this drug-induced inhibitory process. Lastly, the ability of compound 2 as a silver nanoparticle reducing agent (NanoAg), using a factorial design 22, and its performance as a stabilizer in its minimum achieved concentration (0.2 mmol / l) using the glycerol / NaOH, in which derivative 2 was able to stabilize (NanoAg) in basic and neutral (physiological) medium. The results showed that quinoxaline has silver (I) reduction capacity in basic medium, but in slower kinetics. And spectroscopy analyzes in the ultraviolet / visible (UV-Vis) region indicated a formation of spherical NanoAg, and the bandwidth width calculation indicated the formation of more uniform nanoparticles for these assays. Therefore, in both tests the performance of compound 2 against the formation of NanoAg leaves the possibility of future applications of nanostructured systems for cancer therapy.
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.ufrn.br:123456789/24415 |
| Date | 21 July 2017 |
| Creators | Neri, Jannyely Moreira |
| Contributors | 03114939988, Lima, Kassio Michell Gomes de, 03144855464, Elias, Welman Curi, 21881724859, Menezes, Fabricio Gava |
| Publisher | PROGRAMA DE P?S-GRADUA??O EM QU?MICA, UFRN, Brasil |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Source | reponame:Repositório Institucional da UFRN, instname:Universidade Federal do Rio Grande do Norte, instacron:UFRN |
| Rights | info:eu-repo/semantics/openAccess |
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