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Previous issue date: 2016-08-26 / CAPES / Utilizando a estratégia de hibridação molecular, neste trabalho foi construído uma
quimioteca de heterocíclicos furânicos, triazólicos e quinolínicos contendo o núcleo
naftoquinona, reunindo características estruturais de compostos bioativos distintos,
originando assim, moléculas híbridas com amplo potencial farmacológico.
Inicialmente, foram sintetizados seis derivados 2-acetoxi-3-alquinill-1,4naftoquinonas
via reação de acoplamento Sonogashira entre o 2-acetoxi-3-iodo-1,4naftoquinona
e diversos alquinos terminais funcionalizados com rendimentos que
variaram de 40-73%, que posteriormente foram submetidos a uma heterocilização
intramolecular, formando os derivados furanonaftoquinonas com rendimentos bons
entre 72-85%. Os derivados 2-acetoxi-3-alquinil-1,4-naftoquinonas e os
furanonaftoquinonas foram submetidos à avaliação do potencial citotóxico em três
linhagens de células de glioblastomas, GBMO2, GBM95 e A172, apresentando, no
geral, resultados satisfatórios para inibição do crescimento celular. Os compostos 2acetoxi-3-feniletinil-1,4-naftoquinona,
2-acetoxi-3-(4-metoxilfeniletinil)-1,4naftoquinona
e 2-acetoxi-3-(4-metilfeniletinil)-1,4-naftoquinona se destacaram dentre
as substâncias analisadas por apresentarem menor CI50 para as três linhagens
celulares de glioblastomas testadas, resultados estes significativos para dar
continuidade nos estudos de citotoxicidade. Em seguida, foi desenvolvida uma nova
rota sintética para obtenção por “click chemistry” de novos compostos aminoalquiltriazóis
naftoquinônicos através das reações de cicloadição 1,3-dipolar entre 2azidoalquilamino-1,4-naftoquinonas
e diversos alquinos terminais, sendo
sintetizados vinte novos derivados 2-[(1H-1,2,3-triazol-1-il)alquilamino]-1,4naftoquinonas
com rendimentos entre 70-97%. Estes heterocíclicos triazólicos foram
avaliados frente às linhagens tumorais HEp-2 (carcinoma de laringe humana), NCIH292
(carcinoma mucoepidermoide de pulmão humano), HT-29 (adenocarcinoma de
colón humano), MCF-7 (câncer de mama humano) e HL-60 (leucemia promielocitica
aguda). Os compostos 2-[2-(4-propil-1H-1,2,3-triazol-1-il)etilamino]-1,4-naftoquinona
e 2-{3-[4-(2-hidroxibutan-2-il)-1H-1,2,3-triazol-1-il]propilamino}-1,4-naftoquinona
exibiram citotoxicidade moderada frente às linhagens HL-60, HL-60 e MCF-7,
respectivamente, demonstrando ação inibitória seletiva. Por fim, foram sintetizados
vinte quatro derivados 6-alquilamino-5,8-quinolinoquinonas a partir de uma direta
aminação nucleofílica do 7-bromo-5,8-quinolinoquinona com aminas primárias e
secundárias, sendo desenvolvida uma nova estratégia sintética para a obtenção dos
compostos 6-alquilamino-5,8-quinolinoquinonas a partir de aminas primárias. Estes
compostos são promissores candidatos para desenvolvimento de novas drogas
antitumorais. / By using the strategy of molecular hybridization, in this work it was built a chemical
library with furan, triazole and quinoline heterocyclic compounds, containing the
naphthoquinone nucleus, gathering structural characteristics of distinct bioactives
resulting in hybrid molecules with large pharmacological potencial. Initially, six 2acetoxy-3-alkynyl-1,4-naphthoquinone
derivatives were synthesized through
Sonogashira cross coupling reaction involving 2-acetoxy-3-iodo-1,4-naphthoquinone
and several functionalized terminal alkynes in 40-73% yields, which later were
submitted to intramolecular heterocyclization, forming the furan derivatives in 72-85%
yields. The 2-acetoxy-3-alkynyl-1,4-naphthoquinone and furanonaphthoquinone
derivatives were submitted to cytotoxic screening against three glioblastoma cell
lines GBMO2, GBM95 e A172, resulting in satisfactory results to the inhibition of
cellular growth. The 2-acetoxy-3-phenylethynyl-1,4-naphthoquinone, 2-acetoxy-3-(4methoxyphenylethynyl)-1,4-naphthoquinone
and 2-acetoxy-3-(4methylphenylethynyl)-1,4-naphthoquinone
stood out among the substances analyzed
by their lower IC50 for the three cell lines tested glioblastomas. These results are
significant to continue in the cytotoxicity studies. Then, a new synthetic route by “click
chemistry” was developed to obtain new aminoalkyl-triazoles naphthoquinone
compounds through the reactions of 1,3-dipolar cycloaddition between 2azidoalkylamino-1,4-napthoquinones
and several terminal alkynes. A serie of twenty
2-[(1H-1,2,3-triazole-1-yl)alkylamino]-1,4-naphthoquinones derivatives were
synthetized in 70-97% yields. These triazole heterocyclics were tested against the
tumor cell lines HEp-2 (human laryngeal carcinoma), NCI-H292 (human
mucoepidermoid lung carcinoma), HT-29 (human colon adenocarcinoma), MCF-7
(human breast cancer) and HL-60 (human promyelocytic leukemia). The compounds
2-[2-(4-propyl-1H-1,2,3-triazole-1-yl)ethylamino]-1,4-naphthoquinone and 2-{3-[4-(2hydroxybut-2-yl)-1H-1,2,3-triazole-1-yl]propylamino}-1,4-naphthoquinone
showed
moderated cytotoxicity against HL-60, HL-60 e MCF-7, showing a selective inhibition
profile. Finally, twenty four 6-alkylamino-5,8-quinolinequinones were obtained by
direct nucleophilic amination of 7-bromo-5,8-quinolinequinone with primary and
secondary alkylamines, providing a new synthetic strategy to the acquisition of 6alkylamino-5,8-quinolinequinones
compounds from primary amines. These
compounds are promising candidates for the development of new antitumor drugs.
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.ufpe.br:123456789/20259 |
| Date | 26 August 2016 |
| Creators | SILVA, Mauro Gomes da |
| Contributors | http://lattes.cnpq.br/4500025814149366, CAMARA, Celso de Amorim |
| Publisher | Universidade Federal de Pernambuco, Programa de Pos Graduacao em Quimica, UFPE, Brasil |
| Source Sets | IBICT Brazilian ETDs |
| Language | Breton |
| Detected Language | Portuguese |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Source | reponame:Repositório Institucional da UFPE, instname:Universidade Federal de Pernambuco, instacron:UFPE |
| Rights | Attribution-NonCommercial-NoDerivs 3.0 Brazil, http://creativecommons.org/licenses/by-nc-nd/3.0/br/, info:eu-repo/semantics/openAccess |
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