Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2017-08-04T13:56:59Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Tese de doutorado - Mauro Gomes..pdf: 11151423 bytes, checksum: 8078c54c11b179c8f72bccc64042575f (MD5) / Made available in DSpace on 2017-08-04T13:56:59Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Tese de doutorado - Mauro Gomes..pdf: 11151423 bytes, checksum: 8078c54c11b179c8f72bccc64042575f (MD5) 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.