Planejamento, síntese e avaliação biológica de derivados pirozolínicos e bis-chalconas simétricas: estudos de correlação estrutura/atividade

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Físicas e Matemáticas, Programa de Pós-Graduação em Química, Florianópolis, 2015.Esta tese apresenta o planejamento e a síntese de moléculas bioativas baseadas na estrutura de moléculas que já tiveram sua atividade comprovada e está subdividida em dois capítulos, de acordo com a classe de compostos e patologia-alvo. No capítulo 1, foram planejadas e sintetizadas trinta e três bis-chalconas simétricas (com substituintes estratégicos que já mostraram atividade anteriormente), obtidas com rendimentos entre 59-93%. Os compostos foram planejados no intuito da obtenção de potenciais inibidores da proteína ABCG2. Esta proteína está relacionada com a resistência a múltiplos fármacos, um dos principais obstáculos para a quimioterapia contra o câncer. Os resultados obtidos mostraram que dentre os compostos sintetizados, dois deles, o (2E,2'E)-1,1'-(1,4-fenileno)bis(3-(2,6-dimetoxifenil)prop-2-en-1-ona) 3p (EC50 = 0,2 ± 0,04µM) e o (2E,2'E)-3,3'-(1,4-fenileno)bis(1-(3,5-dimetoxifenil)prop-2-en-1-ona) 6i (EC50 = 0,5 ± 0,3µM) mostraram a mais pronunciada atividade e são promissores para o estudo de inibidores de ABCG2. No capítulo 2, foram planejadas e sintetizadas quarenta e oito pirazolinas a partir das chalconas previamente sintetizadas, que foram obtidas com rendimentos entre 60 e 98% e mostraram atividade inibitória considerável frente à PtpA e PtpB de Mycobacterium tuberculosis e YopH de Yersinia enterocolitica. Estas proteínas são essênciais para a sobrevivência das respectivas bactérias no hospedeiro e sua inibição surge como uma forma de combate às patologias relacionadas com cada proteína. Os resultados obtidos mostraram uma maior atividade dos compostos frente à YopH de Y. enterocolitica e dois compostos, o 1-fenil-3-(3,4-dimetóxifenil)-5-(naftalen-2-il)-4,5-dihidro-1H-pirazol 8c (8,8 ± 2,6 µM) e 1-fenil-3-(2,5-dimetoxifenil)-5-(naftalen-1-il)-4,5-dihidro-1H-pirazol 8p (8,9 ± 0,8 µM) foram os inibidores mais potentes. Estudos de modelagem molecular e de cinética enzimática mostram que esses são inibidores não competitivos, que ligam-se a um sítio alostérico da YopH.Abstract : This thesis describes the design and synthesis of bioactive molecules based on known molecules by their activities already described in the literature. This work is subdivided into two chapters, according to the class of compounds and target disease. In Chapter 1, thirty-three symmetrical bis-chalcones were designed and synthesized (with strategic substituents that have shown activity previously), with yields between 59-93%. The compounds were designed in order to obtain potential inhibitors of ABCG2 protein. This protein is an efflux transporter that have been shown to be associated with multi-drug resistance, a major obstacle to successful cancer chemotherapy. The results showed that among the compounds synthesized, (2E,2'E)-1,1'-(1,4-phenylene)bis(3-(2,6-dimethoxyphenyl)prop-2-en-1-one) 3p (EC50 = 0.2 ± 0,04µM) and (2E,2'E)-3,3'-(1,4-phenylene)bis(1-(3,5-dimethoxyphenyl)prop-2-en-1-one) 6i (EC50 = 0.5 ± 0,3µM) showed the most pronounced activities and are promising ABCG2 inhibitors. In chapter 2, were designed and synthesized forty-eight 1,3,5-triaryl-2-pyrazolines (obtained in yields between 60 and 98%) derived from chalcones that had already shown activity as inhibitors of PtpA and PtpB from Mycobacterium tuberculosis or of YopH from Yersinia enterocolitica. Previous studies have revealed that the action of phosphatases, especially PTPs, is crucial in determining the pathogenicity of bacteria. The results obtained show a higher activity of compounds against the YopH from Y. enterocolitica and compounds 3-(3,4-dimethoxyphenyl)-5-(naphthalen-2-yl)-1-phenyl-4,5-dihydro-1H-pyrazole 8c (8.8 ± 2.6 mM) and 3-(2,5-dimethoxyphenyl)-5-(naphthalen-1-yl)-1-phenyl-4,5-dihydro-1H-pyrazole 8p (8.9 ± 0.8 mM) were the most potent inhibitors. Molecular modeling and enzyme kinetics studies showed that both compounds are non-competitive inhibitiors and may bind to an allosteric site

Mechanisms underlying the antiproliferative effects of a series of quinoxaline-derived chalcones

The present study aimed to characterize the effects of quinoxaline-derived chalcones, designed on the basis of the selective PI3Kγ inhibitor AS605240, in oral cancer cells. Three lead compounds, namely N9, N17 and N23, were selected from a series of 20 quinoxaline-derived chalcones, based on an initial screening using human and rat squamous cell carcinoma lineages, representing compounds with at least one methoxy radical at the A-ring. The selected chalcones, mainly N9 and N17, displayed marked antiproliferative effects, via apoptosis and autophagy induction, with an increase of sub-G1 population and Akt inhibition. The three chalcones displayed marked in vitro antitumor effects in different protocols with standard chemotherapy drugs, with acceptable toxicity on normal cells. There was no growth retrieval, after exposure to chalcone N9 alone, in a long-term assay to determine the cumulative population doubling (CPD) of human oral cancer cells. A PCR array evaluating 168 genes related to cancer and inflammation, demonstrated striking actions for N9, which altered the expression of 74 genes. Altogether, our results point out quinoxalinic chalcones, mainly N9, as potential strategies for oral cancer treatment