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We here report the synthesis of novel chalcone-sulfonamide compounds based on the hybridization at 2′ position and nitro substitution at the side chalcone phenyl ring followed by ...tandem cyclization into quinolinone derivatives and then a further aldol condensation only as a function of the reaction time. Therefore, for the first time, we have controlled the sequential preparation of chalcone-sulfonamide hybrids, quinolinones and then (E)-3-ene-2,3-dihydroquinolinones simply stopping reaction over increasing time periods. Furthermore, a new molecular scaffold based on a chalcone-(bis)sulfonamide hybrid has been gotten through changing the sequence of coupling reactions and catalyst. This study means practical and useful ways of constructing in high yields new biologically active compounds bearing diversified molecular scaffolds.
Two new diterpenoid derivatives 7
,12
,17-triacetoxy-6
19-dihydroxy-13
,16-spirocicloabiet-8-ene-11,14-dione ( 1: ) and 6
-acetoxy-3
,7
,12
-trihydroxy-13
,16-spirocicloabiet-8-ene-11,14-dione ( 2: ) ...along with 11 ( 3: - 13: ) miscellaneous compounds were isolated from the leaves of
Codd. Their structures were elucidated by spectroscopic analysis and gauge independent atomic orbitals
C NMR calculations. The isolated compounds were screened for their effects on intestinal motility using guinea-pig ileum and duodenum and by their cytotoxicity against 4 human cancer cell lines (HCT-116, SF-295, PC-3, and HL-60). Compounds 6: and 9: were moderately cytotoxic against HL-60, whereas 6: and 13: were more active on SF-295 and HCT-116.
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•The extracts presented similar phytochemical composition.•The Mimosa extracts presented antioxidant and antimicrobial activity.•First reports about the biological potential of Mimosa ...pteridifolia Benth.•The extracts did not show toxicity in cancer and normal cells.
Plant extracts and components are commonly used in popular medicine to relieve the symptoms of several diseases. They can also be used scientifically for drug testing due to their wide biological potential, acting as antibacterial, antifungal, and anticancer agents, for example. Some plants belonging to the Fabaceae family, Mimosa genus, which are popularly known as Jurema, have been used for a long time by indigenous people and are still widely used in popular medicine. The presence of different secondary metabolites, such as phenolic compounds, like flavonoids and tannins, for example, attribute to these plants several biological applications, such as antibacterial and antifungal properties, supporting their use in traditional medicine. In this study, ethanolic extracts were produced using the barks of three plants of the Mimosa genus. Phytochemical assays were performed to analyze the composition of the extracts and their antimicrobial, cytotoxic, hemolytic, and antioxidant activities were evaluated. To the best of our knowledge, the present study may be the pioneer in the investigation of the biological activities of Mimosa pteridifolia. Besides, all the extracts showed considerable biological activity, mainly because of their phytochemical composition, which consists of tannins and flavonoids. Further studies should be carried out to identify the active principle and investigate the mechanisms of action responsible for these biological activities.
In the present study, the effect of sulfonamide-chalcone 185 (SSC185) was investigated against B16–F10 metastatic melanoma cells aggressive actions, besides migration and adhesion processes, by in ...silico and in vitro assays. In silico studies were used to characterize the pharmacokinetic profile and possible targets of SSC185, using the pkCSM web server, and docking simulations with AutoDock Tools. Furthermore, the antimetastatic effect of SSC185 was investigated by in vitro experiments using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide), colony, scratch, and cell adhesion assays, and atomic force microscopy (AFM). The molecular docking results show better affinity of SSC185 with the metalloproteinases-2 (MMP-2) and α5β1 integrin. SSC185 effectively restricts the formation of colonies, migration, and adhesion of B16–F10 metastatic melanoma cells. Through the AFM images changes in cells morphology was identified, with a decrease in the filopodia and increase in the average cellular roughness. The results obtained demonstrate the potential of this molecule in inhibit the primordial steps for metastasis, which is responsible for a worse prognosis of late stage cancer, being the main cause of morbidity among cancer patients.
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•MMP-2 and α5β1 integrin are putative targets of SSC185.•SSC185 decreased migration and adhesion of metastatic cells in vitro.•SSC185 causes changes in cell morphology with loss of filopodia and rearrangements in the cytoskeleton.
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•A novel series of nine quinoxalinyl-hydrazones was synthesized and characterized.•(E)-2-2-(2-Pyridin-2-ylmethylene)hydrazinylquinoxaline (PJOV56) showed strong cytotoxic activity ...against a panel of human tumor-derived cancer cell lines.•PJOV56 exhibited antiproliferative activity against HCT116 cells suppressing cell growth in the time- and dose-dependent manner.•Low concentrations (1.5 and 3.0 µmol.L−1) of PJOV56 induced cell cycle arrest in S-phase without apparent cell death in HCT116 cells.•High concentration (6.0 µmol.L−1) of PJOV56 led to a cell cycle arrest in G0/G1-phase and to a significant level of apoptotic cell death in HCT116 cells.•PJOV56 induced intense vacuolization in HCT116 cells that ressemble autophagic process induction.
Quinoxaline derivatives are reported as antineoplastic agents against a variety of human cancer cell lines, with some compounds being submitted to clinical trials. In this work, we report the synthesis, characterization and cytotoxicity potential of a new series of quinoxalinyl-hydrazones. The most cytotoxic compound was (E)-2-2-(2-pyridin-2-ylmethylene)hydrazinylquinoxaline (PJOV56) that presented a time-dependent effect against HCT-116 cells. After 48 h of incubation, PJOV56 was able to induce autophagy and apoptosis of HCT-116 cells, mediated by upregulation of Beclin 1, upregulation of LC3A/B II and activation of caspase 7. Apoptosis was induced along with G0/G1 cell cycle arrest at the highest concentration of PJOV56 (6.0 µM). Thus, PJOV56 showed a dose-dependent mode of action related to induction of autophagy and apoptosis in HCT-116 cells.
CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior
The use of substances from natural products has grown over the years, being the basis of therapeutic products. Lignans are molecules with ...large pharmaceutical use, which has aroused interest in search of new drugs to treat diseases. Much interest has been focused on their effectiveness as an antineoplastic agent. Thus, the aim of this study was to evaluate the in vitro anticancer potencial of compounds isolated from ethanolic extract of Combretum fruticosum, as well as, to study the possible mechanisms of action of a dibenzylbutyrolactone type lignan, trachelogenin, in colorectal cancer cells. The fractionation of the ethanolic extract of C. fruticosum resulted in the isolation of seven compounds: three triterpenes, two mixtures of β-sitosterol and stigmasterol steroids and two lignans Among them, the lignan, trachelogenin showed higher cytotoxic activity, with IC50 values ranging from 0.8 to 32.4 ÂM in glioblastoma (SF-295) and leukemic (HL-60) cells, respectively. While in normal cells (3T3-L1 and PBMC cells) the IC50 values were greater than 64.3 ÂM. The antiproliferative profile of different times of incubation was performed in SF-295 and HCT-116 cells. The cytotoxic effect on SF-295 cells was only observed after 72 hours of incubation, whereas in HCT-116 cells, this effect was observed after 48 hours, and it was enhanced after 72 hours of incubation. Before these results, analyzing cell cycle profile, membrane integrity, phosphatidylserine externalization and expression of proteins related to cell death by apoptosis in HCT-116 cells, it was not observed significantly changed, suggesting that the antiproliferative effect of this lignan is not related to mechanisms of cell death such as apoptosis and/or necrosis. Autophagy seems to be one of the cell death mechanisms involved in the antiproliferative effect of trachelogenin, because we observed an increase on number and size of acidic vesicular organelles (AVO) as well as the expression of proteins recruited during autophagy (LC3 A and B-II and Beclin-1) in cells treated with trachelogenin, although this seems not to be the only process involved. Therefore, we conclude that trachelogenin showed potent antitumor activity in vitro, and this effect may be related to the induction of autophagy. However, further tests should be conducted to confirm these proposals and to evaluate its mechanism of action and the therapeutic potential of this molecule better.
A utilizaÃÃo de substÃncias derivadas de produtos naturais tem crescido com o passar dos anos, formando a base dos produtos terapÃuticos. As lignanas sÃo molÃculas com amplo uso farmacÃutico, o que tem despertado interesse na pesquisa e busca de novos fÃrmacos no tratamento de doenÃas. Muito interesse tem sido focado na sua eficÃcia como agente antineoplÃsico. Com isso, o objetivo desse trabalho foi avaliar o potencial anticÃncer in vitro de compostos isolados a partir do extrato etanÃlico dos talos da Combretum fruticosum, bem como, estudar os possÃveis mecanismos de aÃÃo da trachelogenina, uma lignana do tipo dibezilbutirolactona, em cÃlulas de cÃncer colorretal (HCT-116). O fracionamento do extrato etanÃlico da C. fruticosum resultou no isolamento de sete compostos: trÃs triterpenos, duas misturas dos esteroides β-sitosterol e estigmasterol e duas lignanas. Dentre eles, a trachelogenina mostrou maior atividade citotÃxica, apresentando valores de CI50 que variaram de 0,8 a 32,4 ÂM em cÃlulas tumorais de glioblastoma (SF-295) e leucÃmicas (HL-60), respectivamente, apÃs 72 horas de incubaÃÃo. Enquanto que, para cÃlulas nÃo tumorais (3T3-L1 e CMSP) esses valores foram maiores que 64,3 ÂM. O perfil antiproliferativo em diferentes perÃodos de incubaÃÃo foi realizado em cÃlulas SF-295 e HCT-116. O efeito citotÃxico em cÃlulas SF-295 foi observado apenas apÃs 72 horas de incubaÃÃo, enquanto que, em cÃlulas HCT-116, esse efeito foi observado apÃs 48 horas, sendo intensificados apÃs 72 horas de incubaÃÃo. Diante desses resultados, em cÃlulas HCT-116, a anÃlise do perfil do ciclo celular, integridade de membrana, externalizaÃÃo da fosfatidilserina e expressÃo de proteÃnas relacionadas ao processo de morte celular por apoptose nÃo apresentou alteraÃÃes significativas, sugerindo que o efeito antiproliferativo desta lignana nÃo està relacionado com processos de morte por apoptose e/ou necrose. A autofagia parece estar envolvida no mecanismo antiproliferativo da trachelogenina, visto que foi possÃvel verificar um aumento do nÃmero e do tamanho de organelas vesiculares Ãcidas (AVOs) bem como um aumento da expressÃo de proteÃnas recrutadas durante a autofagia (LC3 A e B II e Beclina-1) nas cÃlulas tratadas com a trachelogenina, embora nÃo pareÃa ser o Ãnico processo envolvido. Logo, podemos concluir que a trachelogenina apresentou potente atividade anticÃncer in vitro, e este efeito pode estar relacionado com a induÃÃo da autofagia. No entanto, outros testes devem ser realizados para confirmar as propostas acima apresentadas e para uma melhor avaliaÃÃo do mecanismo de aÃÃo e do potencial terapÃutico desta molÃcula.
MOURA, Andrea Felinto. Bioprospecção de compostos isolados de Combretum fruticosum com potencial antiproliferativo em células tumorais in vitro. 2015. 93 f. Dissertação (Mestrado em Farmacologia) - ...Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2015.
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Previous issue date: 2015
The use of substances from natural products has grown over the years, being the basis of therapeutic products. Lignans are molecules with large pharmaceutical use, which has aroused interest in search of new drugs to treat diseases. Much interest has been focused on their effectiveness as an antineoplastic agent. Thus, the aim of this study was to evaluate the in vitro anticancer potencial of compounds isolated from ethanolic extract of Combretum fruticosum, as well as, to study the possible mechanisms of action of a dibenzylbutyrolactone type lignan, trachelogenin, in colorectal cancer cells. The fractionation of the ethanolic extract of C. fruticosum resulted in the isolation of seven compounds: three triterpenes, two mixtures of β-sitosterol and stigmasterol steroids and two lignans Among them, the lignan, trachelogenin showed higher cytotoxic activity, with IC50 values ranging from 0.8 to 32.4 µM in glioblastoma (SF-295) and leukemic (HL-60) cells, respectively. While in normal cells (3T3-L1 and PBMC cells) the IC50 values were greater than 64.3 µM. The antiproliferative profile of different times of incubation was performed in SF-295 and HCT-116 cells. The cytotoxic effect on SF-295 cells was only observed after 72 hours of incubation, whereas in HCT-116 cells, this effect was observed after 48 hours, and it was enhanced after 72 hours of incubation. Before these results, analyzing cell cycle profile, membrane integrity, phosphatidylserine externalization and expression of proteins related to cell death by apoptosis in HCT-116 cells, it was not observed significantly changed, suggesting that the antiproliferative effect of this lignan is not related to mechanisms of cell death such as apoptosis and/or necrosis. Autophagy seems to be one of the cell death mechanisms involved in the antiproliferative effect of trachelogenin, because we observed an increase on number and size of acidic vesicular organelles (AVO) as well as the expression of proteins recruited during autophagy (LC3 A and B-II and Beclin-1) in cells treated with trachelogenin, although this seems not to be the only process involved. Therefore, we conclude that trachelogenin showed potent antitumor activity in vitro, and this effect may be related to the induction of autophagy. However, further tests should be conducted to confirm these proposals and to evaluate its mechanism of action and the therapeutic potential of this molecule better.
A utilização de substâncias derivadas de produtos naturais tem crescido com o passar dos anos, formando a base dos produtos terapêuticos. As lignanas são moléculas com amplo uso farmacêutico, o que tem despertado interesse na pesquisa e busca de novos fármacos no tratamento de doenças. Muito interesse tem sido focado na sua eficácia como agente antineoplásico. Com isso, o objetivo desse trabalho foi avaliar o potencial anticâncer in vitro de compostos isolados a partir do extrato etanólico dos talos da Combretum fruticosum, bem como, estudar os possíveis mecanismos de ação da trachelogenina, uma lignana do tipo dibezilbutirolactona, em células de câncer colorretal (HCT-116). O fracionamento do extrato etanólico da C. fruticosum resultou no isolamento de sete compostos: três triterpenos, duas misturas dos esteroides β-sitosterol e estigmasterol e duas lignanas. Dentre eles, a trachelogenina mostrou maior atividade citotóxica, apresentando valores de CI50 que variaram de 0,8 a 32,4 µM em células tumorais de glioblastoma (SF-295) e leucêmicas (HL-60), respectivamente, após 72 horas de incubação. Enquanto que, para células não tumorais (3T3-L1 e CMSP) esses valores foram maiores que 64,3 µM. O perfil antiproliferativo em diferentes períodos de incubação foi realizado em células SF-295 e HCT-116. O efeito citotóxico em células SF-295 foi observado apenas após 72 horas de incubação, enquanto que, em células HCT-116, esse efeito foi observado após 48 horas, sendo intensificados após 72 horas de incubação. Diante desses resultados, em células HCT-116, a análise do perfil do ciclo celular, integridade de membrana, externalização da fosfatidilserina e expressão de proteínas relacionadas ao processo de morte celular por apoptose não apresentou alterações significativas, sugerindo que o efeito antiproliferativo desta lignana não está relacionado com processos de morte por apoptose e/ou necrose. A autofagia parece estar envolvida no mecanismo antiproliferativo da trachelogenina, visto que foi possível verificar um aumento do número e do tamanho de organelas vesiculares ácidas (AVOs) bem como um aumento da expressão de proteínas recrutadas durante a autofagia (LC3 A e B II e Beclina-1) nas células tratadas com a trachelogenina, embora não pareça ser o único processo envolvido. Logo, podemos concluir que a trachelogenina apresentou potente atividade anticâncer in vitro, e este efeito pode estar relacionado com a indução da autofagia. No entanto, outros testes devem ser realizados para confirmar as propostas acima apresentadas e para uma melhor avaliação do mecanismo de ação e do potencial terapêutico desta molécula.
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