117 research outputs found
N-Aryl-N'-(chroman-4-yl)ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: screening, synthesis of simplified derivatives, and structure-activity relationship analysis.
A series of chroman derivatives previously reported as potassium channel openers, as well as some newly synthesized simplified structures, were examined for their in vitro effects on the growth of three human high-grade glioma cell lines: U373, T98G, and Hs683. Significant in vitro growth inhibitory activity was observed with 2,2-dimethylchroman-type nitro-substituted phenylthioureas, such as compounds 4o and 4p. Interestingly, most tested phenylureas were found to be slightly less active, but more cell selective (normal versus tumor glial cells, such as 3d, 3e, and 3g), thus less toxic, than the corresponding phenylthioureas. No significant differences were observed in terms of chroman-derivative-induced growth inhibitory effects between glioma cells sensitive to pro-apoptotic stimuli (Hs683 glioma cells) and glioma cells associated with various levels of resistance to pro-apoptotic stimuli (U373 and T98G glioma cells), a feature that suggests non-apoptotic-mediated growth inhibition. Flow cytometry analyses confirmed the absence of pro-apoptotic effects for phenylthioureas and phenylureas when analyzed in U373 glioma cells and demonstrated U373 cell cycle arrest in the G0/G1 phase. Computer-assisted phase-contrast videomicroscopy revealed that 3d and 3g displayed cytostatic effects, while 3e displayed cytotoxic ones. As a result, this work identified phenylurea-type 2,2-dimethylchromans as a new class of antitumor agents to be further explored for an innovative therapeutic approach for high-grade glioma and/or for a possible new mechanism of action
Chemoenzymatic Synthesis of Triazololactams Structurally Related to Pancratistatin
Four tricyclic lactams that structurally resemble alkaloids with the pancratistatin skeleton were synthetized from bromobenzene by a chemoenzymatic strategy. The sequence involved enzymatic dihydroxylation, efficient stereodirected oxidation of double bonds, inter- or intramolecular Huisgen cycloaddition, and a solvent-free cyclization. The complex structures were obtained in high chemical and optical purity and may be good candidates for biological testing.Fil: de la Sovera, Victoria. Universidad de la RepĂșblica. Facultad de QuĂmica. Departamento de QuĂmica OrgĂĄnica; UruguayFil: Suescun, Leopoldo. Universidad de la RepĂșblica. Laboratorio de CristalografĂa, Estado SĂłlido y Materiales; UruguayFil: Bellomo Peraza, Ana Ines. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias ; ArgentinaFil: GonzĂĄlez, David. Universidad de la RepĂșblica. Facultad de QuĂmica. Departamento de QuĂmica OrgĂĄnica; Urugua
Antiproliferative and Apoptotic Effects Triggered by Grape Seed Extract (GSE) versus Epigallocatechin and Procyanidins on Colon Cancer Cell Lines
Grape seed extract has been proven to exert anticancer effects on different tumors. These effects are mainly ascribed to catechin and procyanidin content. Analytical studies demonstrated that grape seed extract composition is complex and it is likely other components could exert biological activities. Using cell count and flow cytometry assays, we evaluated the cytostatic and apoptotic effects produced by three different grape seed extracts from Italia, Palieri and Red Globe cultivars, on Caco2 and HCT-8 colon cancer cells. These effects were compared to those induced by epigallocatechin and procyanidins, alone or in association, on the same cell lines. All the extracts induced growth inhibition and apoptosis in Caco2 and HCT-8 cells, along the intrinsic apoptotic pathway. On both cell lines, growth inhibition induced by Italia and Palieri grape seed extracts was significantly higher than that it has been recorded with epigallocatechin, procyanidins and their association. In Caco2 cells, the extract from Red Globe cultivar was less effective in inducing growth inhibition than procyanidins alone and in association with epigallocatechin, whereas, in HCT-8 cells, only the association of epigallocatechin and procyanidins triggers a significant proliferation decrease. On both cell lines, apoptosis induced by Italia, Palieri and Red Globe grape seed extracts was considerably higher than has been recorded with epigallocatechin, procyanidins and their association. These data support the hypothesis by which other compounds, present in the grape seed extracts, are likely to enhance the anticancer effects
Antioxidant, antibacterial, cytotoxic, and apoptotic activity of stem bark extracts of Cephalotaxus griffithii Hook. f
<p>Abstract</p> <p>Background</p> <p><it>Cephalotaxus </it>spp. are known to possess various therapeutic potentials. <it>Cephalotaxus griffithii</it>, however, has not been evaluated for its biological potential. The reason may be the remoteness and inaccessibility of the habitat where it is distributed. The main aim of this study was to: (1) evaluate multiple biological potentials of stem bark of <it>C. griffithii</it>, and (2) identify solvent extract of stem bark of <it>C. griffithii </it>to find the one with the highest specific biological activity.</p> <p>Methods</p> <p>Dried powder of stem bark of <it>C. griffithii </it>was exhaustively extracted serially by soaking in petroleum ether, acetone and methanol to fractionate the chemical constituents into individual fractions or extracts. The extracts were tested for total phenolic and flavonoid content, antioxidant (DPPH radical scavenging, superoxide radical scavenging, and reducing power models), antibacterial (disc diffusion assay on six bacterial strains), cytotoxic (MTT assay on HeLa cells), and apoptotic activity (fluorescence microscopy, DNA fragmentation assay, and flow cytometry on HeLa cells).</p> <p>Results</p> <p>Among the three extracts of stem bark of <it>C. griffithii</it>, the acetone extract contained the highest amount of total phenolics and flavonoids and showed maximum antioxidant, antibacterial, cytotoxic (IC<sub>50 </sub>of 35.5 ± 0.6 Όg/ml; P < 0.05), and apoptotic (46.3 ± 3.6% sub-G0/G1 population; P < 0.05) activity, followed by the methanol and petroleum ether extracts. However, there was no significant difference observed in IC<sub>50 </sub>values (DPPH scavenging assay) of the acetone and methanol extracts and the positive control (ascorbic acid). In contrast, superoxide radical scavenging assay-based antioxidant activity (IC<sub>50</sub>) of the acetone and methanol extracts was significantly lower than the positive control (P < 0.05). Correlation analysis suggested that phenolic and flavonoid content present in stem bark of <it>C. griffithii </it>extracts was responsible for the high antioxidant, cytotoxic, and apoptotic activity (P < 0.05).</p> <p>Conclusions</p> <p>Stem bark of <it>C. griffithii </it>has multiple biological effects. These results call for further chemical characterization of acetone extract of stem bark of <it>C. griffithii </it>for specific bioactivity.</p
Organic synthesis and pharmacological characterization of antitumor properties of di- and trivanillic polyphenols
La chimiothĂ©rapie conventionnelle est principalement constituĂ©e dâagents pro-apoptotiques. Or, de nombreux cancers sont intrinsĂšquement rĂ©sistants Ă lâapoptose et cela explique en grande partie les mauvais pronostics associĂ©s Ă certains cancers, dont les cancers mĂ©tastatiques, en raison de leur rĂ©sistance aux chimiothĂ©rapies pro-apoptotiques. La thĂ©matique de ce travail sâinscrit dans la recherche de molĂ©cules prĂ©sentant des modes dâactions diffĂ©rents afin de vaincre les mĂ©canismes de rĂ©sistance des cellules cancĂ©reuses. <p><p>Une nouvelle sĂ©rie de composĂ©s di- et trivanilliques a ainsi Ă©tĂ© dĂ©clinĂ©e. La structure de ces composĂ©s est inspirĂ©e de molĂ©cules naturelles divanilliques Ă©tudiĂ©es pour leurs propriĂ©tĂ©s anti-falciformation dans la drĂ©panocytose. Notre stratĂ©gie a Ă©tĂ© de transposer lâactivitĂ© prĂ©sumĂ©e de ces composĂ©s sur le cytosquelette des Ă©rythrocytes falciformes au niveau de la prolifĂ©ration et de la migration des cellules cancĂ©reuses. A cette fin, des mĂ©thodes pour analyser lâactivitĂ© antitumorale de cette sĂ©rie de nouveaux composĂ©s ont Ă©tĂ© mises en place.<p><p>In vitro, les composĂ©s que nous qualifions dâactifs inhibent la croissance dâune dizaine de populations cellulaires cancĂ©reuses distinctes Ă des valeurs inhibitrices de croissance Ă 50 % (indice IC50) de lâordre de 30 ”M. Les dĂ©rivĂ©s trivanilliques se classent parmi les composĂ©s les plus actifs de la sĂ©rie, en particulier le composĂ© trivanillique chlorĂ© 13c qui exerce un effet cytostatique sur les lignĂ©es cellulaires cancĂ©reuses analysĂ©es tout en prĂ©sentant un certain taux de biosĂ©lectivitĂ© vis-Ă -vis des cellules normales. Nous avons ainsi consacrĂ© une partie de ce travail Ă approfondir la comprĂ©hension du mĂ©canisme dâaction du composĂ© 13c et Ă le comparer Ă ses analogues de synthĂšse pour tenter dâĂ©tablir une relation de type structure-activitĂ©.<p><p>Le dĂ©rivĂ© 13c est cytostatique car il interfĂšre avec le processus mitotique et il inhibe Ă plus de 75 % lâactivitĂ© de 26 kinases Ă la concentration de 2 ”M qui est donc plus de dix fois infĂ©rieure Ă la concentration inhibitrice IC50 moyenne de 30 ”M rapportĂ©e ci-avant. Huit de ces 26 kinases sont directement impliquĂ©es dans lâorganisation du cytosquelette dâactine et notamment dans les processus de cytokinĂšse. Parmi les kinases dont lâactivitĂ© est la plus fortement modifiĂ©e par le composĂ© 13c figurent les Aurora kinases qui sont de puissants contrĂŽleurs de la cytokinĂšse. Nos rĂ©sultats montrent Ă©galement que lâactivitĂ© cytostatique du composĂ© 13c entraĂźnant une dĂ©sorganisation du cytosquelette dâactine pourrait ĂȘtre induite non seulement par lâinhibition de lâactivitĂ© de certaines kinases mais aussi par des modifications induites par ce produit au niveau de lâhomĂ©ostasie du calcium intracellulaire.<p><p>LâefficacitĂ© des agents chimiothĂ©rapeutiques est souvent altĂ©rĂ©e par une rĂ©sistance tumorale intrinsĂšque appelĂ©e rĂ©sistance multidrogue (le phĂ©notype MDR). In vitro, le composĂ© 13c sâest montrĂ© tout aussi efficace sur des lignĂ©es cancĂ©reuses possĂ©dant cette rĂ©sistance multidrogue que sur des cellules cancĂ©reuses sensibles aux agents chimiothĂ©rapeutiques. De mĂȘme, diverses lignĂ©es cellulaires rĂ©sistantes aux stimuli pro-apoptotiques sont Ă©galement sensibles Ă lâactivitĂ© inhibitrice de croissance in vitro du trivanillate 13c. <p><p>Enfin, lâactivitĂ© du composĂ© 13c a Ă©tĂ© testĂ©e in vivo sur un modĂšle de pseudomĂ©tastases pulmonaires issues du mĂ©lanome B16F10 murin. Les tumeurs pulmonaires prĂ©sentent une cible intĂ©ressante pour le composĂ© 13c au vu de son activitĂ© anti-tyrosine kinase comprenant la kinase EGFR et ses formes mutĂ©es EGFR-L858R et EGFR-T790M frĂ©quemment retrouvĂ©es au sein des cancers du poumon non-Ă -petites-cellules (NSCLC). Le principe actif a Ă©tĂ© administrĂ© dans les poumons par inhalation via un dispositif endotrachĂ©al. La voie inhalĂ©e est avantageuse par rapport Ă la voie systĂ©mique pour lâadministration du produit 13c car cette molĂ©cule possĂšde des liaisons esters qui sont hydrolysables par les estĂ©rases plus prĂ©sentes au niveau des voies systĂ©miques que dans les tissus pulmonaires. Lâinhalation permet aussi de cibler mieux le site tumoral afin de rĂ©duire les dommages collatĂ©raux. <p><p>Ce travail offre des perspectives au niveau de lâĂ©laboration de formulations permettant dâaugmenter la biodisponibilitĂ© de la molĂ©cule 13c. Une association dâun traitement au composĂ© 13c et dâune chimiothĂ©rapie conventionnelle est envisagĂ©e car elle pourrait potentialiser les effets de ces deux traitements. <p>Doctorat en Sciences biomĂ©dicales et pharmaceutiquesinfo:eu-repo/semantics/nonPublishe
New polyol vanilloyl esters with anti-tumor effects trough the targetting of kinases controling the actin cytoskeleton
info:eu-repo/semantics/nonPublishe
Evaluation of the antiproliferative activity of diterpene isonitriles from the sponge Pseudoaxinella flava in apoptosis-sensitive and apoptosis-resistant cancer cell lines.
One new (1) and three known (2-4) isonitrile diterpenes, isolated from the Caribbean sponge Pseudoaxinella flava, were assayed in human cancer cell lines in vitro using an MTT colorimetric assay and quantitative videomicroscopy. Compounds 1-4 displayed activity for human PC3 prostate apoptosis-sensitive cancer cell lines. Compounds 3 and 4 demonstrated similar growth inhibitory effects for three apoptosis-sensitive and three apoptosis-resistant cancer cell lines. Quantitative videomicroscopy analysis revealed that compounds 1 and 2 exerted their activity through cytotoxic effects, and compounds 3 and 4 through cytostatic effects. These results identify marine diterpene isonitriles as potential lead compounds for anticancer drug discovery.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe
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