9 research outputs found
Inhibition of matrix metalloproteinases and cancer cell detachment by Ru(II) polypyridyl complexes containing 4,7-diphenyl-1,10-phenanthroline ligands : new candidates for antimetastatic agents
Primary tumor targeting is the dominant approach in drug development, while metastasis is the leading cause of cancer death. Therefore, in addition to the cytotoxic activity of a series of Ru(II) polypyridyl complexes of the type [Ru(dip)(2)L](2+) (dip: 4,7-diphenyl-1,10-phenanthroline while L = dip; bpy: 2,2′-bipyridine; bpy-SC: bipyridine derivative bearing a semicarbazone 2-formylopyridine moiety; dpq, dpq(CH(3))(2), dpb: quinoxaline derivatives) their ability to inhibit cell detachment was investigated. In vitro studies performed on lung cancer A549 cells showed that they accumulate in cells very well and exhibit moderate cytotoxicity with IC(50) ranging from 4 to 13 µM. Three of the studied compounds that have dip, bpy-SC, or dpb ligands after treatment of the cells with a non-toxic dose (<(1)/(2)IC(50)) enhanced their adhesion properties demonstrated by lower detachment in the trypsin resistance assay. The same complexes inhibited both MMP-2 and MMP-9 enzyme activities with IC(50) ranging from 2 to 12 µM; however, the MMP-9 inhibition was stronger. More detailed studies for [Ru(dip)(2)(bpy-SC)](2+), which induced the greatest increase in cell adhesion, revealed that it is predominately accumulated in the cytoskeletal fraction of A549 cells. Moreover, cells treated with this compound showed the localization of MMP-9 to a greater extent also in the cytoskeleton. Taken together, our results indicate the possibility of a reduction of metastatic cells escaping from the primary lesion to the surrounding tissue by prevention of their detachment and by influencing the activity of MMP-2 and MMP-9
Bioconjugation of holo-transferrin with hypoxia-enhanced fluorescent sensor for the selective imaging of cancer cells
Nitro-pyrazinotriazapentalene scaffolds : nitroreductase quantification and in vitro fluorescence imaging of hypoxia
Separation and identification of selected enantiomers of (2,3-dihydrobenzofuran-2-yl)phenylmethanol
W wyniku trójetapowej syntezy otrzymano (2,3-dihydrobenzofuran-2-ylo)fenylometanol, który posiada właściwości pomocnika chiralnego w reakcji asymetrycznej redukcji grupy karbonylowej α-ketokwasów. Metodą chromatografii kolumnowej dokonano rozdziału mieszaniny stereoizomerów tytułowego alkoholu na dwie formy diastereoizomeryczne, a następnie przeprowadzono prace zmierzające w kierunku rozdzielenia wybranej pary enancjomerów badanego alkoholu. W tym celu enancjomery te przekształcono w ester kamforosulfonowy i podjęto próbę rozdziału tak otrzymanych pochodnych diastereoizomerycznych metodami chromatograficznymi oraz poprzez krystalizację. Zarejestrowano widma elektronowego dichroizmu kołowego (ECD) dla wszystkich stereoizomerów badanego alkoholu rozdzielonych metodą wysokosprawnej chromatografii cieczowej. Na podstawie obliczeń kwantowo-mechanicznych wygenerowano porównawcze widma teoretyczne ECD dla wybranej pary diastereoizomerów badanego alkoholu, co w połączeniu z analizą odpowiednich stałych sprzężeń odczytanych z ich widm 1H NMR umożliwiło określenie konfiguracji absolutnej wszystkich stereoizomerów (2,3-dihydrobenzo-furan-2-ylo)fenylometanolu.The three-step synthetic route led to (2,3-dihydrobenzofuran-2-yl)phenylmethanol, which possesses a chiral auxiliary characteristics in the asymmetric reduction of the carbonyl group of α-ketoacid. Stereoisomers of the title alcohol were separated by column chromatography into two diastereomeric forms and afterwards there where made an attempts on resolution of its one selected pair of enantiomers. For this purpose, the mentioned enantiomers were converted into camphorsulfonic ester in the form of diastereomeric derivatives which were underwent numerous separation tests using chromatographic techniques and through crystallization. For all stereoisomers of the tested alcohol, separated by high-performance liquid chromatography, the electron spectra of circular dichroism (ECD) were measured. On the basis of quantum¬ mechanical calculations, the comparative ECD spectra for the chosen pair of diastereomers were simulated, which combined with the analysis of the respective coupling constants read from the 1H NMR spectra enabled the determination of the absolute configuration of all stereoisomers (2,3-dihydrobenzofuran-2-yl)phenylmethanol
The characterization of selective sensors for optical imaging of hypoxia in cancer cells and study of its effect on the anticancer effectiveness of polypyridyl ruthenium complexes
Investigation of the effect of polypyridyl ligands (L) in ruthenium complexes of the type [Ru(dip)2L]2+ on their cytotoxicity and photocytotoxicity
Celem niniejszej pracy była charakterystyka biologiczna polipirydylowych kompleksów rutenu opartych na układzie typu [Ru(dip)2L]2+ ( gdzie: dip – 4,7-difenylo-1,10-fenantrolina, natomiast jako L występowały dpb - 2,3-bis(2-pirydylo)-naftalenopirazyna, dpq - 2,3-bis(2-pirydylo)chinoksalina oraz dpq-(CH¬3)2 - 6,7-dimetylo-2,3-bis(2-pirydylo)chinoksalina) w kontekście wykorzystania w terapii fotodynamicznej (PDT) leczenia nowotworów. Przeprowadzono testy cytotoksyczności oraz fototoksyczności kompleksów po naświetleniu na linii komórkowej ludzkiego nowotworu trzustki (PANC-1) oraz mysiego nowotworu jelita grubego (CT-26). Zaprezentowane wyniki wykazały znaczny wzrost cytotoksyczności kompleksów po naświetleniu w stosunku do testów prowadzonych w ciemności. Ponadto wykorzystując sondy fluorescencyjne wyznaczono poziom generowania reaktywnych form tlenu w komórkach traktowanych kompleksami rutenu w ciemności oraz po naświetleniu. We wszystkich przypadkach zaobserwowano silny wzrost produkcji 1O2, •OH oraz H2O2 po naświetleniu. Metodą cytometrii przepływowej zweryfikowano indukcję apoptozy jako preferowanego mechanizmu śmierci komórkowej przez kompleksy rutenu w warunkach termicznych i fotochemicznych. Uzyskane w ramach realizacji badań wyniki wskazują na wysoki potencjał badanych związków w wykorzystaniu ich jako fotosensybilizatorów w terapii PDT.The aim of this work was the biological characterization of polypyridyl ruthenium complexes of the type [Ru(dip)2L]2+ (where dip – 4,7-difenylo-1,10-phenantroline, dpq – 2,3-bis(2-pyridyl)quinoxaline, dpb – 2,3-bis(2-pyridyl)-benzoquinoxaline, dpq-(CH3)2 – 6,7-dimethylo-2,3-bis(2-pyridyl)quinoxaline) in the context of the use in photodynamic therapy (PDT) of cancer treatment. Cytotoxicity and photocytotoxicity tests were performed on two cell lines: human pancreatic tumor (PANC-1) and mouse colorectal cancer (CT-26). The obtained results showed a significant increase in the cytotoxicity of the complexes after irradiation in relation to the tests conducted in the dark. In addition, by using fluorescent probes, the level of reactive oxygen species generation was determined in cells treated with ruthenium complexes in the dark and after irradiation. In all cases, a strong increase in the production of 1O2, •OH and H2O2 after irradiation was observed. The apoptosis as the preferred mechanism of cell death induced by ruthenium complexes both under thermal and photochemical conditions was verified by flow cytometry. The overall obtained results indicate a high potential of the tested compounds in their use as photosensitizers in PDT therapy
Significance of Specific Oxidoreductases in the Design of Hypoxia-Activated Prodrugs and Fluorescent Turn off–on Probes for Hypoxia Imaging
Hypoxia is one of the hallmarks of the tumor microenvironment and can be used in the design of targeted therapies. Cellular adaptation to hypoxic stress is regulated by hypoxia-inducible factor 1 (HIF-1). Hypoxia is responsible for the modification of cellular metabolism that can result in the development of more aggressive tumor phenotypes. Reduced oxygen concentration in hypoxic tumor cells leads to an increase in oxidoreductase activity that, in turn, leads to the activation of hypoxia-activated prodrugs (HAPs). The same conditions can convert a non-fluorescent compound into a fluorescent one (fluorescent turn off–on probes), and such probes can be designed to specifically image hypoxic cancer cells. This review focuses on the current knowledge about the expression and activity of oxidoreductases, which are relevant in the activation of HAPs and fluorescent imaging probes. The current clinical status of HAPs, their limitations, and ways to improve their efficacy are briefly discussed. The fluorescence probes triggered by reduction with specific oxidoreductase are briefly presented, with particular emphasis placed on those for which the correlation between the signal and enzyme expression determined with biochemical methods is achievable
Inhibition of Metastasis by Polypyridyl Ru(II) Complexes through Modification of Cancer Cell Adhesion – In Vitro Functional and Molecular Studies
International audienceThe effect of polypyridyl Ru(II) complexes on the ability of cancer cells to migrate and invade, two features important in the formation of metastases, is evaluated. In vitro studies are carried out on breast cancer cell lines, MDA-MB-231 and MCF-7, as well as melanoma cell lines A2058 and A375. Three Ru(II) complexes comprising two 4,7-diphenyl-1,10-phenanthroline (dip) ligands and as a third ligand 2,2′-bipyridine (bpy), or its derivative with either 4-[3-(2-nitro-1H-imidazol-1-yl)propyl] (bpy-NitroIm), or 5-(4-{4′-methyl-[2,2′-bipyridine]-4-yl}but-1-yn-1-yl)pyridine-2-carbaldehyde semicarbazone (bpy-SC) moiety attached are examined. The low sub-toxic doses of the studied compounds greatly affected the cancer cells by inhibiting cell detachment, migration, invasion, transmigration, and re-adhesion, as well as increasing cell elasticity. The molecular studies revealed that the Ru(II) polypyridyl complexes impact the activity of the selected integrins and upregulate the expression of focal adhesion components such as vinculin and paxillin, leading to an increased number of focal adhesion contacts