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Fluorinated derivatives of 1,4-naphthoquinones are highly potent inhibitors of Cdc25A and Cdc25B phosphatases; they suppress the growth of tumor cells. Four derivatives of phosphonium betaines derived from hexafluoro-1,4-naphthoquinone: (triphenyl[5,6,7,8-tetrafluoro-1-oxido-4-oxo-3-(phenylimino)-3,4-dihydronaphthalen-2-yl]phosphonium) (4), ((3,5-difluorophenyl)(methyl)phenyl(5,6,7,8-tetrafluoro-3-oxido-1,4-dioxo-1,4-dihydronaphthalen-2-yl)phosphonium) (5), ((2,5-difluorophenyl)(methyl)phenyl(5,6,7,8-tetrafluoro-3-oxido-1,4-dioxo-1,4-dihydronaphthalen-2-yl)phosphonium) (6) and ((3,5-difluorophenyl)diphenyl(5,6,7,8-tetrafluoro-3-oxido-1,4-dioxo-1,4-dihydronaphthalen-2-yl)phosphonium) (7) were synthesized for the first time. Their cytotoxicity toward human mammary adenocarcinoma, human myeloma, hamster and murine and fibroblasts as well as their antioxidant and mutagenic effects on a Salmonella tester strain were analyzed. All four substances showed comparable IC50 values in terms of suppression of tumor cell growth, which were from two- to ninefold lower comparing with those of fibroblasts. To identify the features of spatial orientation and noncovalent interactions of the new phosphonium betaines in the binding site of Cdc25B, a molecular docking analysis was carried out. It showed that the interactions of the analyzed compounds with a Cdc25B model binding site are characterized by the presence of a large number of acceptors (fluorine and oxygen atoms, forming halogen and hydrogen bonds) and by participation of pi-systems and phosphorus in specific electrostatic interactions that may result in inhibition of enzymes of the Cdc25 family. In addition, compounds 5 and 6 (especially the latter) were found to be effective antioxidants protecting bacterial cells from H2O2-induced and spontaneous and mutagenesis at significantly lower concentrations (IC50 = 0.09 to 1.8 μM) than those of derivatives 4 and 7 (86–92 μM). Taking into account these data (together with the good cytotoxic effect on cancer cells comparing with normal mammalian cells) we can propose compounds 5 and 6 as possible useful inhibitors of tumor cell growth and antioxidants.

Aim: Synthesis and analysis of antioxidant and antitumor properties of fluorinated phosphorus- containing derivatives of tetrafluoro-1,4-benzoquinone and hexafluoro-1,4-naphthoquinone. Methodology: All compounds were synthesized by amino- and phosphanodefluorination with corresponding amines and phosphanes. The cytotoxicity of these fluorinated benzoquinones and Original Research Article

La sobrecarga de trabajo de los docentes puede ocasionar desafios para los docentes que provoquen agotamiento a largo plazo si no se abordan. En consecuencia, el presente estudio tiene como objetivo examinar las fuentes de prevencion del agotamiento desde las perspectivas de los supervisores EFL (ingles como lengua extranjera). Los participantes fueron 85 supervisores de EFL iranies cuyo trabajo consistia en observar y dar retroalimentacion a los maestros sobre su desempeno docente en varios niveles de dominio del idioma, desde los niveles de primaria hasta los avanzados. En este estudio se empleo un diseno secuencial de metodo mixto. Primero, la recopilacion de datos cualitativos se realizo mediante entrevistas con 30 participantes para determinar las fuentes de prevencion del agotamiento desde la perspectiva de los supervisores. A continuacion, se diseno un cuestionario de prevencion de agotamiento utilizando los resultados de las entrevistas, despues de lo cual se administro a los participantes restantes. Los datos recopilados fueron analizados por factores para identificar los componentes de la construccion de prevencion de agotamiento. Los resultados del analisis de contenido de los datos de la entrevista indicaron que el apoyo de los maestros por parte de sus colegas, la situacion menos estresante y la satisfaccion laboral fueron las principales fuentes de prevencion del agotamiento. El analisis factorial mostro las mismas fuentes de agotamiento que los componentes principales de la construccion de prevencion de agotamiento. Los hallazgos de este estudio enfatizan la contribucion del apoyo educativo y emocional de los maestros, proporcionando un lugar de trabajo constructivo y saludable, asi como ingresos deseables como formas de prevencion del agotamiento en los maestros de EFL.

This study describes a simple and efficient procedure to synthesize a series of benzene-fluorinated 2,2-dimethyl-2,3-dihydro-1 H -quinolin-4-ones by the PTSA-catalyzed cyclocondensation reaction of the corresponding ortho -alkynylanilines prepared by the Sonogashira reaction of fluoro-substituted 2-iodanilines with 2-methylbut-3-yn-2-ol. The photofluorescent properties (shape of bands, λ ex , λ em , Stokes shift) of the new compounds were investigated. It has been revealed that the 2,3-dihydroquinolinones with different number of fluoro-substituents have almost the same fluorescence properties. The cytotoxicity evaluation of the 2,3-dihydroquinolinones against human myeloma, human mammary adenocarcinoma, human hepatocellular carcinoma HepG2 epithelial tumor cells, normal mouse fibroblasts and Chinese hamster Ag 17 cells was performed. It has been found that the benzo-perfluorinated derivatives of 2,2-dimethyl-2,3-dihydro-1 H -quinolin-4-ones show enhanced cytotoxic effect against the tumor RPMI (human myeloma) cells line compared with the normal cells. Mutagenic and antioxidant properties of the compounds using Salmonella tester strain were studied. It has been shown, that the compounds are well antioxidants.

New conjugates of polyfluorinated 1,4-naphthoquinone core with amino acid fragments were synthesized by the reactions of hexafluoro-1,4-naphthoquinone (1) with ethyl aminoacetate, glycine, 3-aminopropanoic, 4-aminobutanoic, and 6-aminohexanoic acids. In all the cases, the quinone 1 aminodefluorination on the 2-position occurred to give ethyl (3,5,6,7,8-pentafluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)aminoacetate (2), (3,5,6,7,8-pentafluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino]acetic (3), 3-[(3,5,6,7,8-pentafluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino]propanoic (4), 4-[(3,5,6,7,8-pentafluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino]butanoic (5), and 6-[(3,5,6,7,8-pentafluoro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino]hexanoic acid (6), respectively. A possibility to further modify a carboxylic function of ω-[5,6,7,8-tetrafluoro-1,4-naphthoquinon-2-yl]aminocarboxylic acids was demonstrated by transformation of acids 3 and 5 into the corresponding acyl chlorides 10 and 12 followed by their in situ conversion into N,N-diethylamides 13 and 14 or ethyl esters 15 and 16. Upon the analogous treatment of acid 4 the primary generated acyl chloride 11 underwent an intramolecular N-acylation to yield 2,5,6,7,8-pentafluoro-3-(2-oxopyrrolidin-1-yl)naphthalene-1,4-dione (17) which was smoothly diethylaminodefluorinated at the 3-position to afford 2-(2-oxopyrrolidin-1-yl)-3-diethylamino-5,6,7,8-tetrafluoronaphthalene-1,4-dione (18). The cytotoxicity evaluation of twelve new quinones in human myeloma, human mammary adenocarcinoma, human hepatocellular carcinoma HepG2 epithelial tumor cells, normal mouse fibroblasts and Chinese hamster Ag 17 cells as well as their mutagenic and antioxidant properties in a Salmonella tester strain was performed. All the compounds effectively suppressed the growth of three lines of tumor cells. These data together with the better cytotoxic effect against cancer cells compared to normal mammalian cells, the bacterial cells protection against spontaneous and H2O2-dependent mutagenesis, and lower general toxicity toward different cells, reveal quinones 2, 13, 15, 16, and 18 as best inhibitors of tumor cells growth among the tested substances.

A large series of polyfluorinated diarylacetylenes and indoles was evaluated for antitumor activity in MCF-7, RPMI 8226, T98 G, HCT 116 human cancer cells and for cytotoxicity effect on HEK-293, WI-38, LMTK, AG 17 normal mammalian cell lines. It was found that with the increased number of fluorine atoms on the benzene ring of the compounds, their cytotoxicity increases, reaching a maximum in case of the perfluorinated structures. Polyfluorinated diarylacetylenes containing three fluorine atoms and trifluoromethyl and amino groups in one aryl ring, inhibit the proliferation of human myeloma RPMI 8226 and human breast cancer MCF-7 cells. Indoles showed more pronounced cytotoxicity as compared with their arylacetylene precursors. Compounds I9, I11, and I13 were found to have a high growth-inhibitory activity toward the human cancer cell lines tested, with half-inhibitory concentrations (IC50) of 1–10 μM. The structures of these compounds are characterized by complete fluorination of the benzene part of the indole core and the presence of an aromatic moiety at the 2nd position of the five-membered ring. Further, DNA fragmentation and Annexin V-FITC/PI staining assays confirm that I9 – I11 induce apoptosis. Mutagenic and antioxidant properties of the polyfluorinated indoles and of selected diarylacetylenes were also studied. On a Salmonella tester strain, it was demonstrated that the compounds are good antioxidants.

This study describes a simple and efficient procedure to synthesize a series of benzene-fluorinated 2,2-dimethyl-2,3-dihydro-1 H -quinolin-4-ones by the PTSA-catalyzed cyclocondensation reaction of the corresponding ortho -alkynylanilines prepared by the Sonogashira reaction of fluoro-substituted 2-iodanilines with 2-methylbut-3-yn-2-ol. The photofluorescent properties (shape of bands, λ ex , λ em , Stokes shift) of the new compounds were investigated. It has been revealed that the 2,3-dihydroquinolinones with different number of fluoro-substituents have almost the same fluorescence properties. The cytotoxicity evaluation of the 2,3-dihydroquinolinones against human myeloma, human mammary adenocarcinoma, human hepatocellular carcinoma HepG2 epithelial tumor cells, normal mouse fibroblasts and Chinese hamster Ag 17 cells was performed. It has been found that the benzo-perfluorinated derivatives of 2,2-dimethyl-2,3-dihydro-1 H -quinolin-4-ones show enhanced cytotoxic effect against the tumor RPMI (human myeloma) cells line compared with the normal cells. Mutagenic and antioxidant properties of the compounds using Salmonella tester strain were studied. It has been shown, that the compounds are well antioxidants.

Fluorinated derivatives of 1,4-naphthoquinones are highly potent inhibitors of Cdc25A and Cdc25B phosphatases and growth of tumor cells. Eight new derivatives of polyfluoro-1,4-naphthoquinone were synthesized and their cytotoxicity in human myeloma, human mammary adenocarcinoma, mouse fibroblasts and primary mouse fibroblast cells as well as their mutagenic and antioxidant properties in a Salmonella tester strain were studied. The efficiency of suppressing the growth of two lines of tumor cells decreased in the order: 2-(2-hydroxy-ethylamino)-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (1), 2,3-dimethoxy-5,6,7,8-tetrafluoro-1,4-naphthoquinone (2), 2-[2-hydroxyethyl(methyl)amino]-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (3), 2-morpholino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (4), 2-[bis-(2-hydroxyethyl)amino]-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (5), 2-[(2-hydroxy)ethylsulfanyl)]-5,6,7,8-tetrafluoro-1,4-naphthoquinone (6), 2-methoxy-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (7), and 1,4-dioxo-3-(1-pyridinio)-1,4-dihydro-5,6,7,8-tetrafluoronaphthalene-2-olate (8). Taking into account these data together with the better cytotoxic effect against cancer cells as compared with normal mammalian cells, protecting of bacterial cells from spontaneous and H(2)O(2)-dependent mutagenesis, and lower general toxicity of the compounds towards different cells, one can propose that compounds 3-5 may be considered as useful potential inhibitors of growth of tumor cells.

Quinone (I) reacts easily with aliphatic amines to afford the corresponding 2-alkylaminonaphthoquinones.

Fluorinated derivatives of 1,4-naphthoquinone are highly potent inhibitors of Cdc25A and Cdc25 phosphatases and growth of tumor cells. Five new N-substituted polyfluorinated derivatives of 2-amino-1,4-naphthoquinone were synthesized and their mutagenic and antioxidant properties in Salmonella cells, as well as cytotoxicity in human myeloma (RPMI 8226), human mammary adenocarcinoma (MCF-7), mouse fibroblasts (LMTK) and primary mouse fibroblast cells (PMF) were studied. 2-tert-Butylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (1) inhibited the growth of normal control and tumor cells at the same concentration. Three compounds: 2-diethylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (2), 2-ethylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (3), 2-phenylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (4) exhibited a 50% decrease in the growth of cancer cells at low and comparable concentrations (2.4-8.6 microM) while being remarkably less cytotoxic toward normal LMTK and PMF cells. Quinones (1)-(4), but not 2-phenylamino-3-methyl-5,6,7,8-tetrafluoro-1,4-naphthoquinone (5), efficiently suppressed spontaneous mutagenesis in Salmonella cells, while all compounds 1-5 decreased the mutagenic effect of H2O2 on bacterial cells. Their possible perspectives as anticancer drugs are shortly discussed.

Four new n-butylamino and two sulfur-containing derivatives of polyfluoro-1,4-naphthoquinone were synthesized and their mutagenic and antioxidant properties in Salmonella cells, as well as the cytotoxicity in human myeloma (RPMI 8226), human mammary adenocarcinoma (MCF-7), mouse fibroblasts (LMTK) and primary mouse fibroblast cells (PMF) were studied. 2-n-Butylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (1) showed efficient inhibition of the growth of the tumor cells. 2,8-Di-(n-butyl-amino)-3,5,6,7-tetrafluoro-1,4-naphthoquinone (2) had significantly less growth-inhibiting properties, while 2,6-di-(n-butylamino)-3,5,7,8-tetrafluoro-1,4-naphthoquinone (3) and 2,6,8-tri-(n-butylamino)-3,5,7-tetrafluoro-1,4-naphthoquinone (4), demonstrated very low cytotoxicity. Compounds 1 and 2 were remarkably less cytotoxic while compound 3 and 4 were not cytotoxic toward LMTK and PMF cells as compared with tumor human cell lines. Cytotoxicity of 2-(2'-methylthioethyl)amino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (5) and (2,2'-dithiodi-2)-3,5,6,7,8-pentafluoro-1,4-naphthoquinone-2-ylamino)ethan (6) toward mammalian cells was compared with that for compounds 1 and 2.

The objective of this study was to investigate the CYP1A1 and CYP1A2 mRNAs and enzyme activities in mouse liver during induction with o-aminoazotoluene (OAT) as well as the capability of the hepatic S9-fraction from OAT-treated mice to induce its own activation to mutagens in the Ames test using S. typhymurium strain TA98. The data obtained indicate that when used at appropriate doses, OAT is a PAH-type inducer of mouse hepatic microsomal monooxygenases, which activity is not less than that of the known inducer 3,4-benzo[alpha]pyrene. In the absence of S9-fraction enzymes no OAT-mediated mutagenicity was observed in the Ames test. In the presence of the S9-fraction from OAT-pretreated mice, OAT induced as high revertant numbers, as it did in the presence of the S9 fraction from the liver of Aroclor 1254-treated mice. Thus, OAT does induce the enzymes of its own mutagenic activation in mouse liver.

A new site-directed method for inserting long single-stranded DNA fragments into any region of a duplex vector is described. Its major advantage is independence of the location of the restriction sites. The method involves the assembly of single-stranded DNA fragments by ligation to both ends of the inserted fragments of two cohesive flanks that are complementary to the target region. Short oligonucleotide templates are used to direct the ligation. The resulting fragments, designated further as omega fragments with cohesive flanks, are hybridized with a gapped DNA vector. The heteroduplexes are transformed into Escherichia coli cells without enzymatic filling and sealing of gapped DNA. As a consequence of intracellular repair and heteroduplex resolution, insertion mutants are recovered. To demonstrate the method's efficiency, we inserted a 51-nucleotide synthetic DNA fragment containing a modified glucocorticoid receptor binding site into the region of pBR322, near the transcription starting point of the tet gene. The method we developed makes possible site-directed insertion of synthetic and genome-derived DNA fragments at least 200 nucleotides long.