- A comprehensive assessment of a new series of 5′,6′-difluorobenzotriazole-acrylonitrile derivatives as microtubule targeting agents (MTAs)
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Microtubules (MTs) are the principal target for drugs acting against mitosis. These compounds, called microtubule targeting agents (MTAs), cause a mitotic arrest during G2/M phase, subsequently inducing cell apoptosis. MTAs could be classified in two groups: microtubule stabilising agents (MSAs) and microtubule destabilising agents (MDAs). In this paper we present a new series of (E) (Z)-2-(5,6-difluoro-(1H)2H-benzo[d] [1,2,3]triazol-1(2)-yl)-3-(R)acrylonitrile (9a-j, 10e, 11a,b) and (E)-2-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-(R)acrylonitrile derivatives (13d,j), which were recognised to act as MTAs agents. They were rationally designed, synthesised, characterised and subjected to different biological assessments. Computational docking was carried out in order to investigate the potential binding to the colchicine-binding site on tubulin. From this first prediction, the di-fluoro substitution seemed to be beneficial for the binding affinity with tubulin. The new fluorine derivatives, here presented, showed an improved antiproliferative activity when compared to the previously reported compounds. The biological evaluation included a preliminary antiproliferative screening on NCI60 cancer cells panel (1–10 μM). Compound 9a was selected as lead compound of the new series of derivatives. The in vitro XTT assay, flow cytometry analysis and immunostaining performed on HeLa cells treated with 9a showed a considerable antiproliferative effect, (IC50 = 3.2 μM), an increased number of cells in G2/M-phase, followed by an enhancement in cell division defects. Moreover, β-tubulin staining confirmed 9a as a MDA triggering tubulin disassembly, whereas colchicine-9a competition assay suggested that compound 9a compete with colchicine for the binding site on tubulin. Then, the co-administration of compound 9a and an extrusion pump inhibitor (EPI) was investigated: the association resulted beneficial for the antiproliferative activity and compound 9a showed to be client of extrusion pumps. Finally, structural superimposition of different colchicine binding site inhibitors (CBIs) in clinical trial and our MDA, provided an additional confirmation of the targeting to the predicted binding site. Physicochemical, pharmacokinetic and druglikeness predictions were also conducted and all the newly synthesised derivatives showed to be drug-like molecules.
- Riu, Federico,Sanna, Luca,Ibba, Roberta,Piras, Sandra,Bordoni, Valentina,Scorciapino, M. Andrea,Lai, Michele,Sestito, Simona,Bagella, Luigi,Carta, Antonio
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- Vinylene-bridged difluorobenzo[: C] [1,2,5]-thiadiazole (FBTzE): A new electron-deficient building block for high-performance semiconducting polymers in organic electronics
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A new class of an acceptor unit, vinylene-bridged 5,6-difluorobenzothiadiazole FBTzE, has been developed. Palladium-catalyzed Migita-Kosugi-Stille coupling reactions of 1 with 2, yielding 3 and its sequential dehydrogenative coupling with 4, readily affor
- Asanuma, Yuya,Mori, Hiroki,Takahashi, Ryosuke,Nishihara, Yasushi
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p. 905 - 916
(2019/02/01)
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- METALLOENZYME INHIBITOR COMPOUNDS
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Provided are compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
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Paragraph 0556; 0557; 0558; 0559
(2018/07/29)
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- A simple and efficient: In situ generated ruthenium catalyst for chemoselective transfer hydrogenation of nitroarenes: Kinetic and mechanistic studies and comparison with iridium systems
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The catalytic activities of a series of in situ generated homogeneous ruthenium systems based on commercially available [RuCl2(p-cymene)]2 and various ligands in transfer hydrogenation of nitroarenes to anilines were investigated. Combination of [RuCl2(p-cymene)]2 and tridentate phenanthroline based ligand 2-(6-methoxypyridin-2-yl)-1,10-phenanthroline (phenpy-OMe) exhibited the highest catalytic activity for this reaction using 2-propanol as hydrogen source. This protocol provides a facile route to access aromatic amines under mild conditions in excellent yields. Notably, this system chemoselectively reduced the nitro groups over an array of other reactive functionalities such as ketone, alkene, amide, nitrile, and aryl halide. Operational simplicity, high yields, mild reaction conditions and short reaction times make this an attractive methodology for accessing various functionalized anilines. A series of controlled experiments and careful mechanistic investigation with the possible intermediates suggested that transformation of nitrobenzene to aniline with ruthenium and iridium system proceeded via direct route and condensation route respectively.
- Paul, Bhaskar,Chakrabarti, Kaushik,Shee, Sujan,Maji, Milan,Mishra, Anju,Kundu, Sabuj
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p. 100532 - 100545
(2016/11/09)
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- Fluorinated 2-Amino-4-(Benzylamino)Phenylcarbamate Derivatives
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The invention relates to fluorinated compounds and their use as anti-epileptic, muscle-relaxing, fever-reducing and peripherally analgesically acting medications and as imaging agents. Novel fluorinated 2-amino-4-(benzylamino)phenyl carbamate derivatives of ezogabine and pharmaceutically acceptable salts or solvates thereof and their use are described.
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Paragraph 0144; 0145
(2013/11/06)
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- CHARGE-TRANSPORT MATERIALS, METHODS OF FABRICATION THEREOF, AND METHODS OF USE THEREOF
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Briefly described, embodiments of this disclosure include charge-transport materials, methods of forming charge-transport materials, and methods of using the charge-transport materials.
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Page/Page column 119
(2008/06/13)
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- Synthesis of novel fluorobenzofuroxans by oxidation of anilines and thermal cyclization of arylazides
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The synthesis of several fluorobenzofuroxans by oxidation of fluoroanilines and thermal cyclization of fluoroarylazides is presented. The fluorobenzofuroxans prepared in this study presented tautomerism as evidenced by their NMR data. Benzofuroxans in general have biological activity and are synthetic intermediates for the preparation of several compounds with important pharmaceutical applications.
- Leyva, Socorro,Castanedo, Víctor,Leyva, Elisa
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p. 171 - 175
(2007/10/03)
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- Fluorinated Heterocycles: II. Synthesis of Quinoxaline 1,4-Dioxides
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7-Amino-6-fluoroquinoxaline 1,4-dioxides have been synthesized by reaction of 5,6-difluorobenzofuroxan with enamines derived from cycloalkanones and with malononitrile. The transformation of 5,6-difluorobenzofuroxan into quinoxalin 1,4-dioxides in the pre
- Kotovskaya,Charushin,Chupakhin,Kozhevnikova
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p. 369 - 374
(2007/10/03)
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- 6-FLUORO-7-(1-PIPERAZINYL)QUINOXALINE 1,4-DIOXIDES. PART I. 2-(N-2-HYDROXYALKYLCARBAMOYL) DERIVATIVES
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A series of N--β-aminoalkanol 1,4-dioxides (12a-h) have been synthesized for bioassay via the Beirut reaction of 5(6)-fluoro-6(5)-(4-methyl-1-piperazinyl)benzofuroxan (9) with the appropriate N-acetoacetyl-β-aminoalkanol in the presence of triethylamine.Preliminary in vitro investigations have indicated that none of the title compounds exhibits any significant antibacterial potency at concentrations /= 200 μg/ml.
- El-Abadelah, Mustafa M.,Nazer, Musa Z.,El-Abadla, Naser S.,Meier, Herbert
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p. 2203 - 2220
(2007/10/03)
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- Hypoxia-Selective Agents Derived from Quinoxaline 1,4-Di-N-oxides
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Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy.Thus the identification of drugs with selective toxicity toward hypoxic cells is an important objective in anticancer chemotherapy.The benzotriazine di-N-oxide (SR 4233, Tirapazamine) has been shown to be an efficient and selective cytotoxin for hypoxic cells.Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the 1,4-di-N-oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,4-di-N-oxides with a range of electron-donating and -withdrawing substituents in the 6- and /or 7- positions has been synthesized and evaluated for toxicity to hypoxic cells.Electrochemical studies of the quinoxaline di-N-oxides and Tirapazamine showed that as the electron-withdrawing nature of the 6(7)-substituent increases, the reduction potential becomes more positive and the compound is more readily reduced.Apart from the unsubstituted 6a and the 6,7-dimethyl derivative 6c, the quinoxaline di-N-oxide have reduction potentials significantly more positive than Tirapazamine (Epc -0.90 V).The most potent cytotoxins to cells in culture were the 6,7-dichloro and 6,7-difluoro derivatives 6i and 6l, which were 30-fold more potent than Tirapazamine.The 6(7)-fluoro and 6(7)-chloro compounds, 6e and 6h, showed the greatest hypoxia selectivity.Four of the compounds, 6e, 6f, 6h and 6i, killed the inner cells of multicellular tumor spheroids in vitro.In vivo Balb/c mice tolerated a dose of these four compounds twice the size of that of Tirapazamine.This study demonstrates that quinoxaline 1,4-di-N-oxides could provide useful hypoxia-selective therapeutic agents.
- Monge, Antonio,Palop, Juan A.,Cerain, Adela Lopez de,Senador, Virginia,Martinez-Crespo, Francisko J.,et al.
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p. 1786 - 1792
(2007/10/02)
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- Benzoheterocyclic compounds
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Novel 4-oxoquinoline-3-carboxylic acid compounds of the formula: STR1 wherein R3 is C1 -C6 alkyl and RF is C1 -C6 alkyl, and a pharmaceutically acceptable salts thereof, said compounds havi
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- 1-Cyclopropyl-6-fluoro-7-piperazinyl-1,4-Dihydro-4-oxo-quinoline-3-carboxylic acid derivatives
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Novel 4-oxoquinoline-3-carboxylic acid compounds of the formula: STR1 wherein R2 is a heterocyclic group: STR2 in which RA is H, C1 -C6 alkyl or phenyl (C1 -C6) alkyl, RB is 2-ox
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- 1-cyclopropyl-6-fluoro-8-alkyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives
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Novel 4-oxoquinoline-3-carboxylic acid compounds of the formula: STR1 wherein R2 is 1-pyrrolidinyl which may have 1 to 2 substituents selected from the group consisting of (i) C1 -C6 alkyl, (ii) amino-(C1 -Csub
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- Halogenobenzoic acid derivatives and their preparation
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The present invention is concerned with certain novel halogenobenzoic acid derivatives of the following formula, STR1 wherein R is a chlorine atom, amino group or hydroxy group, X is a chlorine atom or bromine atom, which are useful intermediates for the
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- Benzoylacetic acid ester derivatives and process for their preparations
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The present invention is concerned with certain novel benzoylacetic acid ester derivatives (I) which are useful as a intermediates for synthesis of antibacterial agests. STR1 wherein R is a lower alkyl group, X is a halogen atom and Y is a chlorine or bro
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- Process for the preparation of quinolonecarboxylic acid derivatives
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The present invention is concerned with certain novel process for the preparation of quinolonecarboxylic acid derivatives of the following formula, wherein R1 is a lower alkyl group, X is a chlorine or bromine atom and Y is a halogen atom, which are usefu
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- Salts of dihalo-3,4-dihydro-3-oxo-2-quinoxaline carboxylic acids and hindered amines
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Salts of 6,7-dihalo-3,4-dihydro-3-oxo-2-quinoxaline carboxylic acids and hindered amines, useful in combating influenza A and B.
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- Treatment of influenza with 2-estersubstituted-3,4-dihydro-3-oxoquinoxalines
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3,4-Dihydro-3-oxoquinoxalines carrying a carboxylic acid or ester function in the 2 position, used as antiviral agents, particularly against influenza virus, both A and B strains.
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