- 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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- Direct para-Selective C-H Amination of Iodobenzenes: Highly Efficient Approach for the Synthesis of Diarylamines
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Iodine(III)-mediated synthesis of 4-iodo-N-phenylaniline from iodobenzene has been achieved, and the reaction can proceed under mild conditions. A variety of functional groups were well tolerated, providing the corresponding products in moderate to good yields. The remaining iodine group provides an effective platform for converting the products into several valuable asymmetric diphenylamines. Most importantly, this reaction can be easily scaled up to the ten-gram scale, highlighting its synthetic utility. The mechanistic study revealed that the in situ generated aryl hypervalent iodine intermediate is the key factor to realize this para-selective C-H amination reaction.
- Chen, Yujie,Huang, Zhibin,Jiang, Yaqiqi,Shu, Sai,Yang, Shan,Shi, Da-Qing,Zhao, Yingsheng
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p. 8226 - 8235
(2021/06/28)
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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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supporting information
p. 905 - 916
(2019/02/01)
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- Synthesis, antibacterial activities, mode of action and acute toxicity studies of new oxazolidinone-fluoroquinolone hybrids
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To combat bacterial resistance, a series of new oxazolidinone-fluoroquinolone hybrids have been synthesized and characterized. All synthetic hybrids were preliminarily evaluated for their in vitro antibacterial activities against 6 standard strains and 3 clinical isolates. The majority of hybrids displayed excellent activities against Gram-positive bacteria, but limited activities against Gram-negative bacteria. Hybrids OBP-4 and OBP-5 were found to be the most promising compounds. Further, in vitro antibacterial activities, mode of action and acute toxicity in mice of hybrids OBP-4 and OBP-5 were investigated. Hybrids OBP-4 and OBP-5 exhibited potent activities against Gram-positive bacteria, including drug-resistant strains. Correspondingly, studies on the mode of action of hybrids OBP-4 and OBP-5 indicated a strong inhibitory activity on protein synthesis by binding the active site of 50S subunit, but a weak inhibitory action on DNA synthesis. In addition, LD50 values of hybrids OBP-4 and OBP-5 in the acute oral toxicity were larger than 2000 mg/kg, suggesting a good safety profile.
- Liu, Lili,Shao, Liping,Li, Jing,Cui, Haifeng,Li, Bing,Zhou, Xuzheng,Lv, Pengyue,Zhang, Jiyu
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- Activation of C-F bonds in ionic liquids catalyzed by nickel complex compounds
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A nickel complex-catalyzed hydrodefluorination of acet(pentafluoroanilide) with zinc in ionic liquids resulted in the corresponding 2,3,4,5-tetrafluoro, 3,4,5-trifluoro, and 3,4-difluoro derivatives. The influence of the ionic liquid nature and the reaction conditions on its selectivity were studied, a possibility of the multiple reuse of the ionic liquids as the reaction media was demonstrated.
- Prikhod'Kv,Adonin, N. Yu.,Parmon
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- Air oxidation of N-cyclopropylanilines
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Air oxidation of N-cyclopropylanilines was shown to occur under either ambient conditions or accelerated conditions (warming or shining light) in an open container. A subsequent fragmentation resulted in formation of the corresponding acetamide. While potential mechanisms have been previously proposed, simple aerobic oxidation to β-hydroxy-propionamides in the absence of a radical promoter has not been previously reported. Copyright Taylor & Francis Group, LLC.
- Blackburn, Anthony,Bowles, Daniel M.,Curran, Timothy T.,Kim, Hui
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p. 1855 - 1863
(2012/04/10)
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- The ionic liquid [bmim]Br as an alternative medium for the catalytic cleavage of aromatic C-F and C-Cl bonds
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The potential of [bmim]Br as an alternative to aprotic dipolar solvents in nickel-catalyzed hydrodehalogenation reactions is demonstrated. Hydrodechlorination of pentafluorochlorobenzene proceeds under the action of zinc in aqueous [bmim]Br. Under the above conditions aromatic C-F bonds also undergo slow cleavage. The reaction is significantly accelerated in the presence of nickel complexes with 2,2′-bipyridine or 1,10-phenanthroline. In the case of pentafluoroacetanilide highly regioselective ortho-hydrodefluorination leading to the formation of 3,4,5-trifluoroacetanilide is observed.
- Prikhod'ko, Sergey A.,Adonin, Nicolay Yu.,Parmon, Valentin N.
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scheme or table
p. 2265 - 2268
(2010/05/18)
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- Comparative catalytic C-H vs. C-Si activation of arenes with Pd complexes directed by urea or amide groups
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Analysis of regiocontrol in Pd-catalysed C-H activation leads to observations of aryltrimethylsilyl activation and to superior results with urea-based substrates.
- Rauf, Waqar,Thompson, Amber L.,Brown, John M.
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supporting information; experimental part
p. 3874 - 3876
(2010/01/06)
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- Reaction of pentafluoroacetanilide with zinc catalyzed by nickel complexes
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The reaction of pentafluoroacetanilide hydrodefluorination under the action of zinc in the presence of catalytic amounts of complexes, generated in situ from nickel chloride and 2,2′-bipyridine or 1,10-phenanthroline, was studied. The influence of the sol
- Prikhodko,Adonin,Parmon
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p. 2304 - 2310
(2014/05/06)
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- Exploration of the diketoacid integrase inhibitor chemotype leading to the discovery of the anilide-ketoacids chemotype
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Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. A previous study of the diketoacid-based chemotype suggested that there are two aryl-binding domains on integrase. In this study, modifications to the indole-based diketoacid chemotype are explored. It is demonstrated that the indole group can be replaced with secondary but not tertiary (e.g., N-methyl) aniline-based amides without sacrificing in vitro inhibitory activity. The difference in activity between the secondary and tertiary amides is most likely due to the opposite conformational preferences of the amide bonds, s-trans for the secondary-amide and s-cis for the tertiary-amide. However, it was found that the conformational preference of the tertiary amide can be reversed by incorporating the amide nitrogen atom into an indoline heterocycle, resulting in very potent integrase inhibitors.
- Walker, Michael A.,Johnson, Timothy,Ma, Zhuping,Zhang, Yunhui,Banville, Jacques,Remillard, Roger,Plamondon, Serge,Pendri, Annapurna,Wong, Henry,Smith, Daniel,Torri, Albert,Samanta, Himadri,Lin, Zeyu,Deminie, Carol,Terry, Brian,Krystal, Mark,Meanwell, Nicholas
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p. 5818 - 5821
(2007/10/03)
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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 120
(2008/06/13)
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- Analogues of camptothecin, their use as medicaments and the pharmaceutical compositions containing them
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A compound of the formula wherein the substituents are defined as in the specification which compounds are useful in the treatment of cancer.
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- Electrochemical fluorination of benzamide and acetanilide in anhydrous HF and in acetonitrile
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Electrochemical fluorination of benzamide in anhydrous hydrogen fluoride does not involve the amide group but occurs exclusively at the aromatic ring, yielding isomeric fluoro- and difluorobenzamides and 3,3,6,6-tetrafluoro-1,4- cyclohexadienecarboxamide.
- Shainyan,Danilevich,Grigor'eva,Chuvashev
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p. 513 - 517
(2007/10/03)
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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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- New analogues of camptothecin, their use as medicaments and the pharmaceutical compositions containing them
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A compound of the formula wherein the substituents are defined as in the specification which compounds are useful in the treatment of cancer.
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- Comptothecin analogues, preparation methods therefor, use thereof as drugs, and pharmaceutical compositions containing said analogues
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The compound of the formula wherein the substituents are defined as in the specification and its non-toxic, pharmaceutically acceptable salts which are useful for the treatment of viral infections, parasitic diseases and the treatment of cancer.
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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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- 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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