- DNA-dependent protein kinase (DNA-PK) inhibitors. synthesis and biological activity of quinolin-4-one and pyridopyrimidin-4-one surrogates for the chromen-4-one chemotype
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Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H- chromen-4-one (NU7441) (Leahy, J. J. J.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Richardson, C.; Rigoreau, L.; Smith, G. C. M. Bioorg. Med. Chem. Lett. 2004, 14, 6083-6087) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH 2)nNR1R2, where n = 1 or 2 and the moiety R1R2N was derived from a library of primary and secondary amines (e.g., morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki-Miyaura cross-coupling. Potent DNA-PK inhibitory activity was generally observed across the compound series, with structure activity studies indicating that optimal potency resided in pyridopyrimidin-4- ones bearing a substituted dibenzothiophen-4-yl group. Several of the newly synthesized compounds (e.g., 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)dibenzothiophen-1-yl]acetamide) combined high potency against the target enzyme (DNA-PK IC50 = 8 nM) with promising activity as potentiators of ionizing radiation-induced cytotoxicity in vitro.
- Cano, Céline,Barbeau, Olivier R.,Bailey, Christine,Cockcroft, Xiao-Ling,Curtin, Nicola J.,Duggan, Heather,Frigerio, Mark,Golding, Bernard T.,Hardcastle, Ian R.,Hummersone, Marc G.,Knights, Charlotte,Menear, Keith A.,Newell, David R.,Richardson, Caroline J.,Smith, Graeme C. M.,Spittle, Ben,Griffin, Roger J.
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Read Online
- Design, synthesis, and properties of conformationally fixed semiquinone monoradical species
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(Graph Presented) The design of novel, functionalized semiquinone (SQ) ligands which combine structural rigidity and electron-withdrawing, electron-donating, and electroneutral substituents enables investigation of multiple structure-property relationships and building blocks for new materials, including components of sensors, switches, and molecular spintronics. Along these lines, we report the synthesis of several new SQ ligands containing fused heterocyclic ring systems. Using both electron paramagnetic resonance spectroscopy and quantum chemical calculations, we show how spin density is affected by the fused ring system substituents.
- Shultz, David A.,Sloop, Joseph C.,Washington, Gary
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Read Online
- Blacklight-Induced Hydroxylation of Arylboronic Acids Leading to Hydroxyarenes Using Molecular Oxygen and Tetrabutylammonium Borohydride
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A new simple protocol for the conversion of arylboronic acids to hydroxyarenes was achieved using molecular oxygen in the presence of tetrabutylammonium borohydride under blacklight irradiation (360 nm). A radical chain mechanism in which a superoxide ion (O2?.) plays a key role is proposed.
- Kawamoto, Takuji,Ryu, Ilhyong
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- Cellulose as recyclable organocatalyst for ipso-hydroxylation of arylboronic acids
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Cellulose catalyzed oxidative hydroxylation of aryl and hetero-arylboronic acids to the corresponding phenols under metal and base free strategy has been demonstrated. The sustainable ipso-hydroxylation takes place using hydrogen peroxide as an oxidant in water under mild condition in shorter period of time. Interestingly, easy recovery and reusability of heterogeneous catalyst without significant loss in catalytic yield makes the protocol environmentally benign.
- Laskar, Khairujjaman,Paul, Subham,Bora, Utpal
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- A practical method for preparation of phenols from arylboronic acids catalyzed by iodopovidone in aqueous medium
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A novel and efficient strategy for the ipso-hydroxylation of arylboronic acids to phenols has been developed using inexpensive, readily available, air-stable water-soluble povidone iodine as catalyst and aqueous hydrogen peroxide as oxidizing agent. The reactions were performed at room temperature under metal-, ligand- and base-free condition in a short reaction time. The corresponding substituted phenols were obtained in moderate to good yields by oxidative hydroxylation of arylboronic acids in aqueous medium.
- Dong, Bin,Ke, Yanxiong,Lu, Guangying,Ren, Jiangmeng,Ren, Yaoyao,Zeng, Bu-Bing,Zhou, Bin
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- Trichloroacetonitrile as an efficient activating agent for the: Ipso -hydroxylation of arylboronic acids to phenolic compounds
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A metal-free and base-free Cl3CCN mediated method was developed for the ipso-hydroxylation of aryl boronic acids to their corresponding phenols, which was promoted by a key unstable Lewis adduct intermediate. This transformation has broad functional group tolerance, and late-stage functionalization was successful as well. After simple investigation, two pathways (radical/ionic mechanism) were suggested, and the beneficial action of blue light needs to be further studied.
- Fang, Yuanding,Zhao, Rong,Yao, Yuan,Liu, Yang,Chang, Denghu,Yao, Ming,Shi, Lei
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p. 7558 - 7563
(2019/08/20)
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- Visible-Light-Mediated Aerobic Oxidation of Organoboron Compounds Using in Situ Generated Hydrogen Peroxide
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A simple and general visible-light-mediated oxidation of organoboron compounds has been developed with rose bengal as the photocatalyst, substoichiometric Et3N as the electron donor, as well as air as the oxidant. This mild and metal-free protocol shows a broad substrate scope and provides a wide range of aliphatic alcohols and phenols in moderate to excellent yields. Notably, the robustness of this method is demonstrated on the stereospecific aerobic oxidation of organoboron compounds.
- Weng, Wei-Zhi,Liang, Hao,Zhang, Bo
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supporting information
p. 4979 - 4983
(2018/08/24)
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- Rapid Access to Bi- and Tri-Functionalized Dibenzofurans and their Application in Selective Suzuki–Miyaura Cross Coupling Reactions
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Syntheses of 1,2-, 1,3-, 1,4-, 1,8-, 2,4-, 3,4-, 4,8-, 1,2,4-, 1,2,8- and 1,3,4-functionalized dibenzofurans in few steps with good to excellent yields starting from dibenzofuran-1-ol or -4-ol are presented. These rapidly accessible bi- or tri-functionalized building blocks are of great interest for the synthesis of bioactive substances or functional material development. Furthermore, for intermediates containing both a bromine and a triflate moiety, a selective mono-substitution by means of Suzuki–Miyaura reaction (SMR) is described.
- Wern, Caroline,Ehrenreich, Christian,Joosten, Dominik,Stein, Thorsten vom,Buchholz, Herwig,K?nig, Burkhard
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p. 5644 - 5656
(2018/10/09)
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- A catalytic oxidation fragrant boron class compound preparing phenol method (by machine translation)
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The invention discloses a method for catalytic oxidation of phenolic compounds fragrant boron class compound synthesis method, the flux in the solvent in the aqueous solution, under the action of alkali, adding hydrazine hydrate or acid hydrazides catalyst, catalytic oxidation fragrant boron class compound directly for the preparation of phenolic compound. The invention of the method of preparation of the phenol compound, the catalyst is a cheap hydrazine hydrate or hydrazine compound, the oxidizing agent is atmospheric pressure of air or oxygen, the reaction does not need good and activeness metal catalyst, is extensive and stable substrate, substrate-sensitive functional group compatibility good and wide range of application. In the optimized under the reaction conditions, the yield of the target product separation up to 99%. (by machine translation)
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Paragraph 0073; 0101; 0102
(2017/08/08)
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- Biogenic synthesis of Fe2O3@SiO2 nanoparticles for ipso-hydroxylation of boronic acid in water
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Here, biogenic synthesis of Fe2O3@SiO2 nanoparticles using fruit extract of Zanthoxylum rhetsa is reported. The SiO2 nanoparticles was synthesized using paddy straw which is a byproduct obtained in cultivation of rice. The composite was characterised by spectroscopic method like XRD, SEM, TEM and EDX analysis. The ipso-hydroxylation reactions were carried out with excellent yield within a moderate time period with mild reaction condition in all cases. Therefore, this approach may be considered as simple, easy, cheap and greener, environment friendly protocol for ipso-hydroxylation of arylboronic acids at 50 °C temperature.
- Saikia, Indranirekha,Hazarika, Moushumi,Hussian, Najrul,Das, Manash R.,Tamuly, Chandan
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p. 4255 - 4259
(2017/10/11)
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- Organic electroluminescent materials and devices
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Aluminum chelate complex compounds with two substituted 8-hydroxyquinoline ligand and one dibenzothiophene, dibenzofuran or dibenzoselenophene ligands or aza-analogs of these molecules, attached directly or through an aromatic spacer to the oxygen atom is provided to improve lifetime, operating voltage and efficiency of an OLED. Additional substitution of dibenzothiophene or dibenzofuran ring may also provide charge delocalization, HOMO modification and higher Tg.
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Page/Page column 160
(2017/09/02)
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- How Inter- and Intramolecular Reactions Dominate the Formation of Products in Lignin Pyrolysis
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One of the key challenges in renewable chemical production is the conversion of lignin, especially by fast pyrolysis. The complexity of the lignin pyrolysis process has hindered the elucidation of the mechanism, inhibiting further industrial implementation. By combining pyrolysis of model compounds (4-phenoxyphenol and 2-methoxy-phenoxybenzene) with lignin bond characteristics both under vacuum and under realistic pressure conditions, the roles of inter- and intramolecular reactions were established. On the one hand, the stable 4-O-5 ether bond enables, without breaking, C?C bond formation and even directly forms naphthalene depending on the position and type of the substituent. p-Benzoquinone intermediates, on the other hand, are highly unstable at ambient pressure and directly decompose into coke and carbon monoxide. The system pressure (radical concentration) plays a crucial role in the dominant reaction mechanism by initiating intramolecular reactions, interfering with intramolecular reactions. H-transfer and recombination reactions suppress the decarbonylation of phenoxy radicals, thus yielding a very different product distribution.
- Custodis, Victoria B. F.,Hemberger, Patrick,van Bokhoven, Jeroen A.
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p. 8658 - 8668
(2017/06/30)
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- Metal-free synthesis of substituted phenols from arylboronic acids in water at room temperature
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A convenient, efficient and practical metal-free method for the synthesis of substituted phenols from arylboronic acids has been developed. The protocol uses hydrogen peroxide as a hydroxylating agent, ammonium bicarbonate as an additive, and the reactions were conveniently performed in water at room temperature. The method shows an excellent tolerance of functional groups, so it will find a wide variety of applications in academic and industrial research.
- Jiang, Min,Yang, Hai-Jun,Li, Yong,Jia, Zhi-Ying,Fu, Hua
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supporting information
p. 715 - 719
(2014/06/09)
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- A novel sustainable strategy for the synthesis of phenols by magnetic CuFe2O4-catalyzed oxidative hydroxylation of arylboronic acids under mild conditions in water
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A novel sustainable strategy for the synthesis of phenols has been developed using inexpensive, readily available, air-stable, and recyclable CuFe2O4 nanoparticles as the catalyst, and the corresponding substituted phenols were obtained in moderate to good yields by oxidative hydroxylation of arylboronic acids in water. Importantly, a ligand or an additive was not necessary. The catalyst was completely recoverable with an external magnet and could be reused six times without significant loss of catalytic activity.
- Yang, Daoshan,An, Baojuan,Wei, Wei,Jiang, Min,You, Jinmao,Wang, Hua
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supporting information
p. 3630 - 3634
(2014/05/20)
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- Unexpected hydrazine hydrate-mediated aerobic oxidation of aryl/ heteroaryl boronic acids to phenols in ambient air
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The expedient and efficient sub-stoichimetric hydrazine hydrate-mediated aerobic hydroxylation of boronic acids that proceeds in poly(ethylene glycol) (PEG-400) has been successfully developed, providing diverse phenols in high yields. And heteroaryl boronic acids are also amenable to this protocol. the Partner Organisations 2014.
- Zhong, Yanzhen,Yuan, Linxin,Huang, Zheng,Gu, Wenchao,Shao, Ye,Han, Wei
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p. 33164 - 33167
(2014/08/18)
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- Oxidation of organotrifluoroborates via oxone
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A method for the oxidation of organotrifluoroborates using Oxone was developed. A variety of aryl-, heteroaryl-, alkenyl-, and alkyltrifluoroborates were converted into the corresponding oxidized products in excellent yields. This method proved to be tolerant of a broad range of functional groups, and in secondary alkyl substrates it was demonstrated to be completely stereospecific.
- Molander, Gary A.,Cavalcanti, Livia N.
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experimental part
p. 623 - 630
(2011/03/20)
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- Ester derivatives as phosphodiesterase inhibitors
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are new ester derivatives, methods of preparing such compounds, compositions containing them and therapeutic use thereof
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(2009/07/10)
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- DIBENZOFURAN DERIVATIVES AS INHIBITORS OF PDE-4 AND PDE-10
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The present invention relates to novel heterocyclic compounds that are useful as phosphodiesterase inhibitors (PDEs) in particular phosphodiesterase type 4 (PDE IV) inhibitors and phosphodiesterase type 10 (PDE 10) inhibitors, processes for their preparation, pharmaceutical compositions containing them and their use in treating allergic and inflammatory diseases as well as for inhibiting the production of Tumor Necrosis Factor(TNF-α).
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(2008/06/13)
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- DNA-PK INHIBITORS
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Compounds of formula: (I) wherein A, B and D are respectively selected from the group consisting of: (i) CH, NH, C; (ii) CH, N, N; and (iii) CH, O, C; the dotted lines represent two double bonds in the appropriate locations; and where Z is selected from S, O, C(=O), CH2 and NH are disclosed for use in inhibiting DNA-PK.
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Page/Page column 45
(2008/06/13)
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- TRICYCLIC COMPOUNDS USEFUL FOR THE TREATMENT OF INFLAMMATORY AND ALLERGIC DISORDERS:PROCESS FOR THEIR PREPARATION
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The present invention relates to novel heterocyclic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diasteromers, their polymorphs, their pharmaceutically acceptable salts, their appropriate N-oxides, their pharmaceutically acceptable solvates and their pharmaceutical compositions containing them. The present invention more particularly relates to novel Phosphodiesterase type 4 (PDE4) inhibitors of the formula (1), their analogs, their tautomers, their enantiomers, their diasteromers, their regioisomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their appropriate oxides, their pharmaceutically acceptable solvates and the pharmaceutical compositions containing them.
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- Synthesis of psoralen analogues based on dibenzofuran
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The syntheses of four novel psoralen derivatives, 6a-d, of the benzofurocoumarin (=benzofuro[1]benzopyranone) type containing an ester group are described. These compounds might be of interest in PUVA (psoralen long-wave ultraviolet radiation) therapy. The overall efficiency of the synthetic procedure is greatly limited by the low yields for the penultimate step, i.e., formylation of the dibenzofuranols 3a,c or protected dibenzofuranol 4d to the carboxaldehydes 5 (Scheme 4). However, the final stage to form the pyranone ring from 5a - d proceeds smoothly (Scheme 5).
- Oliveira, Ana M. A. G.,Raposo, M. Manuela M.,Oliveira-Campos, Ana M. F.,Griffiths, John,Machado, Antonio E. H.
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p. 2900 - 2907
(2007/10/03)
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- Products, rates, and mechanism of the gas-phase condensation of phenoxy radicals between 500-840 K
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Phenols are demonstrated precursors of 'dioxins' - polychlorinated dibenzo-p-dioxins (DDs) and dibenzofurans (DFs) - in thermal processes, especially incineration. Heterogeneous catalysis, depending on conditions, can play an important role, but mere gas-phase combination of phenolic entities to ultimately DD and/or DF is always possible. The present paper addresses the fundamental role of phenol itself. Phenol has long been known to give DF upon pyrolysis and in similar thermal reactions. In the liquid phase under oxidative conditions it yields five condensation products (A-E); this clearly occurs through the dimerization of two phenoxy (PhO) radicals, followed by enolisation/rearomatisation. Our study shows that in the gas phase, at the lower T end, such dimers are also formed, but still with very little DF. That DF, indeed, is almost the only condensation product at elevated temperatures is substantiated by thermochemical-kinetic analysis (favouring the pathway of ortho-C/ortho-C combination of two PhO radicals), as well as by results obtained with two plausible intermediates, viz. 2,2'- dihydroxybiphenyl (A) and 2-phenoxyphenol (C). Mechanisms for the requisite enolisation and dehydration steps leading to DF are discussed.
- Wiater, Izabela,Born, Jan G. P.,Louw, Robert
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p. 921 - 928
(2007/10/03)
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- Benzopyrans
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Described are novel reversible photochromic benzopyran compounds, examples of which are compounds substituted at the 2 position of the pyran ring and have fused at the benzo portion of the benzopyran a substituted or unsubstituted heterocyclic ring such as a benzothieno or benzofurano group. Also described are organic host materials that contain or that are coated with such compounds. Articles such as ophthalmic lenses or other plastic transparencies that incorporate the novel benzopyran compounds or combinations thereof with complementary photochromic compounds, e.g., spiro(indoline) type compounds, are also described.
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- Peptide Synthesis by Prior Thiol Capture. 2. Design of Templates for Intramolecular O,N-Acyl Transfer. 4,6-Disubstituted Dibenzofurans as Optimal Spacing Elements
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A central feature of the strategy for amide bond formation by prior thiol capture is an intramolecular acyl transfer across a template that links the phenolic ester function of one peptide with an unsymmetrical disulfide involving the side chain of the N-terminal cysteine residue of a second peptide.The structures of the 4-hydroxy-6-mercaptodibenzofuran (3) and 4-hydroxy-6-mercaptophenoxythiin (4) are established by 1H NMR spectra of deuterated dibenzofuran and phenoxythiin derivatives.On the basis of the criterion of effective molarity, a dibenzofuran template for intramolecular acyl transfer is shown to be approximately 2 orders of magnitude more efficient than a phenoxythiin.An effective local concentration of ca. 5 M and a Hammett ρ value of 2.6 are observed for the intramolecular acyl-transfer reaction 1 -> 2.
- Kemp, D. S.,Galakatos, Nicholas G.,Bowen, Benjamin,Tan, Kenneth
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p. 1829 - 1838
(2007/10/02)
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- Peptide Synthesis by Prior Thiol Capture. 1. A Convenient Synthesis of 4-Hydroxy-6-mercaptodibenzofuran and Novel Solid-Phase Synthesis of Peptide-Derived 4-(Acyloxy)-6-mercaptodibenzofurans
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Peptide bond formation by intramolecular acyl transfer across a rigid template is outlined.The template precursor 6-hydroxy-4-mercaptodibenzofuran (3) is obtained from 4-methoxydibenzofuran by metalation with n-butyllithium, oxidation with elemental sulfur, and demethylation.Routes to 4-(acyloxy)-6-mercaptodibenzofurans 4 are reported.Esters 4 derived from simple urethane N-blocked α-amino acids are conveniently prepared by direct acylation of 6-hydroxy-4-(methoxycarbonyldithio)dibenzofuran (12), followed by reduction with tri-n-butylphosphine.Esters 4 derived from the C-terminal carboxyl groups of peptides are prepared by a novel variant of conventional solid-phase peptide synthesis in which the chain elongation steps are carried out on the 4-((α-aminoacyl)oxy)-6-dibenzo-furanyldithio function linked through the disulfide to a polymeric support.At the completion of the elongation steps, release of 4 from the resin is achieved by reduction of the disulfide bond with tri-n-butylphosphine.
- Kemp, D. S.,Galakatos, Nicholas George
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p. 1821 - 1829
(2007/10/02)
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