- Novel Hypoxia-Inducible Factor 1α (HIF-1α) Inhibitors for Angiogenesis-Related Ocular Diseases: Discovery of a Novel Scaffold via Ring-Truncation Strategy
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Ocular diseases featuring pathologic neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1α, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1α inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1α inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1α inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1α inhibitors that can be used in lieu of a chromene ring.
- An, Hongchan,Lee, Seungbeom,Lee, Jung Min,Jo, Dong Hyun,Kim, Joohwan,Jeong, Yoo-Seong,Heo, Mi Jeong,Cho, Chang Sik,Choi, Hoon,Seo, Ji Hae,Hwang, Seyeon,Lim, Jihye,Kim, Taewoo,Jun, Hyoung Oh,Sim, Jaehoon,Lim, Changjin,Hur, Joonseong,Ahn, Jungmin,Kim, Hyun Su,Seo, Seung-Yong,Na, Younghwa,Kim, Seok-Ho,Lee, Jeewoo,Lee, Jeeyeon,Chung, Suk-Jae,Kim, Young-Myeong,Kim, Kyu-Won,Kim, Sang Geon,Kim, Jeong Hun,Suh, Young-Ger
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p. 9266 - 9286
(2018/10/24)
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- Manganese-Catalyzed Dual-Deoxygenative Coupling of Primary Alcohols with 2-Arylethanols
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Reported herein is a general and efficient dual-deoxygenative coupling of primary alcohols with 2-arylethanols catalyzed by a well-defined Mn/PNP pincer complex. This reaction is the first example of the catalytic dual-deoxygenation of alcohols using a non-noble-metal catalyst. Both deoxygenative homocoupling of 2-arylethanols (17 examples) and their deoxygenative cross-coupling with other primary alcohols (20 examples) proceeded smoothly to form the corresponding alkenes by a dehydrogenation and deformylation reaction sequence.
- Wang, Yujie,Shao, Zhihui,Zhang, Kun,Liu, Qiang
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supporting information
p. 15143 - 15147
(2018/11/01)
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- Stereoselective synthesis of 3,4-di-substituted mercaptolactones via photoredox-catalyzed radical addition of thiophenols
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A visible light mediated radical addition of thiophenols on 4-phenylbut-3-enoic acids to give diastereoselective synthesis of 3,4-disubstituted γ-lactones is reported. The reaction precludes the conventional prerequisite of conjugate addition. Furthermore, the lactones were successfully utilized in the synthesis of γ-ketoamides.
- Kouser, Farzana,Sharma, Vijay Kumar,Rizvi, Masood,Sultan, Shaista,Chalotra, Neha,Gupta, Vivek K.,Nandi, Utpal,Shah, Bhahwal Ali
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supporting information
p. 2161 - 2166
(2018/05/05)
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- Biocatalytic Formal Anti-Markovnikov Hydroamination and Hydration of Aryl Alkenes
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Biocatalytic anti-Markovnikov alkene hydroamination and hydration were achieved based on two concepts involving enzyme cascades: epoxidation-isomerization-amination for hydroamination and epoxidation-isomerization-reduction for hydration. An Escherichia coli strain coexpressing styrene monooxygenase (SMO), styrene oxide isomerase (SOI), ω-transaminase (CvTA), and alanine dehydrogenase (AlaDH) catalyzed the hydroamination of 12 aryl alkenes to give the corresponding valuable terminal amines in high conversion (many ≥86%) and exclusive anti-Markovnikov selectivity (>99:1). Another E. coli strain coexpressing SMO, SOI, and phenylacetaldehyde reductase (PAR) catalyzed the hydration of 12 aryl alkenes to the corresponding useful terminal alcohols in high conversion (many ≥80%) and very high anti-Markovnikov selectivity (>99:1). Importantly, SOI was discovered for stereoselective isomerization of a chiral epoxide to a chiral aldehyde, providing some insights on enzymatic epoxide rearrangement. Harnessing this stereoselective rearrangement, highly enantioselective anti-Markovnikov hydroamination and hydration were demonstrated to convert α-methylstyrene to the corresponding (S)-amine and (S)-alcohol in 84-81% conversion with 97-92% ee, respectively. The biocatalytic anti-Markovnikov hydroamination and hydration of alkenes, utilizing cheap and nontoxic chemicals (O2, NH3, and glucose) and cells, provide an environmentally friendly, highly selective, and high-yielding synthesis of terminal amines and alcohols.
- Wu, Shuke,Liu, Ji,Li, Zhi
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p. 5225 - 5233
(2017/08/17)
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- Synthesis of 3-Arylpyridines via Palladium/Copper-Catalyzed Annulation of Allylamine/1,3-Propanediamine and Aldehydes
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A novel and efficient method for the synthesis of 3-arylpyridines from allylamine/propanediamine and aldehydes by palladium/copper-catalyzed oxidative tandem cyclization has been developed. With this reaction, a series of desired 3-arylpyridines was synthesized in moderate yields via C-C/C-N bond formation and 6-endo/exo-trig cyclization.
- Yang, Xiaodong,Yang, Shenghua,Xiang, Likui,Pang, Xiaobo,Chen, Baohua,Huang, Guosheng,Yan, Rulong
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supporting information
p. 3732 - 3736
(2016/01/25)
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- Catalysed anti-Markovnikov oxidation of terminal aryl alkenes to aldehydes and transformation of methyl aryl tertiary amines to formamides with H2O2 as a terminal oxidant
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Anti-Markovnikov oxidation of terminal aryl alkenes to aldehydes and transformation of N-methyl aryl tertiary amines to formamides with H2O2 as a terminal oxidant under mild conditions have been achieved with moderate to good product yields using [FeIII(TF4DMAP)OTf] as catalyst. This journal is
- Du, Yi-Dan,Tse, Chun-Wai,Xu, Zhen-Jiang,Liu, Yungen,Che, Chi-Ming
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supporting information
p. 12669 - 12672
(2015/05/20)
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- Broad-spectrum catalysts for the ambient temperature anti-Markovnikov hydration of alkynes
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Anti-Markovnikov alkyne hydration provides a valuable route to aldehydes. Half-sandwich ruthenium complexes ligated by 5,5′-bis(trifluoromethyl)-2, 2′-bipyridine are remarkably active for this transformation. In the presence of 2 mol % metal, a wide range of functionalized aliphatic and aromatic alkynes are hydrated in high yield at ambient temperature. Alkyne hydration: Half-sandwich ruthenium complexes derived from 5,5′-bis(trifluoromethyl)- 2,2′-bipyridine show a high activity for the anti-Markovnikov hydration of terminal alkynes (see picture). A wide array of alkynes are efficiently hydrated to aldehydes using 2 mol % metal loadings at 25 °C within 8-24 h.
- Li, Le,Zeng, Mingshuo,Herzon, Seth B.
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supporting information
p. 7892 - 7895
(2014/08/05)
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- Temporal separation of catalytic activities allows anti-Markovnikov reductive functionalization of terminal alkynes
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There is currently great interest in the development of multistep catalytic processes in which one or several catalysts act sequentially to rapidly build complex molecular structures. Many enzymes - often the inspiration for new synthetic transformations - are capable of processing a single substrate through a chain of discrete, mechanistically distinct catalytic steps. Here, we describe an approach to emulate the efficiency of these natural reaction cascades within a synthetic catalyst by the temporal separation of catalytic activities. In this approach, a single catalyst exhibits multiple catalytic activities sequentially, allowing for the efficient processing of a substrate through a cascade pathway. Application of this design strategy has led to the development of a method to effect the anti-Markovnikov (linear-selective) reductive functionalization of terminal alkynes. The strategy of temporal separation may facilitate the development of other efficient synthetic reaction cascades.
- Li, Le,Herzon, Seth B.
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- A continuous flow solution to achieving efficient aerobic anti-Markovnikov Wacker oxidation
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An aerobic anti-Markovnikov Wacker oxidation for the flow-synthesis of arylacetaldehydes is reported. In the process, flow chemistry techniques have provided a means to control and minimise the over-oxidation of sensitive products. The reaction showed general applicability to various functionalised styrenes and provided a process capable of a multi-gram scale. Copyright
- Bourne,Ley
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supporting information
p. 1905 - 1910
(2013/08/23)
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- Biocatalytic production of tetrahydroisoquinolines
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The promiscuity of the enzyme norcoclaurine synthase is described. This biocatalyst yielded a diverse array of substituted tetrahydroisoquinolines by cyclizing dopamine with various acetaldehydes in a Pictet-Spengler reaction. This enzymatic reaction may provide a biocatalytic route to a range of tetrahydroisoquinoline alkaloids.
- Ruff, Bettina M.,Br?se,O'Connor, Sarah E.
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supporting information; experimental part
p. 1071 - 1074
(2012/03/27)
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- Triazole Compounds, Use Thereof and Agents Containing Same
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The present invention relates to compounds of the formula I in which the variables have the meanings defined in the claims and in the description.
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Page/Page column 46-47
(2011/08/02)
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- Imidazole and Triazole Compounds, Their Use and Agents Containing The Same
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The present invention relates to compounds of the formula I in which the variables have the meanings defined in the claims and in the description.
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Page/Page column 55
(2011/08/02)
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- HYDROXAMATE-BASED INHIBITORS OF DEACETYLASES B
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The present teachings relate to compounds of Formula I: and pharmaceutically acceptable salts, hydrates, esters, and prodrugs thereof, wherein R1, R2, R3, Y, Z, and are as defined herein. The present teachings also provide methods of preparing compounds of Formula I and methods of using compounds of Formula I in treating, inhibiting, or preventing pathologic conditions or disorders mediated wholly or in part by deacetylases.
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Page/Page column 49
(2009/10/06)
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- N-Propynyl analogs of β-phenylethylidenehydrazines: Synthesis and evaluation of effects on glycine, GABA, and monoamine oxidase
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A group of β-phenylethylidenehydrazines possessing a variety of substituents (Me, OMe, Cl, F, and CF3) at the ortho-, meta-, or para-positions of the phenyl ring, in conjunction with either a N-bis-(2-propynyl) or a N-mono-(2-propynyl) moiety, were synthesized and compared to the novel neuroprotective drug β-phenylethylidenehydrazine (PEH) with regard to their ability to inhibit the enzymes GABA-transaminase (GABA-T) and monoamine oxidase (MAO)-A and -B in vitro in brain tissue. Two of the analogs synthesized (mono- and bis-N-propynylPEH) were also studied ex vivo in rats to compare their effects to those of PEH with regard to ability to inhibit GABA-T and MAO and to change brain levels of several important amino acids. Unlike PEH, none of the new drugs inhibited GABA-T in vitro at 10 or 100 μM, and all of the drugs (including PEH) were poor inhibitors (at 10 μM) of MAO-A and -B in vitro. The two analogs studied ex vivo inhibited GABA-T to a lesser extent than PEH, unlike PEH that did not elevate brain levels of GABA, and inhibited MAO-A and -B more potently than PEH. Interestingly, unlike PEH, the two analogs caused marked increases in brain levels of glycine; because of the current interest in drugs that increase glycine availability in the brain as potential antipsychotic drugs, these two analogs now warrant further investigation.
- MacKenzie, Erin M.,Fassihi, Afshin,Davood, Asghar,Chen, Qiao-Hong,Rauw, Gillian,Rauw, Gail,Knaus, Edward E.,Baker, Glen B.
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experimental part
p. 8254 - 8263
(2009/04/07)
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- Novel anti-Markovnikov regioselectivity in the Wacker reaction of styrenes
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The Wacker reaction is one of the longest known palladium-catalysed organic transformations, and in the vast majority of cases proceeds with Markovnikov regioselectivity. Palladium(II)-mediated oxidation of styrenes was examined and in the absence of reoxidants was found to proceed in an anti-Markovnikov sense, giving aldehydes. Studies on the mechanism of this unusual transformation were carried out, and indicate the possible involvement of a η4-palladium-styrene complex. With a heteropolyacid as the terminal oxidant, oxidation of styrene to give the anti-Markovnikov aldehyde as the major product was found to be catalytic.
- Wright, Joseph A.,Gaunt, Matthew J.,Spencer, Jonathan B.
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p. 949 - 955
(2007/10/03)
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- Unsubstituted and substituted 4-benzyl-1,3-dihydro-imidazole-2-thiones acting as specific or selective alpha2 adrenergic agonists and methods for using the same
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Compounds of Formula 1 where the variables have the meaning defined in the specification are used to activate alpha2 adrenergic receptors. The compounds of Formula 1 are incorporated in pharmaceutical compositions and are used as medicaments in mammals, including humans, for treatment of diseases and or alleviations of conditions which are responsive to treatment by agonists of alpha2 adrenergic receptors.
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Page/Page column 11
(2010/10/20)
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- Design and biological evaluation of phenyl-substituted analogs of β-phenylethylidenehydrazine
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β-Phenylethylidenehydrazine (PEH) has been demonstrated previously to be an inhibitor of γ-aminobutyric acid transaminase (GABA-T) and to cause a marked increase in rat brain levels of GABA, a major neurotransmitter. A group of PEH analogs, possessing a variety of substituents (Me, OMe, Cl, F, and CF3) at the 2-, 3-, and 4-positions of the phenyl ring, were synthesized for evaluation as inhibitors of GABA-T. The details of the synthesis and chemical characterization of the analogs are described. Preliminary in vitro screening for GABA-T inhibition showed that all the analogs possessed activity against this enzyme, although substitution of CF3 at the 2- and 4-positions caused reduced activity. One of the drugs, 4-fluoro-β- phenylethylidenehydrazine, was investigated further ex vivo, where it was shown to inhibit GABA-T, elevate brain levels of GABA, and decrease levels of glutamine, similar to the profile observed previously for PEH.
- Sowa, Bernard,Rauw, Gillian,Davood, Asghar,Fassihi, Afshin,Knaus, Edward E.,Baker, Glen B.
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p. 4389 - 4395
(2007/10/03)
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- Preparation of Some Chromans Substituted at the 3- or 4-Position by an Aryl or Benzyl Group, by the Rhodium-catalysed Intramolecular Nucleophilic Substitution of the Corresponding 3-(2-Fluorophenyl)propanols
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The bis(hexafluorophosphate) salt of the (η5-ethyltetramethylcyclopentadienyl)(η6-benzene)rhodium(III) cation has been used as a catalyst to prepare 3-phenyl-, 3-(4-methoxyphenyl)-, 3-(4-nitrophenyl)-, and 4-benzylchroman by cyclisation of the corresponding substituted 3-(2-fluorophenyl)-propanols in nitromethane-acetone solution. 3-Phenyl-4-hydroxymethylchroman and 3-hydroxymethyl-4-phenylchroman were prepared similarly.An attempt to prepare a bis(chroman) by a double cyclisation with 2-propane-1,3-diol afforded only the monochroman, 4-(2-fluorophenyl)-3-hydroxymethylchroman.Under the conditions of the cyclisation, the erythro and threo forms of 1,4-di(2-fluorophenyl)-butane-2,3-diol afforded only the corresponding 1,3-dioxolanes as the result of the diols reacting with the acetone used as cosolvent.The 1H n.m.r. spectra of the 3-substituted and 3,4-disubstituted chromans which have been prepared are consistent with the heterocyclic ring being in the half-chair conformation (6).
- Houghton, Roy P.,Shervington, Leroy A.
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p. 1872 - 1892
(2007/10/02)
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- 4-Aryl-3-butenoic acids and lower alkyl esters
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Benzyl esters and thiolesters of 4-aryl-3-butenoic acids, intermediates therefor, synthesis thereof, and the use of said esters and thiolesters for the control of pests.
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