- Designing new baeyer-villiger monooxygenases using restricted CASTing
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This paper outlines the design and execution of the first mini-evolution of cyclopentanone monooxygenase (CPMO). The methodology described is a relatively inexpensive and rapid way to obtain mutant enzymes with the desired characteristics. Several successful mutants with enhanced enantioselectivities were identified. For example, mutant-catalyzed oxidation of 4- methoxycyclohexanone gave the corresponding lactone with 92% entantiometric excess (ee) compared to the 46% ee achieved with wild-type cyclohexanone monoxygenase (WT-CHMO). The original design of the mini-evolution and the following evaluation of mutants can provide valuable insights into the active site's construction and dynamics and can suggest other catalytically profitable mutations within the putative active site.
- Clouthier, Christopher M.,Kayser, Margaret M.,Reetz, Manfred T.
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- A novel cluster of C5-curcuminoids: design, synthesis, in vitro antiproliferative activity and DNA binding of bis(arylidene)-4-cyclanone derivatives based on 4-hydroxycyclohexanone scaffold
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A new series (6) of C5-curcuminoid derivatives (2E,6E-2,6-dibenzylidene-4-hydroxycyclohexanones) is described here with their evaluation for in vitro antiproliferative activities. Evaluation of 31 compounds against human A2780 (ovarian), C33A (cervix) and MDA-MB-231 (breast) cancer cell lines was performed to obtain structure activity relation data. The best performer was (2E,6E)-2,6-bis(3′-nitrobenzylidene)-4-hydroxycyclohexanone (6h) with IC50 values of 0.68?μM (A2780), 0.69?μM (C33A) and 0.92?μM (MDA-MB-231) compared to cisplatin with 1.30?μM, 3.69?μM and 19.13?μM, respectively. According to calculated physicochemical properties some members in series 6, namely (2E,6E)-2,6-bis[(4′-pyridinyl)methylene]-4-hydroxycyclohexanone (6p) [IC50 = 0.76?μM (A2780), 2.69?μM (C33A), 1.28?μM (MDA-MB-231)] seem to have improved bioavailability compared to curcumin. Selected members of series 6 were involved in circular dichroism spectroscopic measurements in order to determine their interaction with natural DNA. Based on these data, we conclude that these derivatives do not bind to DNA in vitro. A proposal is summarized based on mass spectrometric assessment for fingerprint analysis in biological research of such C5-curcuminoids.
- Huber, Imre,Zupkó, István,Gyovai, András,Horváth, Péter,Kiss, Eszter,Gulyás-Fekete, Gergely,Schmidt, János,Perjési, Pál
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p. 4711 - 4735
(2019/06/04)
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- Oxidation of Secondary Methyl Ethers to Ketones
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We present a mild way of converting secondary methyl ethers into ketones using calcium hypochlorite in aqueous acetonitrile with acetic acid as activator. The reaction is compatible with various oxygen- and nitrogen-containing functional groups and afforded the corresponding ketones in up to 98% yield. The use of this methodology could expand the application of the methyl group as a useful protecting group.
- Gilissen, Pieter J.,Blanco-Ania, Daniel,Rutjes, Floris P. J. T.
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p. 6671 - 6679
(2017/07/15)
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- Synthesis and NMR spectroscopic conformational analysis of esters of 4-hydroxy-cyclohexanone - The more polar the molecule the more stable the axial conformer
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The esters of 4-hydroxy-cyclohexanone and a series of carboxylic acids R-COOH with R of different electronic and steric influence (R=Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, sec-Bu, t-Bu, CF3, CH2Cl, CHCl 2, CCl3, CH2Br, CHBr2, and CBr 3) were synthesized and the conformational equilibria studied by 1H and 13C NMR spectroscopy at 103 K and at 295 K, respectively. The geometry of optimized structures of the axial/equatorial chair conformers was computed at the ab initio MO and DFT levels of theory. Only one preferred conformation was obtained for the axial and the equatorial conformer as well. When comparing the conformational equilibria of the cyclohexanone esters with those of the corresponding cyclohexyl esters a certain polarity contribution of the cyclohexanone framework was revealed, which is independent of the substituent effects and increases the stability of the axial conformers by a constant amount.
- Kleinpeter, Erich,Heydenreich, Matthias,Koch, Andreas,Linker, Torsten
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p. 2363 - 2373
(2012/04/17)
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- An unexpected oxidation of unactivated methylene C-H using DIB/TBHP protocol
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An in situ generated hypervalent iodine species, bis(tert-butylperoxy) iodobenzene, was used as a peroxy radical source for the oxidation of unreactive, remote, and isolated alkyl (cyclic or aliphatic) esters and amides to the corresponding keto compounds under very mild conditions.
- Zhao, Yi,Yim, Wai-Leung,Tan, Chong Kiat,Yeung, Ying-Yeung
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supporting information; experimental part
p. 4308 - 4311
(2011/10/08)
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- Oligospiroketals as novel molecular rods
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A modular approach for the synthesis of molecular rods based on oligospiroketals has been developed. The strategy relies on different terminal and intermediate segments, which are joined by ketal formation between ketones and diols. For this purpose it was necessary to develop a new ketalization method to circumvent some problems related with the established methods. The terminal segments are either derived from 4-piperidinone or from 4-oxocyclohexane carboxylic acid whereas the intermediate segments rest on pentaerythritol and cyclohexane-1,4-dione. A series of trispiro (14-18), hexaspiro (19) and nonaspiro (20) compounds have been prepared and characterized. From these we realized that it is imperative to use solubility enhancing groups if more than seven rings are joined.
- Wessig, Pablo,Moellnitz, Kristian,Eiserbeck, Christiane
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p. 4859 - 4872
(2008/02/03)
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- Fluorine-substituted cyclofenil derivatives as estrogen receptor ligands: Synthesis and structure-affinity relationship study of potential positron emission tomography agents for imaging estrogen receptors in breast cancer
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In a search for estrogen receptor (ER) ligands to be radiolabeled with fluorine-18 for imaging of ER-positive breast tumors with positron emission tomography (PET), we investigated cyclofenil analogues substituted at the C3 or C4 position of the cyclohexyl group. McMurry coupling of 4,4′- dihydroxybenzophenone with various ketones produced key cyclofenil intermediates, from which C3 and C4 substituents containing alkyl and various oxygen or fluorine-substituted alkyl groups were elaborated. Binding assays to both ERα and ERβ revealed that the C3 site is more tolerant of steric bulk and polar groups than the C4 site, consistent with a computational model of the ERα ligand binding pocket. Fluorine substitution is tolerated very well at some sites, giving some compounds having affinities comparable to or higher than that of estradiol. These fluoro and fluoroalkyl cyclofenils merit further consideration as fluorine-18 labeled ER ligands for PET imaging of ERs in breast tumors.
- Seo, Jai Woong,Comninos, John S.,Chi, Dae Yoon,Kim, Dong Wook,Carlson, Kathryn E.,Katzenellenbogen, John A.
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p. 2496 - 2511
(2007/10/03)
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- Cytotoxic analogues of 2,6-bis(arylidene)cyclohexanones
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A series of 2,6-bis(arylidene)cycloalkanones (1) and related compounds containing one or two substituents at the four position of the cyclohexyl ring were prepared and shown to display cytotoxic activity towards murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. In some of the series of compounds, positive correlations were noted between the potencies of the enones and the magnitude of the Hammett σ values of the aryl substituents. Four representative compounds were cytotoxic to a number of human tumours in vitro, particularly towards colon cancer and leukemic cells. A noteworthy feature of the compounds prepared in this study is that, in general, they were well tolerated when administered to rodents. A number of lead molecules emerged from this investigation as well as guidelines for future expansion of these series of compounds.
- Dimmock, Jonathan R.,Padmanilayam, Maniyan P.,Zello, Gordon A.,Nienaber, Kurt H.,Allen, Theresa M.,Santos, Cheryl L.,De Clercq, Erik,Balzarini, Jan,Manavathu, Elias K.,Stables, James P.
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p. 169 - 177
(2007/10/03)
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- STEREOSTRUCTURE OF RENGYOL AND ISORENGYOL, PHENYLETHANOIDS OF FORSYTHIA SUSPENSA
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Determination of the stereostructure of rengyol (1), a novel nonaromatic phenylethanoid natural product isolated from Forsythia suspensa, by synthetic means has been described.The Reformatsky reaction of 4-acetoxycyclohexanone with ethyl bromoacetate afforded two isomeric acetoxy esters (5, 6) and the one (5) which has an equatorial acetoxyl group yielded on LAH reduction a triol identified as rengyol (1).The isomer (7), obtained similarly from the other isomeric acetoxy ester (6), has also been isolated from the natural source and is named isorengyol.Further, dehydratation of the esters (5, 6) and subsequent pyrolytic deacetoxylation afforded a 1,3-cyclohaxadiene derivative (12), which on photosensitized cis-dioxygenation, followed by reduction, yielded rengyol (1) establishing its stereostructure to have 1,4-cis-cyclohexanediol system.These results supported the previous conclusion based on the 1H and 13C NMR spectral data.
- Endo, Katsuya,Seya, Kazuhiko,Hikino, Hiroshi
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p. 2681 - 2688
(2007/10/02)
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