- Synthesis and biological evaluation of acyclic triaryl (Z)-olefins possessing a 3,5-di-tert-butyl-4-hydroxyphenyl pharmacophore: Dual inhibitors of cyclooxygenases and lipoxygenases
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A new class of regioisomeric acyclic triaryl (Z)-olefins possessing a 3,5-di-tert-butyl-4-hydroxyphenyl (DTBHP) 5-lipoxygenase (5-LOX) pharmacophore that is vicinal to a para-methanesulfonylphenyl cyclooxygenase-2 (COX-2) pharmacophore were designed for evaluation as selective COX-2 and/or 5-LOX inhibitors. The target compounds were synthesized via a highly stereoselective McMurry olefination cross-coupling reaction. This key synthetic step afforded a (Z):(E) olefinic mixture with a predominance for the (Z)-olefin stereoisomer. Structure-activity studies for the (Z)-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-methanesulfonylphenyl)-1-phenylalk-1-ene regioisomers showed that COX-1 inhibition decreased, COX-2 inhibition increased, and the COX-2 selectivity index (SI) increased as the chain length of the alkyl substituent attached to the olefinic double bond was increased (Et → n-butyl → n-heptyl). In this group of compounds, inhibition of both 5-LOX and 15-LOX was dependent upon the length of the alkyl substituent with the hex-1-ene compound 9c having a n-butyl substituent exhibiting potent inhibition of both 5-LOX (IC50 = 0.3 μM) and 15-LOX (IC50 = 0.8 μM) relative to the inactive (IC50 > 10 μM) Et and n-heptyl analogs. Compound 9c is of particular interest since it also exhibits a dual inhibitory activity against the COX (COX-1 IC50 = 3.0 μM, and COX-2 IC50 = 0.36 μM, COX-2 SI = 8.3) isozymes. A comparison of the relative inhibitory activities of the two groups of regioisomers investigated shows that the regioisomers in which the alkyl substituent is attached to the same olefinic carbon atom (C-2) as the para-methanesulfonylphenyl moiety generally exhibit a greater potency with respect to COX-2 inhibition. The 4-hydroxy substituent in the 3,5-di-tert-butyl-4-hydroxyphenyl moiety is essential for COX and LOX inhibition since 3,5-di-tert-butyl-4-acetoxyphenyl derivatives were inactive inhibitors. These structure-activity data indicate acyclic triaryl (Z)-olefins constitute a suitable template for the design of dual COX-2/LOX inhibitors.
- Moreau, Anne,Praveen Rao,Knaus, Edward E.
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p. 5340 - 5350
(2008/02/07)
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- Synthesis and Electrochemical Characteristics of 1-(3,5-Di-tert-butyl-4-hydroxyphenyl)alkyl(aryl)ketones and Radicals Obtained Therefrom
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1-(3,5-Di-tert-butyl-4-hydroxyphenyl)alkyl(aryl) ketones were prepared by treating 2,6-di-tert-butylphenol with aliphatic acids anhydrides and aroyl chlorides. The products were characterized with IR and 1H NMR spectra. Electrochemical reductio
- Monastyrskaya,Lyutkin,Gorbunov,Klimov
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p. 1409 - 1416
(2007/10/03)
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- Formation of Diphenyl Ethers from Cyclohexa-2,5-dienones via 4-phenoxy-4-(1-alkoxy)cyclohexa-2,5-dienones as Probable Intermediates
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Acid-catalysed reactions of the cyclohexa-2,5-dienones (3) and (14) with phenol afford diphenyl ethers.Quinol ethers are considered to be intermediates in these reactions, with aromatisation of the cyclohexa-2,5-dienone ring by loss of the 4-(1-alkoxy) side-chain as an aldehyde constituting the driving force.
- Karhu, Matti
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p. 303 - 306
(2007/10/02)
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- Reactions of 4-Bromo-4-(1-hydroxypropyl)-2,6-di-t-butylcyclohexa-2,5-dienone in Methanolic Sulphuric Acid
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Reactions of the title compound (1) in methanolic sulphuric acid are described.At high acid concentrations the main reaction is the cleavage of the side chain as propionic aldehyde.At low acid concentrations the products are mainly formed by hydrolysis of (1) and subsequent reduction and oxidation reactions involving the bromide ion and bromine.
- Karhu, Matti
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p. 1595 - 1598
(2007/10/02)
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- Quinone Dehydrogenation. Oxidation of Benzylic Alcohols with 2,3-Dichloro-5,6-dicyanobenzoquinone
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2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ) reacts with primary and secondary aryl-substituted alcohols under mild conditions in dioxane solution to give the corresponding carbonyl compounds in high yields.In contrast to other oxidants, DDQ can be applied advantageously for the oxidation of hydroxyaryl-substituted alcohols.A mechanism involving participation of the phenolic hydroxyl group in the dehydrogenation reaction is discussed.Oxidations of hydroxyaryl-substituted alcohols by DDQ in methanolsolution resulting in the formation of benzoquinones by loss of the hydroxyaryl side chain are interpreted in terms of phenol oxidation.An example of a pyridine-catalyzed Smiles rearrangement of an o-hydroxy-substituted diphenyl ether is reported.
- Becker, Hans-Dieter,Bjoerk, Anders,Adler, Erich
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p. 1596 - 1600
(2007/10/02)
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- Anti-inflammatory method
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Compounds in which 2,6-di(t-butyl)phenol is substituted in the 4 position by an acyl group have valuable pharmacological activity as anti-inflammatory agents. This is a continuation of application Ser. No. 797,138 filed May 16, 1977 now abandoned.
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