- Evaluation of the anti-inflammatory effects of synthesised tanshinone I and isotanshinone I analogues in zebrafish
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During inflammation, dysregulated neutrophil behaviour can play a major role in a range of chronic inflammatory diseases, for many of which current treatments are generally ineffective. Recently, specific naturally occurring tanshinones have shown promising anti-inflammatory effects by targeting neutrophils in vivo, yet such tanshinones, and moreover, their isomeric isotanshinone counterparts, are still a largely underexplored class of compounds, both in terms of synthesis and biological effects. To explore the anti-inflammatory effects of isotanshinones, and the tanshinones more generally, a series of substituted tanshinone and isotanshinone analogues was synthesised, alongside other structurally similar molecules. Evaluation of these using a transgenic zebrafish model of neutrophilic inflammation revealed differential anti-inflammatory profiles in vivo, with a number of compounds exhibiting promising effects. Several compounds reduce initial neutrophil recruitment and/or promote resolution of neutrophilic inflammation, of which two also result in increased apoptosis of human neutrophils. In particular, the methoxy-substituted tanshinone 39 specifically accelerates resolution of inflammation without affecting the recruitment of neutrophils to inflammatory sites, making this a particularly attractive candidate for potential pro-resolution therapeutics, as well as a possible lead for future development of functionalised tanshinones as molecular tools and/or chemical probes. The structurally related β-lapachones promote neutrophil recruitment but do not affect resolution. We also observed notable differences in toxicity profiles between compound classes. Overall, we provide new insights into the in vivo anti-inflammatory activities of several novel tanshinones, isotanshinones, and structurally related compounds.
- Foulkes, Matthew J.,Tolliday, Faith H.,Henry, Katherine M.,Renshaw, Stephen A.,Jones, Simon
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- Synthesis, inhibitory activity and in silico docking of dual COX/5-LOX inhibitors with quinone and resorcinol core
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Based on the significant anti-inflammatory activity of natural quinone primin (5a), series of 1,4-benzoquinones, hydroquinones, and related resorcinols were designed, synthesized, characterized and tested for their ability to inhibit the activity of cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) enzymes. Structural modifications resulted in the identification of two compounds 5b (2-methoxy-6-undecyl-1,4-benzoquinone) and 6b (2-methoxy-6-undecyl-1,4-hydroquinone) as potent dual COX/5-LOX inhibitors. The IC50 values evaluated in vitro using enzymatic assay were for compound 5b IC50 = 1.07, 0.57, and 0.34 μM and for compound 6b IC50 = 1.07, 0.55, and 0.28 μM for COX-1, COX-2, and 5-LOX enzyme, respectively. In addition, compound 6d was identified as the most potent 5-LOX inhibitor (IC50 = 0.14 μM; reference inhibitor zileuton IC50 = 0.66 μM) from the tested compounds while its inhibitory potential against COX enzymes (IC50 = 2.65 and 2.71 μM for COX-1 and COX-2, respectively) was comparable with the reference inhibitor ibuprofen (IC50 = 4.50 and 2.46 μM, respectively). The most important structural modification leading to increased inhibitory activity towards both COXs and 5-LOX was the elongation of alkyl chain in position 6 from 5 to 11 carbons. Moreover, the monoacetylation in ortho position of bromo-hydroquinone 13 led to the discovery of potent (IC50 = 0.17 μM) 5-LOX inhibitor 17 (2-bromo-6-methoxy-1,4-benzoquinone) while bromination stabilized the hydroquinone form. Docking analysis revealed the interaction of compounds with Tyr355 and Arg120 in the catalytic site of COX enzymes, while the hydrophobic parts of the molecules filled the hydrophobic substrate channel leading up to Tyr385. In the allosteric catalytic site of 5-LOX, compounds bound to Tyr142 and formed aromatic interactions with Arg138. Taken together, we identified optimal alkyl chain length for dual COX/5-LOX inhibition and investigated other structural modifications influencing COX and 5-LOX inhibitory activity.
- Sisa, Miroslav,Dvorakova, Marcela,Temml, Veronika,Jarosova, Veronika,Vanek, Tomas,Landa, Premysl
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- PRIMIN DERIVATIVES, METHOD OF PREPARATION THEREOF AND USE THEREOF
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The present invention provides primin derivatives of general formula II and/or III, wherein R1 is selected from the group consisting of methyl and hydrogen, R2 is selected from the group consisting of methoxy, hydroxy, hydrogen, Rsu
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Page/Page column 6
(2017/03/28)
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- ONO-pincer ruthenium complex-bound norvaline for efficient catalytic oxidation of methoxybenzenes with hydrogen peroxide
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The enhanced catalytic activity of ruthenium complex-bound norvaline Boc-l-[Ru]Nva-OMe 1, in which the ONO-pincer ruthenium complex Ru(pydc)(terpy) 2 is tethered to the α-side chain of norvaline, has been demonstrated for the oxidation of methoxybenzenes to p-benzoquinones with a wide scope of substrates and unique chemoselectivity.
- Yoshida, Ryota,Isozaki, Katsuhiro,Yokoi, Tomoya,Yasuda, Nobuhiro,Sadakane, Koichiro,Iwamoto, Takahiro,Takaya, Hikaru,Nakamura, Masaharu
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supporting information
p. 7468 - 7479
(2016/08/16)
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- Facile construction of 3-hydroxyphenanthrene-1,4-diones: Key intermediates to tanshinone i and its A-ring-modified analogue
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A mild synthetic approach was established allowing for a convenient construction of tricyclic hydroxyphenanthraquinones, the key precursor for total synthesis of tanshinone I. This tandem process includes decarboxylative radical alkylation, intramolecular C-H arylation and one-pot O-demethylation and aromatization. Variously substituted phenylpropanoic acids were well tolerated in this approach, and synthesis of tanshinone I (1) was finally successful in six straight steps in 19% overall yields from commercially available 5-bromovanillin.
- Jiao, Mingkun,Ding, Chunyong,Zhang, Ao
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p. 2976 - 2981
(2014/04/17)
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- Synthesis of indolequinones from bromoquinones and enamines mediated by Cu(OAc)2H2O
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A Cu(II)-mediated synthesis of indolequinones from the corresponding bromoquinones and enamines is reported. The key oxidative cyclization proceeds in good yield for a broad range of substrates and can be performed on a multigram scale, allowing access to biologically interesting structures.
- Inman, Martyn,Moody, Christopher J.
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supporting information; experimental part
p. 6023 - 6026
(2010/11/20)
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- Tracheal smooth muscle relaxant
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The present invention offers a tracheal smooth muscle relaxant containing the compound represented by the following formula (1) or pharmacologically acceptable salt thereof as an effective ingredient. [In the formula, X and Y each is any group selected from a group consisting of CH2, CHW1 (where W1 is halogen atom, hydroxyl group or lower alkoxy group) and C=O when the bond of X and Y is a single bond while, when it is a double bond, X and Y each is any group selected from a group consisting of CH and COW2 (where W2 is lower alkyl group or lower alkylcarbonyl group); Z is O, S, S=O or SO2; and R1?R8 each is selected from a group consisting of hydrogen atom, VR9 (where V is O, S, S=O or SO2; and R9 is hydrogen atom, lower alkyl group, hydroxy lower alkyl group, lower acyl group, trihalomethyl group or carboxyl lower alkyl group), carboxyl lower alkyl group, hydroxy lower alkyl group, hydroxy lower alkenyl group, hydroxy lower alkynyl group, halogen atom, lower alkyl group, lower alkyl ketone, trihalomethyl group, trimethylsilylethynyl, nitro group, amino group, N-carbonyl lower alkyl group, lower alkylphenyl group and phenyl group].
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- Anti-oxidative tricyclic, condensed heterocyclic compound
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Providing a novel tricyclic, condensed heterocyclic compound having an anti-oxidative action and being promising for use in pharmaceutical agents, cosmetics, chemical products and the like. By chemical synthesis, a novel anti-oxidative, tricyclic, condensed heterocyclic compound represented by the following formula: STR1 (wherein X--Y represents CH2 --C=O, CH2 --CH2 or CH=CH; Z represents O, S, or S=O; R1 to R8 represent independently those selected from the group consisting of hydrogen atom, a hydroxyl group, a halogen group, a lower alkyl group, a lower alkoxyl group, a lower alkyl ketone group and CF3 ; and at least two of R1 to R4 are hydroxyl groups); and the salts thereof are provided. The compound has an anti-oxidative activity at the same degree as or higher than the activity of α-tocopherol, so the compound is promising as a therapeutic drug for a variety of diseases, such as cancer, arteriosclerosis, or liver diseases, in which it is believed that biological lipid peroxides may be involved.
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- AZEPINE SYNTHESIS VIA A DIELS-ALDER REACTION
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Disclosed are methods of preparing azepines by a multistep synthesis including a Diels-Alder reaction. Also disclosed are methods of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the hyperactivity of the excitatory amino acids, as well as treating anxiety, chronic pain, convulsions, inducing anesthesia and treating or preventing opiate tolerance are disclosed by administering to an animal in need of such treatment an azepine which has high binding to the NMDA glycine site.
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- Solid state redox chemistry of hydroquinones and quinones
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Solid state ceric ammonium nitrate (CAN) oxidation of hydroquinones to the corresponding quinones, gives best results when operating with ultrasonic irradiation. Nitrogen dioxide plays a key role in these 'solid-solid' oxidations. The oxidation of hydroquinones to quinones can also be achieved in a unique 'solid-solid-solid' reaction, i.e., by using a limited amount of CAN in the presence of a full equivalent of a solid cooxidant such as KBrO3. Reduction of quinones with sodium dithionite in the solid state gives rise to the corresponding highly colored quinhydrones and, eventually, to hydroquinones.
- Morey,Saa
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p. 105 - 112
(2007/10/02)
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- ON THE REGIOSELECTIVITY OF THE FREMY'S SALT OXIDATION OF PHENOLS
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A detailed study of the regioselectivity of the Fremy's salt oxidation of phenols, including a series of MNDO calculations of the intermediate phenoxy radicals, has been carried out.The analysis of these results has led us to establish a new rule for the para vs. ortho regioselectivity, namely: "C-4 unsubstituted phenols, as well as phenols substituted at C-4 with easy-to-displace groups, undergo oxidation (or oxidative degradation) by the action of Fremy's salt, thus eventually providing the corresponding p-quinones".A similar rule for the ortho vs. ortho' regioselectivity could not be so precisely formulated since now steric effects play a significant major role.
- Deya, Pedro M.,Dopico, Mercedes,Raso, Angel Garcia,Morey, Jeronimo,Saa, Jose M.
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p. 3523 - 3532
(2007/10/02)
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- A NOVEL DEGRADATIVE STRATEGY FOR THE SYNTHESIS OF p-QUINONES.
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p-Hydroxybenzylalcohols undergo Fremy's salt promoted degradative oxidation to give the corresponding p-benzoquinones.A novel strategy for the synthesis of p-benzoquinones based on the regioselective metalation of 2-methoxy-4-methoxymethyl phenols is presented.
- Saa, Jose M.,Morey, Jeronimo,Costa, Antonio
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p. 5125 - 5128
(2007/10/02)
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