- 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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- Attempt to synthesize 2,3,5,4′-tetrahydroxystilbene derived from 2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside (THSG)
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An attempt to synthesize aglycone 1 derived from 2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside (THSG) via the Wittig reaction and Mizoroki-Heck reaction is described. In the Wittig protocol, 2,3,5,4′-tetramethoxystilbene 2 was obtained. Additionally, a palladium-catalyzed Mizoroki-Heck reaction strategy yielded 2-aryl-2,3-dihydrobenzofuran 13 instead of derivative 12 in good yield.
- Tamura, Masafumi,Koshibe, Yuhei,Kaji, Kiho,Ueda, Jun-Ya,Shirataki, Yoshiaki
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p. 122 - 125
(2015/02/19)
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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 the Sesquiterpenes Albicanol, Drimanol, and Drimanic Acid, and the Marine Sesquiterpene Hydroquinone Deoxyspongiaquinol
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A TiIII-mediated radical cyclization cascade has been used for the synthesis of the sesquiterpenes (+)-albicanol, (+)-drimanol, and (+)-drimanic acid. Starting from all-trans-farnesol, (+)-albicanol could be prepared in seven steps in an overal
- G?hl, Matthias,Seifert, Karlheinz
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p. 6975 - 6982
(2016/02/19)
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- ENHANCING AUTOPHAGY OR INCREASING LONGEVITY BY ADMINISTRATION OF UROLITHINS OR PRECURSORS THEREOF
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Disclosed are methods, compounds, and compositions useful for increasing autophagy and promoting longevity. The methods, compounds, and compositions relate to urolithins and urolithin precursors and use thereof. Certain urolithins are represented by Formula I, while certain urolithin precursors are represented by Formula IV. The urolithin may be urolithin A, urolithin B, urolithin C, or urolithin D. The urolithin precursor may be ellagic acid or an ellagitannin. The methods include in vivo, ex vivo, and in vitro uses of the compounds and compositions.
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- Synthesis of polyhydroxylated flavonoids bearing a lipophilic decyl tail as potential therapeutic antioxidants
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Antioxidants have potential for the treatment of stroke and neurodegeneration, and chimeric compounds that combine a flavon-3-ol head group related to myricetin and a lipophilic decyl tail are known to protect membranes from oxidative damage at least as well as vitamin E. New flavon-3-ols that are highly hydroxylated in the B ring in ways not found in natural flavon-3-ols and bearing a lipophilic decyl tail have been prepared from trimethoxy-and tetramethoxybenzoic acids accessed by lithiation-carboxylation reactions. Direct enolate acylation was preferred over Baker-Venkataraman rearrangement when there were methoxy groups at both the 2-and the 6-position of the benzoic acid derivatives.
- Caldwell, Stuart T.,McPhail, Donald B.,Duthie, Garry G.,Hartley, Richard C.
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scheme or table
p. 23 - 33
(2012/03/07)
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- 2-Amino-4-methyl-5-phenylethyl substituted-7-N-benzyl-pyrrolo[2,3-d] pyrimidines as novel antitumor antimitotic agents that also reverse tumor resistance
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Gangjee et al. recently reported a novel series of 2-amino-4-methyl-5- phenylethyl substituted-7-benzyl-pyrrolo[2,3-d]pyrimidines, some of which exhibited two digit nanomolar antitumor and antimitotic activity and were not subject to P-glycoprotein (Pgp)
- Gangjee, Aleem,Namjoshi, Ojas A.,Keller, Staci N.,Smith, Charles D.
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experimental part
p. 4355 - 4365
(2011/08/09)
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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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- Ga(IIl)-catalyzed cycloisomerization approach to (±)-icetexone and (±)-epi-icetexone
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"Chemical eqation presented" A Ga(III)-catalyzed cycloisomerization reaction provides expedient access to a benzannulated cycloheptadiene bearing a cyano group, which has been applied to the syntheses of several icetexane diterpenoids including icetexone
- De Jesus Cortez, Felipe,Sarpong, Richmond
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supporting information; experimental part
p. 1428 - 1431
(2010/07/03)
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- Studies on the structure and biosynthesis of tridentoquinone and related meroterpenoids from the mushroom Suillus tridentinus (Boletales)
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Tridentoquinone (1), the main pigment of Suillus tridentinus, is accompanied by the known meroterpenoid bolegrevilol (3) and a dimer, tridentorubin (5). The absolute configuration of 1 was unambiguously established by a single-crystal X-ray analysis of the corresponding (-)-camphanoate. The structure of 5 was elucidated by 2D NMR techniques including a 2D INADEQUATE experiment. Feeding experiments with [1-13C]-labeled 4-hydroxybenzoic acid (6*) and 3,4-dihydroxybenzoic acid (7*) proved the incorporation of these precursors into all three metabolites. Tridentoquinone (1) was monolabeled at C-1 suggesting the formation of the ansa ring by oxidative cyclisation of 2-geranylgeranyl-6-hydroxybenzoquinone (10). This was supported by the isolation of the expected intermediate, deoxytridentoquinone (11), from the mushroom extract. Tridentorubin (5) may be formed by addition of precursor 10 to tridentoquinone (1). This hypothesis is backed up by the in vitro formation of an analogous product 13 from 1 and 1,4-benzoquinone. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Lang, Martin,Muehlbauer, Andrea,Graef, Claudia,Beyer, Juergen,Lang-Fugmann, Susanne,Polborn, Kurt,Steglich, Wolfgang
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experimental part
p. 816 - 825
(2009/04/11)
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- Strongylophorine-26, an inhibitor of cancer cell invasion: SAR revealed by synthesis of analogues
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The absolute configuration of strongylophorine-26 (1) was determined to be 4S, 5R, 8R, 9S, 10S, 13S, 14S by single-crystal X-ray diffraction analysis of the derivative 7 prepared from the co-occurring metabolite strongylophorine-8 (4) and chemical interconversion to the bislactone 8. Synthetic analogues (+)- and (-)-3 have been prepared in order to explore the structure-activity relationship for the anti-invasion pharmacophore of stronglylophorine-26. These studies revealed the unanticipated importance of the A ring lactone moiety for the anti-invasion activity of 1.
- Warabi, Kaoru,Patrick, Brian O.,Austin, Pamela,Roskelley, Calvin D.,Roberge, Michel,Andersen, Raymond J.
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p. 736 - 740
(2008/02/10)
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- A concise and efficient synthesis of protected actinoidic acid, the degradation product of vancomycin
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Protected actinoidic acid 2, one of the degradation products of vancomycin, has been efficiently synthesized by a convergent route which is amenable to large scale application as well as to asymmetric synthesis.
- Zhu, Jieping,Beugelmans, Rene,Bigot, Antony,Singh, Girij Pal,Bois-Choussy, Michele
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p. 7401 - 7404
(2007/10/02)
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