- Rhodium(III)-Catalyzed Meta-Selective C-H Alkenylation of Phenol Derivatives
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Rhodium(III)-catalyzed remote meta-selective-C-H alkenylation of phenol derivatives has been developed using a traceless organosilicon template as the directing group. This transformation proceeds smoothly with good yields and high meta-selectivities toward a series of phenol and alkene substrates. In addition, this protocol provides an effective strategy for late-stage transformations of various meta-alkenylated aromatic compounds.
- Mi, Rui-Jie,Sun, Yong-Zhen,Wang, Jing-Yun,Sun, Jing,Xu, Zhaoqing,Zhou, Ming-Dong
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supporting information
p. 5126 - 5129
(2018/09/12)
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- A biocompatible alkene hydrogenation merges organic synthesis with microbial metabolism
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Organic chemists and metabolic engineers use orthogonal technologies to construct essential small molecules such as pharmaceuticals and commodity chemicals. While chemists have leveraged the unique capabilities of biological catalysts for small-molecule production, metabolic engineers have not likewise integrated reactions from organic synthesis with the metabolism of living organisms. Reported herein is a method for alkene hydrogenation which utilizes a palladium catalyst and hydrogen gas generated directly by a living microorganism. This biocompatible transformation, which requires both catalyst and microbe, and can be used on a preparative scale, represents a new strategy for chemical synthesis that combines organic chemistry and metabolic engineering. Reduction to practice: A hydrogenation reaction has been developed that employs hydrogen generated in situ by a microorganism and a biocompatible palladium catalyst to reduce alkenes on a synthetically useful scale. This type of transformation, which directly combines tools from organic chemistry with the metabolism of a living organism for small-molecule production, represents a new strategy for chemical synthesis.
- Sirasani, Gopal,Tong, Liuchuan,Balskus, Emily P.
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supporting information
p. 7785 - 7788
(2014/08/05)
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- Improved and large-scale synthesis of 10-methyl-aplog-1, a potential lead for an anticancer drug
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10-Methyl-aplog-1 (1), a simplified analog of tumor-promoting aplysiatoxin, is a potential lead for cancer therapy that exhibits marked and selective growth inhibitory effects against several human cancer cell lines and negligible tumor-promoting activity in vivo. However, more detailed evaluations of its toxicity and anticancer activity in vivo are hampered by supply problems associated with a non-optimal synthetic method. We here addressed this issue through a more practical and reliable synthetic method that afforded several hundred milligrams of 1 with high purity (>98%) in 23 steps from commercially available m-hydroxycinnamic acid with an overall yield of 1.1%. The utilization of two key reactions, substrate-controlled epoxidation and the oxidative cleavage of alkene with a free hydroxyl group, successfully reduced the existing five synthetic steps and markedly improved the handling of large amounts of intermediates. We also demonstrated for the first time that such an analog was synthetically accessible in reliable quantities and also that this large supply could advance in vivo trials for the treatment of cancer.
- Kikumori, Masayuki,Yanagita, Ryo C.,Irie, Kazuhiro
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p. 9776 - 9782
(2015/01/09)
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- Synthesis and evaluation of dimeric 1,2,3,4-Tetrahydro-naphthalenylamine and Indan-1-ylamine derivatives with mast cell-stabilising and anti-allergic activity
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In a continuation of our studies into 4-Amino-3,4-dihydro-2H-naphthalen-1-ones as novel modulators of allergic and inflammatory phenomena, we have extended our work to include dimeric analogues. Of these derivatives, the most promising activity was seen with tertiary amine 58a, which exhibited potent mast cell-stabilising activity in vitro against a variety of stimuli and also in vivo against passive cutaneous anaphylaxis.
- Barlow, James W.,Walsh, John J.
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scheme or table
p. 25 - 37
(2010/03/04)
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- First synthesis, characterization, and evidence for the presence of hydroxycinnamic acid sulfate and glucuronide conjugates in human biological fluids as a result of coffee consumption
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A systematic investigation of the human metabolism of hydroxycinnamic acid conjugates was carried out. A set of 24 potential human metabolites of coffee polyphenols has been chemically prepared, and used as analytical standards for unequivocal identifications. These included glucuronide conjugates and sulfate esters of caffeic, ferulic, isoferulic, m-coumaric and p-coumaric acids as well as their dihydro derivatives. A particular focus has been made on caffeic and 3,4-dihydroxyphenylpropionic acid derivatives, especially the sulfate conjugates, for which regioselective preparation was particularly challenging, and have so far never been identified as human metabolites. Ten out of the 24 synthesized conjugates have been identified in human plasma and/or urine after coffee consumption. A number of these conjugates were synthesized, characterized and detected as hydroxycinnamic acid metabolites for the first time. This was the case of dihydroisoferulic acid 3′-O-glucuronide, caffeic acid 3′-sulfate, as well as the sulfate and glucuronide derivatives of 3,4-dihydroxyphenylpropionic acid.
- Fumeaux, Rene,Menozzi-Smarrito, Candice,Stalmach, Angelique,Munari, Caroline,Kraehenbuehl, Karin,Steiling, Heike,Crozier, Alan,Williamson, Gary,Barron, Denis
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supporting information; experimental part
p. 5199 - 5211
(2010/12/25)
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- Conversion of dehydrodiferulic acids by human intestinal microbiota
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Plant cell wall associated dehydrodiferulic acids (DFA) are abundant components of cereal insoluble dietary fibers ingested by humans. The ability of human intestinal microbiota to convert DFA was studied in vitro by incubating 8-O-4- and 5-5-coupled DFA with fecal suspensions. 8-O-4-DFA was completely degraded by the intestinal microbiota of the majority of donors, yielding homovanillic acid, 3-(3,4-dihydroxyphenyl)propionic acid, and 3,4-dihydroxyphenylacetic acid as the main metabolites. The transient formation of ferulic acid and presumably 3-(3-hydroxy-4-methoxyphenyl)pyruvic acid suggests an initial cleavage of the ether bond. In contrast to 8-O-4-DFA, the 5-5-coupled DFA was not cleaved into monomers by any of the fecal suspensions. Only the side chains were hydrogenated and the methoxy groups were demethylated. The cleavage of DFA by human intestinal microbiota, which depended on their coupling type, may affect both the bioavailability of DFA and the degradability of DFA-coupled fiber in the gut.
- Braune, Annett,Bunzel, Mirko,Yonekura, Reiko,Blaut, Michael
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experimental part
p. 3356 - 3362
(2010/06/16)
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- Structure-antifungal activity relationship of cinnamic acid derivatives
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A structure-antifungal activity relationship (SAR) study of 22 related cinnamic acid derivatives was carried out. Attention was focused on the antifungal activities exhibited against Aspergillus flavus, Aspergillus terreus, and Aspergillus niger. (E)-3-(4-Methoxy-3-(3-methylbut-2-enyl)phenyl)acrylic acid (16) exhibited antifungal activity against A. niger, comparable to that of miconazole and a significant antifungal effect against A. flavus and A. terreus as well. A structure-activity relationship (SAR) study of related cinnamic acid derivatives has allowed a model to be proposed for the recognition of the minimal structural requirements for the antifungal effect in this series.
- Bisogno, Fabricio,Mascoti, Laura,Sanchez, Cecilia,Garibotto, Francisco,Giannini, Fernando,Kurina-Sanz, Marcela,Enriz, Ricardo
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experimental part
p. 10635 - 10640
(2009/11/30)
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- Structural modification of phenylpropanoid-derived compounds and the effects on their participation in redox processes
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Oxidation and reduction processes are fundamental to many of the proposed mechanisms by which dietary phytochemicals are thought to exert protective effects against cardiovascular disease and some cancers. An understanding of the redox chemistry of these compounds is essential in assessing their potential to participate in these processes. Phenylpropanoid-derived compounds were selected and synthesised where required to represent many of the structural features found in this important group of compounds. Using electron paramagnetic resonance spectroscopy and computational chemistry a structure-redox activity relationship was obtained. Good correlation of computational and experimental results was observed for the mono-hydroxylated compounds. This demonstrated the value of computational chemistry in obtaining information about compounds, not readily available and the effect of electron delocalisation on parent radical stability. For compounds containing more than one hydroxyl, the relationship was found to be more complex. The importance of quinone formation in compounds containing more than one hydroxyl substituent was highlighted, as this was found to have a significant effect on stabilisation and therefore, their participation in redox processes.
- Russell, Wendy R.,Scobbie, Lorraine,Chesson, Andrew
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p. 2537 - 2546
(2007/10/03)
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- A Rapid and Efficient Microwave-Assisted Synthesis of Substituted 3-Phenylpropionic Acids from Benzaldehydes in Minutes
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A convenient, inexpensive, and efficient synthesis of 3-phenylpropionic acids (1a-1f) by reacting benzaldehyde (2a-2f) and malonic acid in acetic acid and piperidine into cinnamic acid (3a-3f) in 77 to 89% followed by its reduction with PdCl2 in the biphase of formic acid and aqueous sodium hydroxide is reported under microwave irradiation which utilizes short reaction time ranging 5 to 7 min to provide 1a-1f in moderate to high yield (69-86%) depending upon methoxy, methylenedioxy, and hydroxy groups present at the phenyl ring.
- Sharma, Anuj,Joshi, Bhupendra P.,Sinha, Arun K.
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p. 1186 - 1187
(2007/10/03)
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- The heterocyclic ring fission and dehydroxylation of catechins and related compounds by Eubacterium sp. strain SDG-2, a human intestinal bacterium
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A human intestinal bacterium, Eubacterium (E.) sp. strain SDG-2, was tested for its ability to metabolize various (3R)- and (3S)-flavan-3-ols and their 3-O-gallates. This bacterium cleaved the C-ring of (3R)- and (3S)flavan-3-ols to give 1,3-diphenylpropan-2-ol derivatives, but not their 3-O-gallates. Furthermore, E. sp. strain SDG-2 had the ability of p-dehydroxylation in the B-ring of (3R)-flavan-3-ols, such as (-)-catechin, (-)-epicatechin, (-)-gallocatechin and (-)-epigallocatechin, but not of (3S)-flavan-3-ols, such as (+)-catechin and (+)-epicatechin.
- Wang, Li-Quan,Meselhy, Meselhy Raga,Li, Yan,Nakamura, Norio,Min, Byung-Sun,Qin, Guo-Wei,Hattori, Masao
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p. 1640 - 1643
(2007/10/03)
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- Palladium-catalyzed cross coupling of organohalostannanes with aryl halides in aqueous medium
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The water-soluble hydroxo complexes formed from organotrihalostannanes in aqueous alkali readily react in the presence of palladium in the same medium with aryl halides to give cross-coupling products in high yields.
- Bumagin,Roshchin
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- Development of an Immunochemical Technique for the Analysis of Trichlorophenols Using Theoretical Models
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An immunoassay has been developed for trichlorophenol analysis on the basis of theoretical chemistry modeling studies. These data have allowed us to choose the optimum chemical structure of the immunizing hapten according to realistic similarities with the target analyte. The synthesis of this hapten and the subsequent application of an appropriate immunization protocol have lead to the production of poryclonal antibodies against the target analyte. A homologous direct competitive ELISA has been developed that can be carried out in about 1 h. It has a limit of detection of 0.2 ± 0.06 μg/L (1.01 ± 0.3 nM) and it has been proven to tolerate a wide range of ionic strengths and pH values. Thus, the assay has acceptable features in samples with ionic strength between 4 and 56 mS/cm and pH values between 5.5 and 9.5. Studies on the selectivity of this immunoassay have demonstrated a high recognition of the corresponding brominated analogues. Other phenolic compounds do not interfere significantly in the analysis of 2,4,6-trichorophenol using this immunochemical technique. The accuracy of the assay has been evaluated using certified and spiked samples.
- Galve, Roger,Camps, Francisco,Sanchez-Baeza, Francisco,Marco, M.-Pilar
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p. 2237 - 2246
(2007/10/03)
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- A synthesis of the C1-N12 tripeptide fragment of sanglifehrin A
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The synthesis of the C1-N12 tripeptide of the novel immunosuppressant sanglifehrin A is described. Evans oxazolidinone methodology was used to install the C8 stereocentre of the meta-tyrosine sub-unit.
- Baenteli, Rolf,Brun, Ivan,Hall, Philip,Metternich, Rainer
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p. 2109 - 2112
(2007/10/03)
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- Lipase-catalysed chemoselective monoacetylation of hydroxyalkylphenols and chemoselective removal of a single acetyl group from their diacetates
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It was demonstrated that Pseudomonas cepacia PS lipase adsorbed on Celite, has the ability to catalyse the chemoselective monoacetylation of various hydroxyalkylphenols or the chemoselective removal of a single acetyl group from the corresponding acetate.
- Allevi, Pietro,Ciuffreda, Pierangela,Longo, Alessandra,Anastasia, Mario
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p. 2915 - 2924
(2007/10/03)
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- Biotransformation of (-)-epicatechin 3-O-gallate by human intestinal bacteria
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The biotransformation of (-)-epicatechin 3-O-gallate (1) and related compounds was undertaken using a human fecal suspension. Of fifteen metabolites isolated, four compounds were new, namely, two epimers of 1-(3'- hydroxyphenyl)-3-(2'',4'',6''-trihydroxyphenyl)propan-2-ols (6, 19); 2'',3''- dihydroxyphenoxyl 3-(3',4'-dihydroxyphenyl)propionate (14) and 1-(3',4'- dihydroxyphenyl)-3-(2'',4'',6''-trihydroxyphenyl)propan-2-ol (18). (-)- Epicatechin (2), (-)-epigallocatechin (16) and their 3-O-gallates (1, 17) were extensively metabolized by a human fecal suspension after incubation for 24 h, whereas the gallates (1, 17) resisted any degradation by a rat fecal suspension, even after a prolonged incubation time (48 h), suggesting a difference in metabolic ability between two intestinal bacterial mixtures from different species.
- Meselhy, Meselhy R.,Nakamura, Norio,Hattori, Masao
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p. 888 - 893
(2007/10/03)
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- Arylamide inhibitors of HIV-1 integrase
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Based on data derived from a large number of HIV-1 integrase inhibitors, similar structural features can be observed, which consist of two aryl units separated by a central linker. For many inhibitors fitting this pattern, at least one aryl ring also requires orth obis-hydroxylation for significant inhibitory potency. The ability of such catechol species to undergo in situ oxidation to reactive quinones presents one potential limitation to their utility. In an effort to address this problem, a series of inhibitors were prepared which did not contain ortho bishydroxyls. None of these analogues exhibited significant inhibition. Therefore an alternate approach was taken, whose aim was to increase potency rather than eliminate catechol substructures. In this latter study, naphthyl nuclei were utilized as aryl components, since a previous report had indicated that fused bicyclic rings may afford higher affinity relative to monocyclic phenyl-based systems. In preliminary work with monomeric units, it was found that the 6,7-dihydroxy- 2-naphthoic acid (17) (IC50 = 4.7 μM) was approximately 10-fold more potent than its 5,6-dihydroxy isomer 19 (IC50 = 62.4 μM). Of particular note was the dramatic difference in potency between free acid 17 and its methyl ester 21 (IC50 > 200 μM). The nearly total loss of activity induced by esterification strongly indicates that the free carboxylic -OH is important for high potency of this compound. This contrasts with the isomeric 5,6-dihydroxy species 19, where esterification had no effect on inhibitory potency (23, IC50 = 52.7 μM). These data provide evidence that the monomeric 6,7- and 5,6-dihydroxynaphthalenes may be interacting with the enzyme in markedly different fashions. However, when these naphthyl nuclei were incorporated into dimeric structures, significant enhancements in potencies each relative to the monomeric acids were observed, with bis-6,7- dihydroxy analogue 49 and bis-5,6-dihydroxy analogue 51 both exhibiting approximately equal potencies (IC50 values of 0.81 and 0.11 μM, respectively).
- Zhao, He,Neamati, Nouri,Mazumder, Abhijit,Sunder, Sanjay,Pommier, Yves,Burke Jr., Terrence R.
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p. 1186 - 1194
(2007/10/03)
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- Nonprostanoid prostacyclin mimetics. 2. 4,5-Diphenyloxazole derivatives
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4,5-Diphenyl-2-oxazolenonanoic acid (18b) was synthesized and found to inhibit ADP-induced aggregation of human platelets with an IC50 of 2.5 μM. Acid 18b displaced [3H]iloprost from human platelet membranes in a concentration-dependent fashion, consistent with 18b inhibiting platelet function by acting as a prostacyclin mimetic. By inserting a phenoxy ring into the side-chain moiety of 18b and systematically varying the pattern of substitution and length of the tethers, more potent inhibitors of platelet aggregation were identified. A phenoxy ring inserted centrally in the side chain proved to be the optimal arrangement but significant activity was observed when the aromatic ring was bound directly to the 2 position of the heterocycle. The meta-substituted cis-(ethenylphenoxy)acetic acid 37 is the most potent platelet aggregation inhibitor synthesized as part of this study with an IC50 of 0.18 μM. Acid 37 displaces [3H]iloprost from human platelet membranes with an IC50 of 6 nM. The trans-olefinic isomer of 37 (25p) is 72-fold weaker as an inhibitor of ADP-induced platelet aggregation, but the saturated derivative 25w (BMY 42393) is intermediate in potency. Structure-activity studies using 25w as a template focused on modification of the tethers intervening between the side-chain phenyl ring and the oxazole and carboxylate termini and substitution of the phenyl ring. These studies revealed that biological activity was sensitive to both the identity of the concatenating atoms and the pattern of ring substitution. The structure- activity relationships provide insight into the topographical relationship between the diphenylated oxazole ring and the carboxylic acid terminus that comprise the nonprostanoid prostacyclin mimetic pharmacophore.
- Meanwell,Rosenfeld,Trehan,Wright,Brassard,Buchanan,Federici,Fleming,Gamberdella,Zavoico,Seiler
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p. 3483 - 3497
(2007/10/02)
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- Studies on drug metabolism by use of isotopes. XXVII: Urinary metabolites of rutin in rats and the role of intestinal microflora in the metabolism of rutin
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Analysis of urinary metabolites of orally administered rutin (I) labeled with deuterium ([2,5',6'-2H]rutin, rutin-d) was carried out by GLC-MS. In rat urine, 3-hydroxyphenylacetic acid (III), 3-methoxy-4-hydroxyphenylacetic acid (IV), 3,4-dihydroxyphenylacetic acid (V), 3,4-dihydroxytoluene (VI), and 3-(m-hydroxyphenyl)propionic acid (VIII) were identified as rutin metabolites and were differentiated from the corresponding endogeneous compounds. Unchanged I and quercetin (II) were not present in the urine. Rutin-d was injected intraperitoneally in rats, administered orally to neomycin-treated rats, and incubated in vitro with the intestinal contents of rats. The experiments suggested the involvement of intestinal microflora in the metabolism of orally administered I.
- Baba,Furuta,Fukioka,Goromaru
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p. 1155 - 1158
(2007/10/02)
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