- Synthesis of a biotin-labeled quorum-sensing molecule: Towards a general method for target identification
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The synthesis of bacterial quorum-sensing regulator N- (3-oxohexanoyl)-L- homoserine lactone (OHHL) and biotin-tagged OHHL is reported. The latter will be applied to developing a general method to address the 'target identification problem' in chemical genetics. Georg Thieme Verlag Stuttgart.
- Spandl, Richard J.,Nicholson, Rebecca L.,Marsden, David M.,Hodgkinson, James T.,Su, Xianbin,Thomas, Gemma L.,Salmond, George P. C.,Welch, Martin,Spring, David R.
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Read Online
- Electrochemical synthesis of versatile ammonium oxides under metal catalyst-, exogenous-oxidant-, and exogenous-electrolyte-free conditions
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An electrochemical oxidative cross-coupling reaction between 2.5-substituted-pyrazolin-5-ones and ammonium thiocyanate has been developed, which resulted in a series of unprecedented cross-coupling products under metal catalyst-, exogenous-oxidant-, and exogenous-electrolyte-free conditions. It is worth noting that since the resulting cross-coupling products are nearly insoluble in MeCN, the pure product could be afforded without silica gel column purification. In addition, the prepared ammonium oxides are versatile building blocks for synthesizing functionalized pyrazole derivatives.
- Yuan, Yong,Li, Liang-Sen,Zhang, Lin,Wang, Feng,Jiang, Lin,Zuo, Lin,Wang, Qi,Hu, Jian-Guo,Lei, Aiwen
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supporting information
p. 2768 - 2771
(2021/03/23)
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- Metabolites of the Anaerobic Degradation of n-Hexane by Denitrifying Betaproteobacterium Strain HxN1
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The constitutions of seven metabolites formed during anaerobic degradation of n-hexane by the denitrifying betaproteobacterium strain HxN1 were elucidated by comparison of their GC and MS data with those of synthetic reference standards. The synthesis of 4-methyloctanoic acid derivatives was accomplished by the conversion of 2-methylhexanoyl chloride with Meldrum's acid. The β-oxoester was reduced with NaBH4, the hydroxy group was eliminated, and the double bond was displaced to yield the methyl esters of 4-methyl-3-oxooctanoate, 3-hydroxy-4-methyloctanoate, (E)-4-methyl-2-octenoate, and (E)- and (Z)-4-methyl-3-octenoate. The methyl esters of 2-methyl-3-oxohexanoate and 3-hydroxy-2-methylhexanoate were similarly prepared from butanoyl chloride and Meldrum's acid. However, methyl (E)-2-methyl-2-hexenoate was prepared by Horner–Wadsworth–Emmons reaction, followed by isomerization to methyl (E)-2-methyl-3-hexenoate. This investigation, with the exception of 4-methyl-3-oxooctanoate, which was not detectable in the cultures, completes the unambiguous identification of all intermediates of the anaerobic biodegradation of n-hexane to 2-methyl-3-oxohexanoyl coenzyme A (CoA), which is then thiolytically cleaved to butanoyl-CoA and propionyl-CoA; these two metabolites are further transformed according to established pathways.
- Küppers, Julian,Mitschke, Nico,Heyen, Simone,Rabus, Ralf,Wilkes, Heinz,Christoffers, Jens
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p. 373 - 380
(2019/11/19)
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- Inversion of cpADH5 Enantiopreference and Altered Chain Length Specificity for Methyl 3-Hydroxyalkanoates
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Expanding the substrate scope of enzymes opens up new routes for synthesis of valuable chemicals. Ketone-functionalized fatty acid derivatives and corresponding chiral alcohols are valuable building blocks for the synthesis of a variety of chemicals including pharmaceuticals. The alcohol dehydrogenase from Candida parapsilosis (cpADH5) catalyzes the reversible oxidations of chiral alcohols and has a broad substrate range; a challenge for cpADH5 is to convert alcohols with small substituents (methyl or ethyl) next to the oxidized alcohol moiety. Molecular docking studies revealed that W286 is located in the small binding pocket and limits the access to substrates that contain aliphatic chains longer than ethyl substituent. In the current manuscript, we report that positions L119 and W286 are key residues to boost oxidation of medium chain methyl 3-hydroxy fatty acids; interestingly the enantiopreference toward methyl 3-hydroxybutyrate was inverted. Kinetic characterization of W286A showed a 5.5 fold increase of Vmax and a 9.6 fold decrease of Km values toward methyl 3-hydroxyhexanoate (Vmax: 2.48 U mg? and Km: 4.76 mm). Simultaneous saturation at positions 119 and 286 library yielded a double mutant (L119M/W286S) with more than 30-fold improved activity toward methyl 3-hydroxyoctanoate (WT: no conversion; L119M/W286S: 30 %) and inverted enantiopreference (S-enantiomer ≥99 % activity decrease and R-enantiomer >20-fold activity improvement) toward methyl 3-hydroxybutyrate.
- Ensari, Yunus,Dhoke, Gaurao V.,Davari, Mehdi D.,Bocola, Marco,Ruff, Anna Jo?lle,Schwaneberg, Ulrich
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p. 12636 - 12645
(2017/09/18)
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- Isolation of the antibiotic pseudopyronine B and SAR evaluation of C3/C6 alkyl analogs
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Natural products are an abundant source of structurally diverse compounds with antibacterial activity that can be used to develop new and potent antibiotics. One such class of natural products is the pseudopyronines. Here we present the isolation of pseudopyronine B (2) from a Pseudomonas species found in garden soil in Western North Carolina, and SAR evaluation of C3 and C6 alkyl analogs of the natural product for antibacterial activity against Gram-positive and Gram-negative bacteria. We found a direct relationship between antibacterial activity and C3/C6 alkyl chain length. For inhibition of Gram-positive bacteria, alkyl chain lengths between 6 and 7 carbons were found to be the most active (IC50?=?0.04–3.8?μg/mL) whereas short alkyl chain analogs showed modest activity against Gram-negative bacteria (IC50?=?223–304?μg/mL). This demonstrates the potential for this class of natural products to be optimized for selective activity against either Gram-positive or Gram-negative bacteria.
- Bouthillette, Leah M.,Darcey, Catherine A.,Handy, Tess E.,Seaton, Sarah C.,Wolfe, Amanda L.
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supporting information
p. 2762 - 2765
(2017/05/29)
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- Characterization of FabG and FabI of the Streptomyces coelicolor dissociated fatty acid synthase
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Streptomyces coelicolor produces fatty acids for both primary metabolism and for biosynthesis of the secondary metabolite undecylprodiginine. The first and last reductive steps during the chain elongation cycle of fatty acid biosynthesis are catalyzed by FabG and FabI. The S. coelicolor genome sequence has one fabI gene (SCO1814) and three likely fabG genes (SCO1815, SCO1345, and SCO1846). We report the expression, purification, and characterization of the corresponding gene products. Kinetic analyses revealed that all three FabGs and FabI are capable of utilizing both straight and branched-chain β-ketoacyl-NAC and enoyl-NAC substrates, respectively. Furthermore, only SCO1345 differentiates between ACPs from both biosynthetic pathways. The data presented provide the first experimental evidence that SCO1815, SCO1346, and SCO1814 have the catalytic capability to process intermediates in both fatty acid and undecylprodiginine biosynthesis.
- Singh, Renu,Reynolds, Kevin A.
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p. 631 - 640
(2015/03/31)
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- Regioselective synthesis of substituted piperidine-2,4-diones and their derivatives via Dieckmann cyclisations
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Abstract A flexible route to piperidine-2,4-diones variously substituted at the 6-, 5,6- and 2,6-positions, both with and without 1-substitution, is described; no N-protective group is required. A related regioselective Dieckmann cyclisation is also described that uses Davies' α-methylbenzylamine auxiliary and affords 6-substituted piperidine-2,4-diones enantioselectively.
- Marson, Charles M.,Yau, Kin Cheung
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p. 7459 - 7469
(2015/08/24)
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- Site-selective aliphatic C-H bromination using N -bromoamides and visible light
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Transformations that selectively functionalize aliphatic C-H bonds hold significant promise to streamline complex molecule synthesis. Despite the potential for site-selective C-H functionalization, few intermolecular processes of preparative value exist. Herein, we report an approach to unactivated, aliphatic C-H bromination using readily available N-bromoamide reagents and visible light. These halogenations proceed in useful chemical yields, with substrate as the limiting reagent. The site selectivities of these radical-mediated C-H functionalizations are comparable (or superior) to the most selective intermolecular C-H functionalizations known. With the broad utility of alkyl bromides as synthetic intermediates, this convenient approach will find general use in chemical synthesis.
- Schmidt, Valerie A.,Quinn, Ryan K.,Brusoe, Andrew T.,Alexanian, Erik J.
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supporting information
p. 14389 - 14392
(2014/12/10)
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- Highly atom-efficient oxidation of electron-deficient internal olefins to ketones using a palladium catalyst
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A 100 % atom-efficient synthesis of ketones from electron-deficient internal olefins was achieved using O2 as a "green" oxidant (see scheme, DMA=N,N-dimethylacetamide, EWG=electron-withdrawing group). Various electron-deficient olefins were oxidized to the corresponding ketones with over 99 % selectivity and without the formation of olefin isomers or their oxidized products. Copyright
- Mitsudome, Takato,Yoshida, Syuhei,Mizugaki, Tomoo,Jitsukawa, Koichiro,Kaneda, Kiyotomi
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p. 5961 - 5964
(2013/06/27)
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- A mild titanium-catalyzed synthesis of functionalized amino coumarins as fluorescence labels
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In contrast to Bronsted and other Lewis acids ClTi(OiPr)3 is especially suited to catalyze the formation of amino-substituted coumarins from aminophenols and functionalized β-oxo esters in a Pechmann condensation. This straightforward protocol allows the synthesis of fluorescence labels and false fluorescent neurotransmitters.
- Wirtz, Lisa,Kazmaier, Uli
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supporting information; experimental part
p. 7062 - 7065
(2012/01/05)
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- Discovery of a potent nicotinic acid receptor agonist for the treatment of dyslipidemia
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Nicotinic acid has been used clinically for decades to control serum lipoproteins. Nicotinic acid lowers very low-density lipoprotein (VLDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and lipoprotein-a (LPa), and it is also effective in raising high-density lipoprotein (HDL)-cholesterol. However, nicotinic acid has several side effects in clinical use. The most notable is intense cutaneous vasodilation "flushing"+ on the upper body and face. We discovered a pyranopyrimidinedione series to be nicotinic acid receptor agonists. A potent nicotinic acid receptor agonist from this series {5-(3-cyclopropylpropyl)-2-(difluoromethyl)-3H-pyrano[2,3-d] pyrimidine-4,7-dione}with reduced flushing side effect in dogs was identified.
- Qin, Jun,Rao, Ashwin,Chen, Xiao,Zhu, Xiaohong,Liu, Zhidan,Huang, Xianhai,Degrado, Sylvia,Huang, Ying,Xiao, Dong,Aslanian, Robert,Cheewatrakoolpong, Boonlert,Zhang, Hongtao,Greenfeder, Scott,Farley, Constance,Cook, John,Kurowski, Stan,Li, Qiu,Van Heek, Margaret,Chintala, Madhu,Wang, Ganfeng,Hsieh, Yunsheng,Li, Fangbiao,Palani, Anandan
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scheme or table
p. 171 - 176
(2011/03/23)
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- CHEMICAL COMPOUNDS
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The invention is directed to to substituted indazole derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R1 - R6 and X are defined herein. The compounds of the invention are inhibitors of PDK1 and can be useful in the treatment of disorders characterized by constitutively activated ACG kinases such as cancer and more specifically leukemia and cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 122
(2010/11/04)
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- Biomimetic synthesis of a new class of bacterial signaling molecules
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The first synthesis of a newly discovered class of bacterial signaling molecules from Streptomyces coelicolor has been developed. These molecules, known as the methylenomycin furans (MMFs), trigger production of the antibiotic methylenomycin. The synthesis features a scandium triflatecatalyzed domino reaction of β-ketoesters and dihydroxyacetone yielding 2,3,4-substituted furans. The proposed reaction sequence (aldol reaction, cyclization, and dehydrative aromatization) may be reminiscent of the biosynthetic reaction in which dihydroxyacetone phosphate and a β-ketothioester are condensed by an enzyme.
- Davis, Jesse B.,Bailey, J. Daniel,Sello, Jason K.
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supporting information; experimental part
p. 2984 - 2987
(2009/12/05)
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- Structure-activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors
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Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling non-regulated necrosis. This form of cell death can be induced in an array of cell types in apoptotic deficient conditions with death receptor family ligands. A series of [1,2,3]thiadiazole benzylamides was found to be potent necroptosis inhibitors (called necrostatins). A structure-activity relationship study revealed that small cyclic alkyl groups (i.e. cyclopropyl) and 2,6-dihalobenzylamides at the 4- and 5-positions of the [1,2,3]thiadiazole, respectively, were optimal. In addition, when a small alkyl group (i.e. methyl) was present on the benzylic position all the necroptosis inhibitory activity resided with the (S)-enantiomer. Finally, replacement of the [1,2,3]thiadiazole with a variety of thiophene derivatives was tolerated, although some erosion of potency was observed.
- Teng, Xin,Keys, Heather,Jeevanandam, Arumugasamy,Porco Jr., John A.,Degterev, Alexei,Yuan, Junying,Cuny, Gregory D.
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p. 6836 - 6840
(2008/03/14)
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- Small molecule inhibitors of bacterial quorum sensing and biofilm formation
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Bacteria monitor their local population densities using small molecules (or autoinducers) in a process known as quorum sensing. Here, we report a new and efficient synthetic route to naturally occurring bacterial autoinducers [N-acyl L-homoserine lactones (AHLs)] that is readily amenable to the synthesis of analogues. This route has been applied in the first synthesis of a library of non-native AHLs. Evaluation of these compounds in bacterial reporter gene and biofilm assays has revealed a potent set of quorum sensing antagonists. These ligands will serve as valuable new tools to explore the role of quorum sensing in bacterial pathogenesis. Copyright
- Geske, Grant D.,Wezeman, Rachel J.,Siegel, Adam P.,Blackwell, Helen E.
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p. 12762 - 12763
(2007/10/03)
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- Analogues of thiolactomycin as potential anti-malarial and anti-trypanosomal agents
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A series of analogues of the naturally occurring antibiotic thiolactomycin (TLM) have been synthesised and evaluated for their ability to inhibit the growth of the malaria parasite, Plasmodium falciparum. Thiolactomycin is an inhibitor of Type II fatty acid synthase which is found in plants and most prokaryotes, but not an inhibitor of Type I fatty acid synthase in mammals. A number of the analogues showed inhibition equal to or greater than TLM. The introduction of hydrophobic alkyl groups at the C3 and C5 positions of the thiolactone ring lead to increased inhibition, the best showing a fourteenfold increase in activity over TLM. In addition, some of the analogues showed activity when assayed against the parasitic protozoa, Trypanosoma cruzi and Trypanosoma brucei.
- Jones, Simon M.,Urch, Jonathan E.,Brun, Reto,Harwood, John L.,Berry, Colin,Gilbert, Ian H.
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p. 683 - 692
(2007/10/03)
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- Method for preparing chiral diphosphines
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The invention concerns a method for preparing a compound of formula (1) wherein: A represents naphthyl or phenyl optionally substituted; and Ar1, Ar2independently represent a saturated or aromatic carbocyclic group, optionally substituted.
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- Asymmetric hydrogenation method of a ketonic compound and derivative
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The present invention relates to a process for the asymmetric hydrogenation of a ketonic compound and derivative. The invention relates to the use of optically active metal complexes as catalysts for the asymmetric hydrogenation of a ketonic compound and derivative. The process for the asymmetric hydrogenation of a ketonic compound and derivative is characterized in that the asymmetric hydrogenation of said compound is carried out in the presence of an effective amount of a metal complex comprising as ligand an optically active diphosphine corresponding to one of the following formulae: STR1
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- Process for producing 3-oxocarboxylic acid esters
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A novel process for producing 3-oxocarboxylic acid esters, which are useful as intermediates in the synthesis of ceramides to be used as a humectant, biodegradable polymers, drugs, etc., at a high purity and a high yield without requiring any troublesome procedure, is disclosed. The process comprises reacting an acetoacetic ester with a calcium compound, a barium compound or a strontium compound in the presence of an organic solvent at a temperature of 10 to 120° C., further reacting the obtained product with a carboxylic acid chloride to thereby acylate it, and then adding thereto an alcohol in an amount 1 to 5 times by mol as much as the calcium compound, barium compound or strontium compound to thereby deacetylate the same.
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- Synthesis of (S)-Mappicine and mappicine ketone via radical cascade reaction of isonitriles
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(S)-Mappicine (2) and mappicine ketone (1) have been prepared from methylacetoacetate (4) by a strategy featuring a radical cascade reaction of an isonitrile as the key step. The introduction of the hydroxy group of (S)- mappicine occurred with moderate selectivity through asymmetric hydroxylation.
- Josien, Hubert,Curran, Dennis P.
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p. 8881 - 8886
(2007/10/03)
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- The chemoselective cyclisation of unsymmetrical γ-diketones to cyclopentenones by ditected aldol reaction using a magnesium chelate
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The feasibility of synthesising disubstituted cyclopent-2-enones chemoselectively from unsymmetrical γ-diketones, using an aldol reaction directed by magnesium chelation, has been studied.Treatment of 3,3-dimethylhexane-2,5-dione 15 with aqueous sodium hydroxide (0.5 mol dm-3) gives a mixture of 3,5,5-trimethyl- 12 and 3,4,4-trimethylcyclopent-2-enone 14 in an isomer ratio 2.2:1.Insertion of an α-methoxycarbonyl grouping as a control element allows formation of a magnesium chelate 17 when treated with magnesium methoxide, and the major product is then mainly the undehydrated aldol 21.This, when treated with aqueous sodium hydroxide (0.5 mol dm-3) to dehydrate, hydrolyse and decarboxylate, gives the 3,5,5-trimethyl- and 3,4,4-trimethylcyclopent-2-enones in a nearly chemospecific ratio of 1:49.When 3-methoxycarbonyl-4,4-dimethylhexane-2,5-dione 16 is treated with aqueous sodium hydroxide (0.5 mol dm-3), omitting the magnesium methoxide treatment, the corresponding ratio of cyclopentenones was still an interesting 1:7.3.Treatment with sodium methoxide in methanol gives, by contrast γ-lactone 27.Treatment of undecane-4,7-dione 34 with aqueous sodium hydroxide (0.5 mol dm-3) at reflux gives 2,3-dipropylcyclopent-2-enone 36 and 3-butyl-2-ethylcyclopent-2-enones 35 in a ratio of almost 1:1.Treatment of 6-methoxycarbonylundecane-4,7-dione 33 with magnesium methoxide in methanol gives undehydrated aldol which when treated with aqueous sodium hydroxide gives the dipropylcyclopent-2-enone 36 and 3-butyl-2-ethylcyclopent-2-enones 35 in 9:1 ratio.Conversely, the 5-methoxycarbonyldione 32 gives a corresponding ratio of 36 to 35 of 1:9.The best ratios attained, 1:15 for 36 and 35 from 32 and 20:1 for 36 and 35 from 33, were when magnesium methoxide in refluxing benzene or toluene were employed.There is still a strong chemoselective effect when the magnesium treatment is omitted.Preliminary examination of the corresponding cyclohex-2-enone systems gave poorer chemoselectivities when either procedure was employed. 6-Methoxycarbonyldodecane-5,9-dione 52 gave 2,3-dipropyl-54 and 3-butyl-2-ethyl-cyclohex-2-enone 55 in a ratio of ca. 4:1 whilst the 5-methoxycarbonyldodecane-4,8-dione 53 gave a 1: ca. 4 ratio.
- Cadman, Michael L. F.,Crombie, Leslie,Freeman, Stephen,Mistry, Jayshree
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p. 1397 - 1408
(2007/10/02)
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- Process for the preparation of β-ketocarboxylic acid esters
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The invention relates to a process for the preparation of β-ketocarboxylic acid esters of the general formula STR1 in which R1 is an alkyl radical having 1 to 4 C atoms, R2 is an alkyl radical or alkenyl radical having 2 to 15 C atoms or a phenyl radical and R3 is hydrogen or an alkyl or alkenyl radical having 1 to 6 C atoms, characterized in that acetocarboxylic acid esters of the general formula STR2 in which R1 and R3 are as defined, are reacted with calcium hydroxide or calcium oxide in the presence of an organic solvent and in the absence of water, the calcium chelate complexes formed are acylated with carboxylic acid chloride and the products are then cleaved with aqueous ammonium salt solution to form the β-ketocarboxylic acid esters of formula (I). The β-ketocarboxylic acid esters readily accessible by the process according to the invention can be used as important intermediates in the synthesis of pharmaceutically active ingredients or plant protection agents.
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- Synthetic Microbial Chemistry, XXI. Synthesis of Differanisole A, an Inducer of Differentiation
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The synthesis of differanisole A (3,5-dichloro-2-hydroxy-4-methoxy-6-propylbenzoic acid, 1) was achieved in five steps from 2-pentanone.
- Mori, Kenji,Kamada, Atsushi,Mori, Hideto
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p. 303 - 306
(2007/10/02)
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- CYCLISATION PHOTOCHIMIQUE D'ALKYL-2 ARYL-3 CYCLOHEXENE-2 ONES
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In methanol, 2-alkyl-3-aryl-2-cyclohexenones undergo an oxidative photocyclization at 254 nm to provide polycyclic compounds with a phenanthrenic skeleton.
- Fort, Yves,Pete, Jean-Pierre
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p. 215 - 218
(2007/10/02)
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- A NEW PREPARATIVE METHOD FOR 1,3-DICARBONYL COMPOUNDS BY THE REGIOSELECTIVE OXIDATION OF α,β-UNSATURATED CARBONYL COMPOUNDS, CATALYZED BY PdCl2 USING HYDROGENPEROXIDES AS THE REOXIDANT OF Pd0
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α,β-Unsaturated esters and ketones are oxidized regioselectively to give β-keto esters and 1,3-diketones in good yields in aqueous acetic acid using Na2PdCl4 as the catalyst and t-butyl hydroperoxide or hydrogen peroxide as the reoxidant of Pd0.
- Tsuji, Jiro,Nagashima, Hideo,Hori, Kimihiko
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p. 257 - 260
(2007/10/02)
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- 1,4-Dihydropyridine carboxylic acid esters useful as coronary vessel dilators and anti-hypertensives
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Certain 1,4-dihydropyridine carboxylic acid esters or their pharmaceutically acceptable non toxic salts are useful as coronary vessel dilators and antihypertensives.
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