- Synthesis and biological activity of methylated derivatives of the Pseudomonas metabolites HHQ, HQNO and PQS
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Selectively methylated analogues of naturally occurring 2-heptyl-4(1H)-quinolones, which are alkaloids common within the Rutaceae family and moreover are associated with quorum sensing and virulence of the human pathogen Pseudomonas aeruginosa, have been prepared. While the synthesis by direct methylation was successful for 3-unsubstituted 2-heptyl-4(1H)-quinolones, methylated derivatives of the Pseudomonas quinolone signal (PQS) were synthesized from 3-iodinated quinolones by methylation and iodine–metal exchange/oxidation. The two N- and O-methylated derivatives of the PQS showed strong quorum sensing activity comparable to that of PQS itself. Staphylococcus aureus, another pathogenic bacterium often co-occurring with P. aeruginosa especially in the lung of cystic fibrosis patients, was inhibited in planktonic growth and cellular respiration by the 4-O-methylated derivatives of HQNO and HHQ, respectively.
- Thierbach, Sven,Wienhold, Max,Fetzner, Susanne,Hennecke, Ulrich
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Read Online
- Application of the Tethered Biginelli reaction for enantioselective synthesis of batzelladine alkaloids. Absolute configuration of the tricyclic guanidine portion of batzelladine B
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Tethered Biginelli condensation of enantioenriched hexahydropyrrolopyrimidines 8 with β-ketoesters provides efficient asymmetric access to tricyclic guanidines 9 having a syn relationship of the angular C2a and C8a hydrogens. This reaction was employed to realize the first practical enantioselective access to this fragment of batzelladine alkaloids B (2) and E (5). The efficiency of this strategy is illustrated in the synthesis of the dextrorotatory enantiomer of batzelladine B methanolysis product 10 in 10 steps and 25% overall yield from 2-nonanone and methyl acetoacetate. The asymmetric synthesis of 1.0 establishes that the absolute configuration of the tricyclic portion of batzelladine B (2) is 25aR,28S,30R. The 4-methyl-7-alkyl-1,2,2a,3,4,5,6,7,8,8a-decahydro-5,6,8b- triazaacenaphthalene-3-carboxylic acid subunit, e.g., 29, of batzelladine alkaloids A (1), D (4), F (6), and G was also prepared for the first time by catalytic hydrogenation of tricyclic guanidines 26 having the 2a,8a-anti stereochemistry.
- Franklin, Alison S.,Ly, Sylvie K.,Mackin, Gilbert H.,Overman, Larry E.,Shaka
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Read Online
- IN VITRO METHOD FOR DETECTION OF INFECTIONS CAUSED BY PSEUDOMONAS AERUGINOSA
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In vitro method for detection of infections caused by pseudomonas aeruginosa. The present invention relates to compounds of general Formula (I) and to their use as haptens. Moreover, the present invention also refers to conjugates comprising the haptens of the invention and to their use for obtaining antibodies. Finally, the invention also relates to an in vitro method for the detection of infections caused by Pseudomonas aeruginosa by means of the identification and/or quantification of the main signaling molecules from the pqs quorum sensing system.
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Page/Page column 12; 14
(2021/10/11)
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- COMPOUND FOR USE AGAINST PATHOGENIC NEISSERIA AND HAEMOPHILUS SPECIES AND MORAXELLA CATARRHALIS
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The present invention relates to a compound, which can be used in the prevention and treatment of infections with pathogenic Neisseria species, in particular N. gonorrhoeae and N. meningitidis (the gonococcus and the meningococcus, respectively), and other pathogenic bacteria (e.g. Haemophilus species or Moraxella catarrhalis ), and which can be used for disinfecting a substrate from said bacteria. Moreover, the present invention relates to a corresponding pharmaceutical composition comprising said compound.
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- Quinolones modulate ghrelin receptor signaling: Potential for a novel small molecule scaffold in the treatment of cachexia
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Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and therapy tolerance, reducing physical function and increasing mortality. Current cachexia treatments are limited and new pharmacological strategies are needed. Agonists for the growth hormone secretagogue (GHS-R1a), or ghrelin receptor, prospectively regulate the central regulation of appetite and growth hormone secretion, and therefore have tremendous potential as cachexia therapeutics. Non-peptide GHS-R1a agonists are of particular interest, especially given the high gastrointestinal degradation of peptide-based structures, including that of the endogenous ligand, ghrelin, which has a half-life of only 30 min. However, few compounds have been reported in the literature as non-peptide GHS-R1a agonists. In this paper, we investigate the in vitro potential of quinolone compounds to modulate the GHS-R1a in both transfected human cells and mouse hypothalamic cells. These chemically synthesized compounds demonstrate a promising potential as GHS-R1a agonists, shown by an increased intracellular calcium influx. Further studies are now warranted to substantiate and exploit the potential of these novel quinolone-based compounds as orexigenic therapeutics in conditions of cachexia and other metabolic and eating disorders.
- Torres-Fuentes, Cristina,Pastor-Cavada, Elena,Cano, Rafael,Kandil, Dalia,Shanahan, Rachel,Juan, Rocio,Shaban, Hamdy,McGlacken, Gerard P.,Schellekens, Harri?t
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- The requirements at the C-3 position of alkylquinolones for signalling in Pseudomonas aeruginosa
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The 'perfect storm' of increasing bacterial antibiotic resistance and a decline in the discovery of new antibiotics, has made it necessary to search for new and innovative strategies to treat bacterial infections. Interruption of bacterial cell-to-cell communication signalling (Quorum Sensing), thus neutralizing virulence in pathogenic bacteria, is a growing area. 2-Alkyl-4-quinolones, HHQ and PQS, play a key role in the quorum sensing circuitry of P. aeruginosa. We report a new set of isosteres of 2-heptyl-6-nitroquinolin-4-one, with alterations at C-3, and evaluate the key structural requirements for agonistic and antagonistic activity in Pseudomonas aeruginosa.
- Shanahan, Rachel,Reen, F. Jerry,Cano, Rafael,O'Gara, Fergal,McGlacken, Gerard P.
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supporting information
p. 306 - 310
(2017/01/13)
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- An Unsaturated Quinolone N-Oxide of Pseudomonas aeruginosa Modulates Growth and Virulence of Staphylococcus aureus
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The pathogen Pseudomonas aeruginosa produces over 50 different quinolones, 16 of which belong to the class of 2-alkyl-4-quinolone N-oxides (AQNOs) with various chain lengths and degrees of saturation. We present the first synthesis of a previously proposed unsaturated compound that is confirmed to be present in culture extracts of P. aeruginosa, and its structure is shown to be trans-Δ1-2-(non-1-enyl)-4-quinolone N-oxide. This compound is the most active agent against S. aureus, including MRSA strains, by more than one order of magnitude whereas its cis isomer is inactive. At lower concentrations, the compound induces small-colony variants of S. aureus, reduces the virulence by inhibiting hemolysis, and inhibits nitrate reductase activity under anaerobic conditions. These studies suggest that this unsaturated AQNO is one of the major agents that are used by P. aeruginosa to modulate competing bacterial species.
- Szamosvári, Dávid,B?ttcher, Thomas
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supporting information
p. 7271 - 7275
(2017/06/13)
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- MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
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Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
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Paragraph 00847
(2017/08/01)
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- COMPOUNDS FOR USE AS AN ANTI-BACTERIAL OR ANTI-FUNGAL AGENT AND AS A ZINC SENSOR
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The present invention relates to a compound, which can be used as an anti-bacterial and/or an anti-fungal agent as well as a zinc sensor. Moreover, the present invention relates to a pharmaceutical composition comprising said compound and methods for treating bacterial or fungal infections in mammals.
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Paragraph 0054; 0055; 0056
(2018/01/18)
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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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- Synthetic quinolone signal analogues inhibiting the virulence factor elastase of Pseudomonas aeruginosa
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We explore the chemical space of Pseudomonas quinolone signal analogs as privileged structures and report the discovery of a thioquinolone as a potent inhibitor of the important virulence factor elastase of the human pathogen Pseudomonas aeruginosa. We provide evidence that the derivative binds to the active site zinc of elastase and additionally acts as a fluorescent zinc sensor.
- Szamosvári, Dávid,Reichle, Valentin F.,Jureschi, Monica,B?ttcher, Thomas
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supporting information
p. 13440 - 13443
(2016/11/19)
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- Preparation of the even-numbered 3-oxo fatty acid nicotinyl esters from C6:0 to C18:0
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Here, we report a systematic comparison of different methods for the transesterification of 3-oxo fatty acid alkyl esters to the corresponding nicotinyl esters. A simple method producing the target esters in high yields and purity has been developed. Nicotinyl esters are of interest for mass spectrometry analysis of fatty acids. Also, the hydrophilic head group of nicotinyl esters can be used as the basis for the preparation of liposome-building molecules.
- Sieben, Daniela,Santana, Alexander,Nowka, Paul,Weber, Sven,Funke, Kai,Hüttenhain, Stefan H.
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supporting information
p. 808 - 810
(2016/02/03)
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- Exploiting interkingdom interactions for development of small-molecule inhibitors of candida albicans biofilm formation
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A rapid decline in the development of new antimicrobial therapeutics has coincided with the emergence of new and more aggressive multidrug-resistant pathogens. Pathogens are protected from antibiotic activity by their ability to enter an aggregative biofilm state. Therefore, disrupting this process in pathogens is a key strategy for the development of next-generation antimicrobials. Here, we present a suite of compounds, based on the Pseudomonas aeruginosa 2-heptyl-4(1H)-quinolone (HHQ) core quinolone interkingdom signal structure, that exhibit noncytotoxic antibiofilm activity toward the fungal pathogen Candida albicans. In addition to providing new insights into what is a clinically important bacterium-fungus interaction, the capacity to modularize the functionality of the quinolone signals is an important advance in harnessing the therapeutic potential of signaling molecules in general. This provides a platform for the development of potent next-generation small-molecule therapeutics targeting clinically relevant fungal pathogens.
- Reen, F. Jerry,Phelan, John P.,Gallagher, Lorna,Woods, David F.,Shanahan, Rachel M.,Cano, Rafael,Muimhneacháin, Eoin ó,McGlacken, Gerard P.,O'Gara, Fergal
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supporting information
p. 5894 - 5905
(2016/11/06)
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- A structure activity-relationship study of the bacterial signal molecule HHQ reveals swarming motility inhibition in Bacillus atrophaeus
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The sharp rise in antimicrobial resistance has been matched by a decline in the identification and clinical introduction of new classes of drugs to target microbial infections. Thus new approaches are being sought to counter the pending threat of a post-antibiotic era. In that context, the use of non-growth limiting small molecules, that target virulence behaviour in pathogens, has emerged as a solution with real clinical potential. We have previously shown that two signal molecules (HHQ and PQS) from the nosocomial pathogen Pseudomonas aeruginosa have modulatory activity towards other microorganisms. This current study involves the synthesis and evaluation of analogues of HHQ towards swarming and biofilm virulence behaviour in Bacillus atrophaeus, a soil bacterium and co-inhibitor with P. aeruginosa. Compounds with altered C6-C8 positions on the anthranilate-derived ring of HHQ, display a surprising degree of biological specificity, with certain candidates displaying complete motility inhibition. In contrast, anti-biofilm activity of the parent molecule was completely lost upon alteration at any position indicating a remarkable degree of specificity and delineation of phenotype.
- Reen, F. Jerry,Shanahan, Rachel,Cano, Rafael,O'Gara, Fergal,McGlacken, Gerard P.
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supporting information
p. 5537 - 5541
(2015/05/20)
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- Chiral Surfactant-Type Catalyst: Enantioselective Reduction of Long-Chain Aliphatic Ketoesters in Water
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A series of amphiphilic ligands were designed and synthesized. The rhodium complexes with the ligands were applied to the asymmetric transfer hydrogenation of broad range of long-chained aliphatic ketoesters in neat water. Quantitative conversion and excellent enantioselectivity (up to 99% ee) was observed for α-, β-, γ-, δ- and ε-ketoesters as well as for α- and β-acyloxyketone using chiral surfactant-type catalyst 2. The CH/π interaction and the strong hydrophobic interaction of long aliphatic chains between the catalyst and the substrate in the metallomicelle core played a key role in the catalytic transition state. Synergistic effects between the metal-catalyzed site and the hydrophobic microenvironment of the core in the micelle contributed to high stereoselectivity. (Chemical Equation Presented).
- Lin, Zechao,Li, Jiahong,Huang, Qingfei,Huang, Qiuya,Wang, Qiwei,Tang, Lei,Gong, Deying,Yang, Jun,Zhu, Jin,Deng, Jingen
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p. 4419 - 4429
(2015/05/13)
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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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- Synthesis of β-ketoesters from renewable resources and Meldrum's acid
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β-Ketoesters are valuable building blocks for the synthesis of compounds with different biological activities. In this study, a series of fatty β-ketoesters were obtained from fatty acids and Meldrum's acid using N,N-dicyclohexylcarbodiimide and dimethylaminopyridine. In addition, we demonstrate for the first time the synthesis of new fatty β-ketoesters from oleic (cis-C18:1), elaidic (trans-C18:1), ricinoleic (cis-C18:1, 12-OH), linoleic (cis,cis-C18:2), and linolenic (cis,cis,cis-C18:3) acids in good yields.
- Brinkerhoff, Rafael C.,Tarazona, Hernan F.,De Oliveira, Patrick M.,Flores, Darlene C.,Montes D'Oca, Caroline Da R.,Russowsky, Dennis,Montes D'Oca, Marcelo G.
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p. 49556 - 49559
(2014/12/10)
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- Rapid total synthesis of cyclic lipodepsipeptides as a premise to investigate their self-assembly and biological activity
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A rapid and efficient total synthesis is reported for the cyclic lipodepsipeptide pseudodesmin A. This member of the Pseudomonas viscosin group is active against Gram-positive bacteria and features self-assembling properties. A conserved serine residue within the lactone macrocycle is exploited for initial immobilization on 2-chlorotrityl chloride resin through ether formation with the side-chain alcohol. Subsequent elongation proceeds through Fmoc solid-phase peptide synthesis, including automated incorporation of the enantioselectively synthesized (R)-3-hydroxydecanoic acid lipid tail. Following esterification to generate the incipient lactone bond, the macrocycle is formed by on-resin head-to-tail macrolactamization and cleaved from the resin to give the desired compound in good purity. The short and efficient synthesis route allows rapid generation of analogues by facile variation of both the peptide and lipid moieties with good control of epimerization while maximizing automation. Synthesis of the pseudodesmin A enantiomer yields identical self-assembly and biological activity to that observed for the natural compound, showing that activity is not mediated by chiral interactions. A D-Asn8 analogue developed en route retains self-assembly, but loses activity. The synthesis strategy should be generally applicable for the rapid generation of analogues from various cyclic lipodepsipeptide groups, allowing an investigation of their self-assembling properties and structure-activity relationships. Accessing cyclic peptides: An efficient, rapid, high-yielding, and versatile total synthesis of the self-assembling Pseudomonas cyclic lipodepsipeptide pseudodesmin A is presented (see figure). The approach involves solid-phase peptide synthesis with serine side-chain immobilization. The route allows rapid analogue production, unlocking structure-activity relationship studies. The self-assembly and biological activity properties of two analogues are reported, including the enantiomer.
- De Vleeschouwer, Matthias,Sinnaeve, Davy,Van Den Begin, Jos,Coenye, Tom,Martins, Jose C.,Madder, Annemieke
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supporting information
p. 7766 - 7775
(2014/07/07)
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- Synthesis of tritium labelled and photoactivatable N-acyl-L-homoserine lactones: Inter-kingdom signalling molecules
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N-Acyl-L-homoserine lactones (AHLs) are signal molecules that are synthesized in nature by Gram-negative bacteria. They allow communication between bacteria (quorum sensing) and between microorganisms and their eukaryotic host cells (inter-kingdom signalling). However, very little is known about the mechanisms of the latter system. Therefore, tritium labelled photoactivatable AHLs were synthesized to identify specific receptors in immune cells (e.g., human polymorphonuclear neutrophils, PMN) that bind to AHL. A photoaffinity label - a diazirine group - was chosen as the smallest possible photoactivatable group that can be activated by light irradiation. The resulting highly active carbene will bind covalently to the closest chemical structure in the pocket of the receptor. The diazirine label was introduced into the AHL molecule according to a literature method. To isolate the labelled receptor from the cellular protein moiety, the AHL was additionally labelled with tritium. During the development of an effective isotopic labelling method, a simple route to hydrogen isotope incorporation into the AHLs was proposed and explored in detail. According to the new protocol, the photoactivatable diazirine-AHL was labelled with deuterium and tritium by a postsynthetic catalytic exchange of the hydrogen with its isotopes, using deuterium or tritium labelled water along with catalytic amounts of metal salts under mild basic conditions. The N-(3-oxo-5-diazirinedodecanoyl-[2-3H2])-L-homoserine lactone was successfully synthesized in five steps. Due to a photoactivatable diazirine group and easily tracked radioactive label, the product could be applied in research on the mechanism of inter-kingdom signalling. Importantly, incorporation of the tritium label takes place in the last step of the synthesis. Copyright
- Jakubczyk, Dorota,Brenner-Weiss, Gerald,Braese, Stefan
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p. 592 - 597
(2014/02/14)
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- Synthesis of Tritium Labelled and Photoactivatable N-Acyl- L -homoserine Lactones: Inter-Kingdom Signalling Molecules
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N-Acyl-L-homoserine lactones (AHLs) are signal molecules that are synthesized in nature by Gram-negative bacteria. They allow communication between bacteria (quorum sensing) and between microorganisms and their eukaryotic host cells (inter-kingdom signalling). However, very little is known about the mechanisms of the latter system. Therefore, tritium labelled photoactivatable AHLs were synthesized to identify specific receptors in immune cells (e.g., human polymorphonuclear neutrophils, PMN) that bind to AHL. A photoaffinity label - a diazirine group - was chosen as the smallest possible photoactivatable group that can be activated by light irradiation. The resulting highly active carbene will bind covalently to the closest chemical structure in the pocket of the receptor. The diazirine label was introduced into the AHL molecule according to a literature method. To isolate the labelled receptor from the cellular protein moiety, the AHL was additionally labelled with tritium. During the development of an effective isotopic labelling method, a simple route to hydrogen isotope incorporation into the AHLs was proposed and explored in detail. According to the new protocol, the photoactivatable diazirine-AHL was labelled with deuterium and tritium by a postsynthetic catalytic exchange of the hydrogen with its isotopes, using deuterium or tritium labelled water along with catalytic amounts of metal salts under mild basic conditions.
- Jakubczyk, Dorota,Brenner-Weiss, Gerald,Br?se, Stefan
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p. 592 - 597
(2015/10/05)
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- The stereochemical course of intramolecular michael reactions
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We present a general model for understanding the stereochemical course of intramolecular Michael reactions. We show that the addition of β- ketoester enolates to α,β-unsaturated esters and imides bearing adjacent stereocenters (X, Y = H, Me, OR) leads to high levels of asymmetric induction. Reinforcing and nonreinforcing stereochemical relationships are evaluated from the syn and anti reactant diastereomers. On the basis of synthetic, spectroscopic, and computational studies, we propose that the outcomes of these reactions can be rationalized by a dipole-minimized chair transition-state model.
- Kwan, Eugene E.,Scheerer, Onathan R.,Evans, David A.
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p. 175 - 203
(2013/04/10)
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- Structure-function analysis of the C-3 position in analogues of microbial behavioural modulators HHQ and PQS
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2-Heptyl-3-hydroxy-4-quinolone (PQS) and its precursor 2-heptyl-4-quinolone (HHQ) are key signalling molecules of the important nosocomial pathogen Pseudomonas aeruginosa. We have recently reported an interkingdom dimension to these molecules, influencing key virulence traits in a broad spectrum of microbial species and in the human pathogenic yeast Candida albicans. For the first time, targeted chemical derivatisation of the C-3 position was undertaken to investigate the structural and molecular properties underpinning the biological activity of these compounds in P. aeruginosa, and using Bacillus subtilis as a suitable model system for investigating modulation of interspecies behaviour.
- Reen, F. Jerry,Clarke, Sarah L.,Legendre, Claire,McSweeney, Christina M.,Eccles, Kevin S.,Lawrence, Simon E.,O'Gara, Fergal,McGlacken, Gerard P.
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supporting information
p. 8903 - 8910
(2013/01/15)
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- Syntheses and studies of amamistatin B analogs reveals that anticancer activity is relatively independent of stereochemistry, ester or amide linkage and select replacement of one of the metal chelating groups
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A series of analogs of the amamistatin natural products was designed and synthesized to facilitate additional anticancer structure-activity relationships. The results indicate that the anticancer activity is relatively independent of stereochemistry, ester or amide linkage and replacement of the oxazoline/oxazole based iron-binding group with a catechol.
- Wu, Chunrui,Miller, Patricia A.,Miller, Marvin J.
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scheme or table
p. 2611 - 2615
(2011/06/20)
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- Robust routes for the synthesis of N-acylated-l-homoserine lactone (AHL) quorum sensing molecules with high levels of enantiomeric purity
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The ready availability of native quorum sensing molecules and related structural analogues is of significant biological interest in the development of methods to manipulate bacterial quorum sensing systems in a useful fashion. In this Letter we report robust routes for the synthesis of a range of N-acylated-l-homoserine lactone (AHL) quorum sensing molecules. Crucially, we have analysed the enantiopurity of the final AHLs and in all cases, excellent levels were observed.
- Hodgkinson, James T.,Galloway, Warren R.J.D.,Casoli, Mariangela,Keane, Harriet,Su, Xianbin,Salmond, George P.C.,Welch, Martin,Spring, David R.
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supporting information; experimental part
p. 3291 - 3294
(2011/06/28)
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- Synthesis of 3-halo-analogues of HHQ, subsequent cross-coupling and first crystal structure of Pseudomonas quinolone signal (PQS)
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2-Aryl- and 2-alkyl-quinolin-4-ones and their N-substituted derivatives have several important biological functions such as the Pseudomonas quinolone signal (PQS) molecule participation in quorum sensing. Herein, we report the synthesis of its biological precursor, 2-heptyl-4-hydroxy-quinoline (HHQ) and possible isosteres of PQS; the C-3 Cl, Br and I analogues. N-Methylation of the iodide was also feasible and the usefulness of this compound showcased in Pd-catalysed cross-coupling reactions, thus allowing access to a diverse set of biologically important molecules. The first crystal structure of PQS is also included.
- McGlacken, Gerard P.,McSweeney, Christina M.,O'Brien, Timothy,Lawrence, Simon E.,Elcoate, Curtis J.,Reen, F. Jerry,O'Gara, Fergal
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scheme or table
p. 5919 - 5921
(2010/11/18)
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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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- Lanthanide triflate-promoted palladium-catalyzed cyclization of alkenyl β-keto esters and amides
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(Matrix presented) Lanthanide triflates were found to promote the palladium-catalyzed cyclization of alkenyl β-keto esters and amides. In the presence of catalytic amounts of PdCl2(MeCN)2 and Ln(OTf)3, various alkenyl β-keto esters and amides underwent regioselective cyclization reactions to give six-, seven-, or eight-membered-ring carbocycles in moderate to excellent yields.
- Yang, Dan,Li, Jin-Heng,Gao, Qiang,Yan, Yi-Long
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p. 2869 - 2871
(2007/10/03)
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- A new approach to the synthesis of 3,6- and 5,6-dialkyl derivatives of 4-hydroxy-2-pyrone. Synthesis of rac-germicidin
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A new approach to the synthesis of 3,6- and 5,6-dialkyl-4-hydroxy-2- pyrones has been developed. The method includes the formation of acylated Meldrum's acids (5-(2-alkyl-3-oxoacyl)-2,2-dimethyl-1,3-dioxane-4,6-diones) followed by their thermal transformation. Introduction of 3-alkyl substituents was accomplished by acylation of 4-hydroxy-2-pyrones and ionic hydrogenation of the 3-acyl derivatives obtained. The effectiveness of this new approach has been demonstrated in the synthesis of rac-germicidin, an autoregulative germination inhibitor of Streptomyces viridochromogenes NRRL B-1551.
- Lokot, Igor P.,Pashkovsky, Felix S.,Lakhvich, Fedor A.
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p. 4783 - 4792
(2007/10/03)
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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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- Process for preparing 2-amino-1,3-alkanediol or derivative thereof, process for preparing optically active dihydrosphingosine derivative, and intermediates for optically active dihydrosphingosine derivative
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A process for preparing an optically active dihydrosphingosine derivative is disclosed, comprising reducing a (2R,3R)-2-amino-3-hydroxyalkanoic acid derivative represented by formula (III): STR1 wherein R3 represents a straight-chain alkyl group having 7 to 21 carbon atoms; and R4 represents an amino group protecting group, (e.g., (2R,3R)-2-benzylamino-3-hydroxyoctadecanoic acid) with sodium tetrahydroborate in the presence of an acid. The process makes it feasible to produce an optically active dihydrosphingosine at high optical purity and through a simple process that is safe and easy to industrialize.
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- Asymmetric syntheses of panclicins A-E via [2+2] cycloaddition of alkyl(trimethylsilyl)ketenes to a β-silyloxyaldehyde
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Panclicins A-E, pancreatic lipase inhibitors from Streptomyces, were synthesised in a modular fashion starting with three alkyl(trimethylsilyl)ketenes, two amino acids and a single aldehyde component, (3R)-3-(tert-butyldimethylsilyloxy)decanal 11. The lone stereocentre in 11 which governs the stereochemistry in subsequent steps was generated by Noyori asymmetric hydrogenation. The key step, a Lewis acid catalysed [2+2] cycloaddition of alkyl(trimethylsilyl)ketenes 13a-c to 11, gave three 3-trimethylsilyloxetan-2-ones with good 1,3-asymmetric induction. After C- and O-desilylation the amino acid side chains were introduced using a Mitsunobu inversion.
- Kocienski, Philip J.,Pelotier, Beatrice,Pons, Jean-Marc,Prideaux, Heather
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p. 1373 - 1382
(2007/10/03)
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- Process for preparing 2-amino-1, 3-alkanediol or a derivative thereof, process for preparing optically active dihydrosphingosine derivatives and intermediates used in that process
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A process for preparing an optically active dihydrosphingosine derivative, comprising reducing a (2R,3R)-2-amino-3-hydroxyalkanoic acid derivative represented by formula (III): wherein R3represents a straight-chain alkyl group having 7 to 21 carbon atoms; and R4represents an amino group protecting group,(e.g., (2R,3R)-2-benzylamino-3-hydroxyoctadecanoic acid) with sodium tetrahydroborate in the presence of an acid. The process of the invention makes it feasible to produce an optically active dihydrosphingosine at high optical purity and provides a simple process that is safe and easy to industrialize.
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- Seven new didemnins from the marine tunicate Trididemnum solidum
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Seven new didemnins-didemnins M (1), N (2), X (3) and Y (4), nordidemnin N (5), epididemnin A1 (6), and acyclodidemnin A (7)-were isolated from an extract of the Caribbean tunicate Trididemnum solidum. The structures of these compounds were assigned, based on FABMS, high-field NMR data, and chemical degradation studies. Biological activities of these peptides are also described.
- Sakai, Ryuichi,Stroh, Justin G.,Sullins, David W.,Rinehart, Kenneth L.
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p. 3734 - 3748
(2007/10/02)
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- Synthesis of (-)-Syringolides 1 and 2
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The enatioselective synthesis of (-)-syringolides 1 and 2 which were isolated as specific elicitors produced by Pseudomonas syringae pv. tomato was accomplished in 11 steps from diethyl D-tartrate.The specific rotations of synthetic samples were in good accord with those of the natural syringolides, and synthetic syringolide 2 showed almost the same biological activity as that of natural syringolide 2.
- Kuwahara, Shigefumi,Moriguchi, Masahiko,Miyagawa, Kazuhiro,Konno, Masako,Kodama, Osamu
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p. 8809 - 8814
(2007/10/02)
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- Synthesis and absolute configuration of syringolide 2, an elicitor from Pseudomonas syringae pv. tomato
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The enantioselective synthesis of syringolide 2, one of the two elicitors produced by Pseudomonas syringae pv. tomato, was accomplished in 11 steps from diethyl D-tartrate.
- Kuwahara, Shigefumi,Moriguchi, Masahiko,Miyagawa, Kazuhiro,Konno, Masako,Kodama, Osamu
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p. 3201 - 3202
(2007/10/02)
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- A Novel, Two-step, Mild and Simple Synthesis of β-, γ-, and δ-Oxo Esters from ω-Nitro Esters.
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A convenient, mild, and simple synthesis of β-, γ-, and δ-oxo esters was achieved from ω-nitro esters.A solvent-free nitroaldol reaction of the ω-nitro esters 2 with the aldehydes 1 on alumina, followed by in situ dehydration, with addition of dichloromethane and warming gave the conjugated nitroalkenes 3, which can be converted into the carbonyl derivatives 4 by sodium hypophosphite.
- Ballini, Roberto,Bosica, Giovanna
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p. 2901 - 2912
(2007/10/02)
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- BIOMIMETIC SYNTHESIS OF LONG-CHAIN ALIPHATIC β-DIKETONES
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Long-chain aliphatic β-diketones found in epicuticular waxes are synthesized according to a "biological Claisen reaction scheme" producing precursor diacyl acetates.
- Bianchi, Giorgio,Grugni, Mario
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p. 633 - 636
(2007/10/02)
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- Meerwein Saponification of Alkyl 3-Oxoalkanoates in the Gas Chromatograph
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Alkyl 3-oxoalkanoates decompose by unevitable traces of water in the gas chromatograph to yield the corresponding methyl ketones and alcohols (Meerwein saponification).Decomposition occurs in the hot injector (T= 270 deg C) of the gas chromatograph and also on glass capillary columns (T> 160 deg C).Decomposition in routine work can be avoided by preparing the corresponding 3-trimethylsilyl enol ethers.
- Thoma, Heinz,Spiteller, Gerhard
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p. 1237 - 1248
(2007/10/02)
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- The Preparation of Optically Pure 3-Hydroxyalkanoic Acid. The Enantioface-differentiating Hydrogenation of the C=O Double Bond with Modified Raney Nickel. XXXVII
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The enantioface-differentiating hydrogenation of methyl 3-oxoalkanoate (CH3(CH2)nCOCH2COOCH3, n=0, 6, 8, 10, 12) over the (R,R)-tartaric acid-NaBr-modified Raney nickel catalyst ((R,R)-TA-NaBr-MRNi) gave methyl (R)-3-hydroxyalkanoate (CH3(CH2)nCH(OH)CH2COOCH3, n=0, 6, 8, 10, 12) in an average optical yield of 85percent.After the methyl ester had been converted to dicyclohexylammonium salt of 3-hydroxyalkanoic acid, the salt was recrystallized three times from acetonitrile and then treated with acid to give optically pure (R)-3-hydroxyalkanoic acid (CH3(CH2)nCH(OH)CH2COOH, n=0, 6, 8, 10, 12) in a reasonable yield.From the hydrogenation product with (S,S)-TA-NaBr-MRNi, optically pure (S)-3-hydroxyalkanoic acid was obtained by the same process as above.
- Nakahata, Masaaki,Imaida, Motomasa,Ozaki, Hiroshi,Harada, Tadao,Tai, Akira
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p. 2186 - 2189
(2007/10/02)
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