- Total Synthesis and Functional Evaluation of Fourteen Derivatives of Lysocin E: Importance of Cationic, Hydrophobic, and Aromatic Moieties for Antibacterial Activity
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Lysocin E (1) is a structurally complex 37-membered depsipeptide comprising 12 amino-acid residues with an N-methylated amide and an ester linkage. Compound 1 binds to menaquinone (MK) in the bacterial membrane to exert its potent bactericidal activity. To decipher the biologically important functionalities within this unique antibiotic, we performed a comprehensive structure-activity relationship (SAR) study by systematically changing the side-chain structures of l-Thr-1, d-Arg-2, N-Me-d-Phe-5, d-Arg-7, l-Glu-8, and d-Trp-10. First, we achieved total synthesis of the 14 new side-chain analogues of 1 by employing a solid-phase strategy. We then evaluated the MK-dependent liposomal disruption and antimicrobial activity against Staphylococcus aureus by 1 and its analogues. Correlating data between the liposome and bacteria experiments revealed that membrane lysis was mainly responsible for the antibacterial functions. Altering the cationic guanidine moiety of d-Arg-2/7 to a neutral amide, and the C7-acyl group of l-Thr-1 to the C2 or C11 counterpart decreased the antimicrobial activities four- or eight-fold. More drastically, chemical mutation of d-Trp-10 to d-Ala-10 totally abolished the bioactivities. These important findings led us to propose the biological roles of the side-chain functionalities.
- Kaji, Takuya,Murai, Motoki,Itoh, Hiroaki,Yasukawa, Jyunichiro,Hamamoto, Hiroshi,Sekimizu, Kazuhisa,Inoue, Masayuki
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supporting information
p. 16912 - 16919
(2016/11/16)
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- Ultrasound technology and molecular sieves improve the thermodynamically controlled esterification of butyric acid mediated by immobilized lipase from Rhizomucor miehei
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In this research, the effects of ultrasound stirring and the addition of molecular sieves on esterification reactions between butyric acid and several alcohols catalyzed by immobilized lipase from Rhizomucor miehei (Lipozyme RM-IM) were studied. Among the tested alcohols, 1-propanol and isobutanol allowed the highest activities, whereas Lipozyme RM-IM showed poor activities for esterification using secondary and tertiary alcohols. Different solvents were also tested and n-hexane was selected because of its reaction effects, besides being cheaper, available at low boiling point, and ease of recovery. Using the preselected alcohol and solvent, other reaction parameters (butyric acid concentration, temperature, substrate molar rate, and biocatalyst content) were studied to optimize the reaction conditions. Optimal conditions were acid concentration, 0.7 M; substrate molar ratio, 11 alcohol-acid; temperature 45 °C; biocatalyst content, 14% (by substrate mass). Under these conditions, it was possible to obtain a yield of 86% of butyl butyrate in 2.5 h. When molecular sieves (90 mg mmol-1 butytic acid) were added to the reaction, the observed yield increased to 96%. The biocatalyst was used in 5 successive reaction cycles keeping 100% of its initial activity. The overall process productivity was improved 2-fold when compared to the traditional mechanical agitation, showing that ultrasound is a promising technology for application in biocatalysis. The Royal Society of Chemistry.
- Fallavena, Lucas P.,Antunes, Fabio H. F.,Alves, Joana S.,Paludo, Natalia,Ayub, Marco A. Z.,Fernandez-Lafuente, Roberto,Rodrigues, Rafael C.
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p. 8675 - 8681
(2014/03/21)
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- The Mechanism of the β-Acyloxyalkyl Radical Rearrangement: Kinetic and 18O-Labelling Studies
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Experiments with 18O-enriched substrates indicate that the rearrangement of 2-butanoyloxy-2,2-dimethyl radical 1 (R=Pr) by migration of the acyloxy group involves complete transposition of the ether and carbonyl oxygen atoms, whereas the similar but much faster rearrangement of the substituted cholestanyl radical 11 proceeds with only 24percent transposition.The rearrangement of 1 is considered to involve a five-membered cyclic transition state 2, while that of 11 probably proceeds via a tight anion-radical-cation pair 21.
- Beckwith, Athelstan L. J.,Duggan, Peter J.
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p. 1777 - 1783
(2007/10/02)
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- Novel Template Effects of Distannoxane Catalysts in Highly Efficient Transesterification and Esterification
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The transesterification of carboxylic esters and the esterification of carboxylic acids are effected under mild conditions under catalysis by 1,3-disubstituted tetraalkyldistannoxanes 1.Various functional groups remain unaffected and otherwise difficult to obtain esters are accessible.An ester bearing a tertiary butyl group in the carboxylic acid moiety remained unchanged in competition experiments with a less bulky ester, which undergoes transesterification quantitatively.The unique features of the reactions are attributable to the template effects of the dimeric structure of 1.The facility with which compounds 1 can be converted into alkoxystannoxanes 2 and the synergistic effect of the proximate tin atoms of 2 play key roles in permitting smooth reactions and high selectivity.Another notable feature of compounds 1 is their unusually high solubility in organic solvents, even though the compounds have a metaloxane core as a major skeletal part.The double-layered structure of 1, in which the inorganic moiety is surrounded by eight alkyl groups, permits esterification to be driven to completion simply by heating a mixture of the carboxylic acid and the alcohol.The distannoxane-catalyzed esterification is irreversible, and thus, no hydrolysis of the product esters occurs when compounds 1 are used as catalysts.
- Otera, Junzo,Dan-oh, Nobushisa,Nozaki, Hitosi
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p. 5307 - 5311
(2007/10/02)
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- CATALYSED LIQUID PHASE OXIDATION OF ACETALS BY MOLECULAR OXYGEN
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Nine different acetals have been oxidized in the presence of Co(OOCCH3)2*4H2O under isobaric conditions (0.1 - 0.2 MPa O2) while following the uptake of molecular oxygen.The reactivity of acetals was expressed by the rate constants of the autocatalytic model of oxidation.The main product of the oxidation are alcohols, esters and acids.The distribution of products and the total reactivity of acetals are controlled by the structure of both parts of acetal molecule.The dominant effects of the course of the reaction exerts the type of carbon atoms on which radicals are formed.The oxidation is accompanied by consecutive and co-oxidation reactions, by deactivation of the catalysts and by decarbonylation of intermediate products.The effect of oxygen pressure is reported and the more detailed radical mechanism of the oxidation is proposed.
- Vcelak, Jaroslav,Klimova, Miroslava,Chvalovsky, Vaclav
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p. 847 - 866
(2007/10/02)
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- Selective Dimerization of Aldehydes to Esters Catalyzed by Hydridoruthenium Complexes
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RuH2(PPh3)4 and other hydridoruthenium complexes catalyze selective conversion of aldehydes into esters in high yields.The method is applicable to most aliphatic aldehydes as well as to aromatic aldehydes.The purity of aldehydes is critical for achieving high conversions, since the presence of carboxylic acid completely inhibits the reaction and alcohol and triphenylphosphine reduce the yields of esters.RuH2(PPh3)4 is converted into Ru(CO)3(PPh3)2 through the reaction indicating the occurrence of decarbonylation of aldehyde.A mechanism involving the acyl-H cleavageof aldehyde is proposed to account for the catalysis and formation of compounds accompanying the reaction.The mechanism is compared with an alternative one which comprises of consecutive insertions of two aldehyde molecules into Ru-H bond followed by β-hydrogen abstraction from an alkoxo intermediate formed.Addition of water changes the reaction course togive carboxylato carbonyl complexes Ru(OCOR)2(CO)m(PPh3)2 (m = 1 and 2).Cross esterification studies showed the reactivity order of RCHO as R = Et > Me > n-Pr > i-Pr >> Ph.
- Ito, Takashi,Horino, Hiroshi,Koshiro, Yoshitaka,Yamamoto, Akio
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p. 504 - 512
(2007/10/02)
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