- Partial Elimination of Valine-oxygen During Penicillin Biosynthesis
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G.c.-m.s. analysis of the methyl ester of penicillin V obtained on incubating Penicillium chrysogenum mycelium with L-valine demonstrated the elimination of one of the two carboxy-oxygen atoms.
- Delderfield, James S.,Mtetwa, Eli,Thomas, Robert,Tyobeka, Themba E.
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- Biomimetic Synthesis of Penicillin
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A working chemical model for the carbon-sulphur bond formation step involved in penicillin biosynthesis is presented; thus, oxidation of a monocyclic β-lactam thiol, or its disulphide form, with dioxygen or hydrogen peroxide, catalysed by iron(II) ion, ascorbic acid, and ethylenediaminetetra-acetic acid, results in direct ring closure to penicillins as well as cephams, in a process similar to the enzymatic synthesis.
- Baldwin, Jack E.,Adlington, R. M.,Bohlmann, Rolf
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- Kinetically controlled acylation of 6-APA catalyzed by penicillin acylase from Streptomyces lavendulae: effect of reaction conditions in the enzymatic synthesis of penicillin V
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Enzymatic synthesis of penicillin V (penV) by acylation of 6-aminopenicillanic acid (6-APA) was carried out using methyl phenoxyacetate (MPOA) as activated acyl donor and soluble penicillin acylase from Streptomyces lavendulae (SlPVA) as biocatalyst. The effect of different reaction conditions on penV synthesis was investigated, such as enzyme concentration, pH, molar ratio of 6-APA to MPOA, as well as presence of DMSO as water-miscible co-solvent at different concentrations. Time-course profiles of all reactions followed the typical pattern of kinetically controlled synthesis (KCS) of β-lactam antibiotics: penV concentration reached a maximum (highest yield or Ymax) and then decreased gradually. Such maximum was higher at pH 7.0, observing that final penV concentration was abruptly reduced when basic pH values were employed in the reaction. Under the selected conditions (100 mM Tris/HCl buffer pH 7.0, 30 °C, 2.7percent (v/v) DMSO, 20 mM MPOA, 0.3 UI/ml of SlPVA), Ymax was enhanced by increasing the substrate molar ratio (6-APA to MPOA) up to 5, reaching a maximum of 94.5percent and a S/H value of 16.4 (ratio of synthetic activity to hydrolytic activity). As a consequence, the use of an excess of 6-APA as nucleophile has allowed us to obtain some of the highest Ymax and S/H values among those reported in literature for KCS of β-lactam antibiotics. Although many penicillin G acylases (PGAs) have been described in kinetically controlled acylations, SlPVA should be considered as a different enzyme in the biocatalytic tool-box for novel potential synthetic processes, mainly due to its different substrate specificity compared to PGAs.
- Arroyo, Miguel,García-Martín, Alberto,Hormigo, Daniel,López-Conejo, María Teresa,Saborido, Ana,Serrano-Aguirre, Lara,de la Mata, Isabel
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- CEPHALOSPORIN DERIVATIVES AND METHODS OF USE
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This invention provides cephalosporin derivatives for killing or inhibiting the spread of microorganisms such as non-replicating Mycobacterium tuberculosis and in the treatment of infectious disease.
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Paragraph 0042; 0043; 00118
(2014/05/24)
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- LIQUID PHARMACEUTICAL FOR ORAL DELIVERY
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A liquid pharmaceutical for oral delivery wherein at the time of use, a solid unit dosage form is added to the liquid wherein the unit dosage form is comprised of a substrate soluble in the liquid and a particulate pharmaceutically active material in a pharmaceutically effective amount. At the time of use, the unit dosage form is added to the liquid, without requiring measurement of the liquid, and the entire liquid is consumed to provide for oral delivery of the pharmaceutically effective amount of material.
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- Method of using deuterated calcium channel blockers
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A method of enhancing the efficiency and increasing the duration of action of drugs (e.g. dihydropyridines and anti-bacterials) and particularly of nifedipine and penicillins wherein one or more hydrogen atoms are deuterated and wherein the deuterated drug has unexpectedly improved properties when used in much lower concentrations than unmodified drug. A method for determining the identity and bioequivalency of a new drug is also disclosed wherein the molecular and isotope structure of a new drug is determined by isotope ratio mass spectrometry and compared with the molecular and isotope structure of a known human drug.
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Page column FIG 25; 25
(2010/02/04)
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- Solvolysis of the methoxymethyl protecting group in penicillin derivatives
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The methoxymethyl (MOM) moiety, used as protecting group for the carboxyl function of penicillin derivatives, their sulfoxides and sulfones, could be easily cleaved in aqueous methanol at room temperature. The rate of deprotection by solvolysis is not sensitive to the nature of the substituent in position 6, but depends on the state of oxidation of the thiazolidine sulfur.
- Vanwetswinkel, Sophie,Carlier, Vincent,Marchand-Brynaert, Jacqueline,Fastrez, Jacques
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p. 2761 - 2762
(2007/10/03)
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- Prodrug derivatives of carboxylic acid drugs
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Novel ester derivatives of carboxylic acid medicaments of formula (I), wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integrer from 1 to 3, and R1 and R2 are the same or different and are selected from a group consisting of an alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may be unsubstituted or substituted, or R1 and R2 together with the N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which heterocyclic group may be substituted. These compounds are highly biolabile prodrug forms of the corresponding carboxylic acid compounds and are highly susceptible to undergoing enzymatic hydrolysis in vivo whereas they are highly stable in aqueous solution. The novel derivatives are less irritating to mucosa than the parent carboxylic acids and may provide an improved bio-availability of the drugs.
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- Extremely Selective and Mild Cleavage of β-Haloalkyl Groups by Cobalt(I)phthalocyanine Anion in Semisyntheses of β-Lactam Antibiotics
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Cleavage of β-haloalkyl groups can be performed extremely selectively by cobalt(I)phthalocyanine anion under very mild conditions, qualifying it best in the chemistry of highly sensitive β-lactam antibiotics.This is demonstrated in penicillin and cephalosporin semisyntheses.
- Eckert, Heiner
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p. 1715 - 1724
(2007/10/02)
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- New Oxidatively Removable Carboxy Protecting Groups
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2,6-Dimethoxybenzyl esters are readily oxidized by 2,3-dichloro-5,6-dicyano benzoquinone (DDQ) to generate the corresponding carboxylic acids.Phenyl esters substituted with hydroxy, methoxy and dimethylamino groups are also efficiently oxidized by ceric ammonium nitrate (CAN) under pH control conditions.
- Kim, C. U.,Misco, P. F.
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p. 2027 - 2030
(2007/10/02)
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- Deacylation of amides
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De-acylation of Penicillins and Cephalosporins to obtain the corresponding 6-aminopenicillanic acid or 7-aminocephalosporanic acid by the imino halide/imino ether process using long chain bases.
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- Penicillin Biosynthesis: Direct Biosynthetic Formation of Penicillin V and Penicillin G
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The enzyme isopenicillin N synthetase is able to convert directly the dipeptides, phenoxyacetylcysteinylvaline and phenylacetylcysteinylvaline into penicillin V and G respectively; these are however very slow compared with substrates of the α-aminoadipoyl or adipoylcysteinylvaline type.
- Baldwin, Jack E.,Abraham, Edward P.,Burge, Geoffrey L.,Ting, Hong-Hoi
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p. 1808 - 1809
(2007/10/02)
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- Synthesis and Reactivity of 6α-Methoxy-2-methyl-6β-phenoxyacetamido-penem-3-carboxylates
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Representatives of the title compounds have been prepared from phenoxymethylpenicillinic acid; the β-lactam linkage of these compounds is exceptionally reactive.
- Perrone, Ettore,Stoodley, Richard J.
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p. 933 - 935
(2007/10/02)
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- β-Lactam antibiotic esterification process using methoxymethyl methane sulfonate
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Disclosed is an improved process for esterifying carboxylic acids, particularly 3-carboxylic acid groups of penicillins and 4-carboxylic acid groups of cephalosporins, to form methoxymethyl esters. Replacement according to the present process of the conventional halomethyl methyl ether esterifying agent with methoxymethyl mesylate avoids the carcinogenicity problem of the prior art reagent while still giving good yields of high quality product.
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- Protection of functional groups during reaction and their subsequent restoration
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In the process for preparing an organic compound of the formula in which X is an amino group, a hydroxyl group or a carboxyl group, and A' is the remainder of the molecule, from an organic compound of the formula in which A is the remainder of the molecule which can undergo reaction to form A', by converting A -- X into a compound of the formula in which Z is --NH--, --O-- or a direct C--C bond, and R is a radical of the formula STR1 IN WHICH Y is a direct C--C single bond, the --CH=CH-- group or an arylene group, R1 to R4 each independently is hydrogen, halogen or an alkyl, aryl, aralkyl, alkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl or cycloalkylaminocarbonyl radical, or R1 + r2 and R3 + R4 each independently completes a 5- or 6-membered carbocyclic ring, or R1 and R3 conjointly with the grouping --C--Y--C-- forms a carbocyclic ring with 5 or 6 carbon atoms, and Hal is halogen, Thereby to protect X, then converting A -- Z -- COOR into a compound of the formula and then treating the compound A' -- Z -- COOR to restore the group X, the improvement which comprises effecting the treatment of the compound A' -- Z -- COOR with an alkali metal compound of a complex of monovalent cobalt. The process is applicable particularly to aminocarboxylic acids including intermediates from various stages of the synthesis of penicillins and cephalosporins.
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