Z Mincheva

Medical University of Sofia, Sofia, Oblast Sofiya-Grad, Bulgaria

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Publications (10)12.16 Total impact

  • N. Stambolieva, Z. Mincheva, B. Galunsky
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    ABSTRACT: Kinetic evidence for formation of an acylenzyme-nucleophile complex is presented for the penicillin amidase (EC 3.5.1.11) catalysed transfer of nonspecific (2-benzoxazolon-3-yl-acetyl) and specific (phenylacetyl) acyl moieties to 7-aminodeacetoxycephalosporanic acid. The specific and nonspecific acylenzymes differ in their binding constants for 7-aminodeacetoxy-cephalosporanic acid, in their values of transferase to hydrolase ratio, “specificity constants” and maximal yields in kinetically controlled cephem synthesis. The 2-benzoxazolon-3-yl-acetyl-penicillin amidase has a higher affinity for the nucleophile (KN=1.4mM) and the acylen-zyme-nucleophile complex formed is quantitatively converted into cephem, the deacylation by water being negligible. The value of transferase to hydrolase ratio is an order of magnitude higher compared to that for the specific acyl donor, while the “specificity constant” for the respective cephem synthesis is two orders of magnitude lower. The phenylacetyl-penicillin amidase has a lower affinity for 7-aminodeacetoxycephalosporanic acid (KN = 8.4 mM), the acylenzyme-nucleophile complex formed undergoing both transfer and hydrolysis. The observed differences imply that the nonspecific acyl donor binds in a different way which enhances the nucleophile specificity. This results in a higher yield in the kinetically controlled synthesis of the respective cephem.
    07/2009; 16(3):225-232.
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    ABSTRACT: (2-benzothiazolon-3-yl)acetic acid–telechelic poly(ethylene oxide)s (1 100–4 440 Da) with narrow molecular mass distributions (MMD) were analysed by matrix-assisted laser desorption-ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and size exclusion chromatography (SEC). The average molecular masses (M̄n and M̄w) determined by both methods were compared and a good agreement established. The cutting of the low molecular part of the initial poly(ethylene glycol) MMD during purification and isolation of the produced telechelic poly(ethylene oxide)s was proved. For this reason, the degree of esterification (x) of poly(ethylene glycol) (PEG) with (2-benzothiazolon-3-yl)acetic acid was calculated by MALDI-TOF MS and SEC, using additional UV data. The two series of x values derived from the M̄n-values, determined by the two methods, are very close. All of them are less than unity and the differences between the two types of x values decrease with the PEG molecular mass growth.
    Macromolecular Chemistry and Physics 01/2002; 203(3):538-543. · 2.39 Impact Factor
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    ABSTRACT: Fast atom bombardment (FAB), matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and plasma desorption (PD) mass spectra of newly synthesized polyethylene glycols (PEGs), (M(w) 600-4000 Da) chemically modified with biologically active (2-benzothiazolon-3-yl)acetyl end-groups are described (products 1-6). The spectra were also used for the determination of the molecular mass characteristics (number average (M(n)) and weight average (M(w)) molecular masses) of the initial and modified PEGs. As expected, M(n) and M(w) of the modified samples are higher than those of the non-modified samples. However, it is shown that molecular mass dispersity (determined by the comparison of the polydispersity indices (PDI = M(w)/M(n)) of both types of PEGs) essentially do not change during this modification. The FAB mass spectra, together with molecular species, show the presence of abundant [M + Na](+) ions of product 1 and [M + Na + H](+) species of 2 and 3, and [M + Na + 2H](+) of product 4. Two main series of fragment ions, derived from the cleavage of the ether bonds, are observed. The number fractions of the molecular adduct ions and fragment adduct ions, determined from the FAB and PD mass spectra of the modified PEGs, are compared. The MALDI-TOF mass spectra of compounds 1-6 show the presence of two series of polymers. The most abundant peaks are due to [M + Na](+) and [M + K](+) ions originating from the polymers, in which the two terminal hydroxyl groups of PEGs are esterified with (2-benzothiazolon-3-yl)acetic acid. The less abundant peaks are due to the monosubstituted polymers.
    Journal of Mass Spectrometry 07/2001; 36(6):626-32. · 3.21 Impact Factor
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    ABSTRACT: Chemical modification of poly(oxyethylene)s (MW from 600 Da to 3000 Da), leading to the obtaining of poly(oxyethylene)s with (2-benzoxazolon-3-yl)acetyl endgroups, is described. The corresponding diesters were synthesized in high yields-70—84% and degree of esterification-82—92% under mild conditions in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine as catalyst. The diesters were characterized by H-NMR, C-NMR and IR spectra, and SEC analysis. The relatively narrow molecular weight distribution was retained in the process of chemical modification. The complex formation between polyacrylic or polymeth-acrylic acids and (2-benzoxazolon-3-yl)acetyl derivatives of poly -(oxyethylene)s was studied in dilute aqueous solutions by potentio-metric titration and viscometry. The presence of (2-benzoxazolon-3-yl)acetyl end groups attached to the poly(oxyethylene)s chains results in a significant decrease of the critical poly(oxyethylene) chain length necessary for the formation of stable polymer-polymer complexes.
    Journal of Macromolecular Science Part A Pure and Applied Chemistry 09/1998; a35(9):1561-1572.
  • Source
    Zoia Mincheva, Veneta Kalcheva, Illya Rashkov
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    ABSTRACT: α,ω-Diaminopolyethers; Jeffamines; Degree of N-Acylation; 2-Benzoxa(thia)zolone Derivatives; Functional Polymers; Terminal Group
    Polymer Journal 09/1998; 30(9):758-760. · 1.50 Impact Factor
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    ABSTRACT: Penicillin amidase (EC 3.5.1.11) catalysed the synthesis of cephem 7-(2-benzoxazolon-3-yl-acetamido)-desacetoxycephalosporanic acid by a kinetically controlled transfer of the non-specific 2-benzoxazolon-3-yl-acetyl moiety from its polyethyleneglycol ester (m.w. 400, nine monomeric units) to the nucleophile 7-aminodesacetoxycephalosporanic acid. Penicillin amidase from E.Coli immobilised in polyacrylamide gel was used as biocatalyst. A high degree of nucleophile conversion (98 %) into the corresponding cephem at biotechnologically relevant concentrations (50 mM) was achieved.
    Biotechnology Techniques 09/1996; 10(10):727-730.
  • Z MINCHEVA, N STAMBOLIEVA, I RASHKOV
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    ABSTRACT: 2-Benzoxazolon-3-yl-acetic acid was esterified with diethylene glycol triethylene glycol and polyethylene glycols with MW in the range of 200–1000 D by means of the dicyclohexylcarbodiimide procedure in tetrahydrofuran, resulting in the corresponding monoesters in comparatively good yields (70–92%). The products were characterized by 1H-NMR, i.r. and u.v.-spectra as well as by GPC, VPO and DSC methods. The relatively narrow molecular weight distribution was preserved in the process of the chemical modification. The degree of esterification is gradually decreasing from 91% to 44% with the increase of the length of the polyether chain. The synthesized conjugates are homogeneous as judged by GPC analysis, but clear evidence for heterogeneity is obtained by the more sensitive HPLC technique. The molecular mass of the polyethylene glycols used affects the physicochemical properties thus providing 2-benzoxazolon-3-yl-acetic acid polyethylene glycol conjugates of variable properties able to meet different kind of demands. We found that the conjugate with PEG400 is extremely useful as a substrate in the penicillin amidase catalysed transfer of 2-benzoxazolon-3-yl-acetyl moiety on 7-aminodesacetoxy-cephalosporanic acid offering a new cephem in high yield (70%).
    European Polymer Journal - EUR POLYM J. 01/1994; 30(7):761-765.
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    ABSTRACT: The methyl ester of 2-benzoxazolon-3-yl-acetic acid was used as an acyl donor in the penicillin amidase-catalysed transfer reaction to 7-aminodesacetoxycephalosporanic acid. The synthesis of 7-(2-benzoxazolon-3-yl-acetamido)-desacetoxycephalosporanic acid was carried out as a kinetically controlled reaction. A characteristic feature of this system is that the benzoxazolone derivatives are very low specific substrates for penicillin amidase (the kcat/Km values for their hydrolysis were shown to be 10(5)-fold lower compared to the corresponding values for phenylacetyl derivatives). Nevertheless, penicillin amidase proved to be an effective catalyst for the synthesis of these new cephem derivatives (50% yield for 6 h). The reason is the observed unusually high value for the transferase-hydrolase activity ratio. The determined value for (k3'/k3)app = 120,000 implies that in this case of low specific acyl moiety, penicillin amidase acts more like a transferase than a hydrolase. The maximum yield has been increased up to 70% by lowering the reaction temperature and stepwise feeding of the reaction medium with the acyl component. The results obtained extend the potential of the penicillin amidase as a catalyst for the synthesis of a new group of biologically active cephem derivatives.
    Enzyme and Microbial Technology 07/1992; 14(6):496-500. · 2.97 Impact Factor
  • V Kalcheva, Z Mincheva
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    ABSTRACT: Two novel cephem derivative series were synthesized: 7-(D-alpha-aminophenyl-acetamido-)-3-methyl-3-cephem-4-carboxylic acid monohydrate (Cephalexin) derivatives and those of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)-thio methyl-3-cephem-4-carboxylic acid (7-AMTCA). The antimicrobial activity of the prepared compounds was studied and compared to that of known cephalosporin antibiotics of the first generation against 12 standard strains and 189 clinical isolates of Gram-positive and Gram-negative microorganisms. The Cephalexin derivatives 4a-f show a narrow activity spectrum and are inactive while 5c and 5d are more active than the Cephalexin and Cephazolin antibiotics against clinically isolated S. aureus and S. epidermidis strains.
    Archiv der Pharmazie 12/1991; 324(11):847-51. · 1.54 Impact Factor
  • V Kalcheva, Z Mincheva, P Andreeva
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    ABSTRACT: New cephalosporin derivatives containing a benzoxazolone ring in the side acylamino chain are synthesized using chlorides of non-substituted and halogen substituted (2-benzoxazolone-3-yl) acetic acids for the acylation of the 7-aminodesacetoxy-cephalosporanic acid and 7-amino-cephalosporanic acid amino group. Some of these new compounds exhibit a biological activity higher than that of cephalexin and cephazolin against clinical strains of Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus group A and B.
    Arzneimittel-Forschung 10/1990; 40(9):1030-4. · 0.56 Impact Factor

Publication Stats

26 Citations
12.16 Total Impact Points

Institutions

  • 1991–2009
    • Medical University of Sofia
      • Department of Chemistry
      Sofia, Oblast Sofiya-Grad, Bulgaria
  • 1996
    • Bulgarian Academy of Sciences
      • Institute of Organic Chemistry with Center for Phytochemistry
      Sofia, Oblast Sofiya-Grad, Bulgaria