Zoia Mincheva

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

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Publications (18)25.54 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 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.
    Biocatalysis and Biotransformation 07/2009; 16(3):225-232. DOI:10.3109/10242429809003200 · 0.69 Impact Factor
  • Zoia Mincheva · Fabien Bonnette · Olivier Lavastre
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    ABSTRACT: Ionic liquid supports (ILS) functionalized with carboxylic, alcoholic or amino groups were synthesized, based on 1-methylimidazolium and pyridinium cations, and bromide, chloride, iodide and tetrafluoroborate anions. These reactive ionic liquids were fully characterized by NMR and HRMS. Ionic liquids based on 1-(6-aminohexyl)-3-methylimidazolium iodide have been used in the conditions of peptide chemistry such as coupling and deprotection reactions. A method for attaching (bromophenyl)silanes to the ionic liquid supports was also developed to introduce traceless linkers. An ionic liquid with attached bromobenzene was reacted with ArB(OH)<sub>2</sub> under the Suzuki cross-coupling conditions and the resulting compound was cleaved by bromodesilylation with Br<sub>2</sub>/pyridine to give the substituted products in good yields. The substrate loading of the ILS is high and can be tuned to between 2.5 and 5.0 mmol/g.
    ChemInform 09/2007; 38(37). DOI:10.1135/cccc20070417
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    ABSTRACT: The apicoplast is a recently discovered, plastid-like organelle present in most apicomplexa. The methylerythritol phosphate (MEP) pathway involved in isoprenoid biosynthesis is one of the metabolic pathways associated with the apicoplast, and is a new promising therapeutic target in Plasmodium falciparum. Here, we check the presence of isoprenoid genes in four coccidian parasites according to genome database searches. Cryptosporidium parvum and C. hominis, which have no plastid genome, lack the MEP pathway. In contrast, gene expression studies suggest that this metabolic pathway is present in several development stages of Eimeria tenella and in tachyzoites of Toxoplasma gondii. We studied the potential of fosmidomycin, an antimalarial drug blocking the MEP pathway, to inhibit E. tenella and T. gondii growth in vitro. The drug was poorly effective even at high concentrations. Thus, both fosmidomycin sensitivity and isoprenoid metabolism differs substantially between apicomplexan species.
    Experimental Parasitology 08/2007; 116(4):375-84. DOI:10.1016/j.exppara.2007.02.002 · 1.64 Impact Factor
  • Z. Mincheva · F. Bonnette · O. Lavastre
  • Fabien Bonnette · Zoia Mincheva · Olivier Lavastre
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    ABSTRACT: A new strategy to obtain pure ionic liquid support with a high loading (3 mmol/g) of primary amino groups is reported. The compatibility of the imidazolium unit was demonstrated with DIC or DCC coupling reactions of protected amino acids and with classical cleavage of BOC or Fmoc protecting groups. In addition, this is the first report of a traceless ionic liquid support based on a silicon linker with a high loading (3 mmol/g) of aryl bromide reactive groups used in a palladium-catalyzed carbon-carbon coupling reaction.
    Combinatorial Chemistry & High Throughput Screening 04/2006; 9(3):229-32. DOI:10.2174/138620706776055485 · 1.22 Impact Factor
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    ABSTRACT: Substituted 3-[2-(diethoxyphosphoryl)propyl]oxazolo[4,5-b]pyridine-2(3H)-ones were obtained by functionalization at 6-position with various substituents (aryl, vinyl, carbonyl chains) via reactions catalysed with palladium. We found that these new fosmidomycin analogues inhibited the accumulation of ajmalicine, a marker of monoterpenoid indole alkaloids production in plant cells. Some of them have greater inhibitory effect than fosmidomycin and fully inhibit alkaloid accumulation at the concentration of 100 microM.
    Phytochemistry 09/2005; 66(15):1797-803. DOI:10.1016/j.phytochem.2005.06.002 · 2.55 Impact Factor
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    ABSTRACT: Fosmidomycin, 3-(N-formyl-N-hydroxyamido) propylphosphonic acid sodium salt, is an efficient inhibitor of 1-deoxy-D-xylulose-5-phosphate (DOXP) reductoisomerase, the second enzyme of the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway notably present in Plasmodium species. We have synthesized a new series of analogues of fosmidomycin, containing a benzoxazolone, benzoxazolethione or oxazolopyridinone ring. As the MEP pathway is involved in the biosynthesis of all isoprenoids, accumulation of ajmalicine in Catharanthus roseus cells was chosen as a marker of monoterpenoid indole alkaloid (MIA) production. None of the twelve studied phosphonic esters 3 and phosphonic acids 4 affected periwinkle cell growth, but some of them (3c, 3e, 3g and 3h) showed a significant inhibition of ajmalicine accumulation: 45-85% at 125 microM. Surprisingly, this effect disappeared by conversion of 3c and 3g into the corresponding acids 4c and 4g, respectively.
    Journal of Enzyme Inhibition and Medicinal Chemistry 01/2005; 19(6):559-65. DOI:10.1080/14756360400004615 · 2.33 Impact Factor
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    ABSTRACT: 1,3 Dipolar cycloadditions of nitrile oxides generated in situ in the presence of a variety of olefins provided 4,5-dihydroisoxazoles. The whole procedure could be performed in a practical and efficient one-pot operation. The products are of excellent purity (95%) and are isolated in 60-83% yields. Some of them enhanced the accumulation of indole alkaloids in periwinkle cell cultures.
    Bioorganic & Medicinal Chemistry 01/2004; 12(1):191-7. DOI:10.1002/chin.200421116 · 2.79 Impact Factor
  • O. Lavastre · N. Pinault · Z. Mincheva
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    ABSTRACT: For Abstract see ChemInform Abstract in Full Text.
    ChemInform 02/2003; 34(6). DOI:10.1002/chin.200306223
  • Zoia Mincheva · George Georgiev · Veneta Kalcheva
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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 02/2002; 203(3):538-543. DOI:10.1002/1521-3935(20020201)203:3<538::AID-MACP538>3.0.CO;2-U · 2.62 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 06/2001; 36(6):626-32. DOI:10.1002/jms.162 · 2.38 Impact Factor
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    ABSTRACT: An abrupt change in the polyzwitterionic swelling ratio as a function of the temperature, sodium chloride concentration and chemical crosslinking density is established. These results are reasonably explained by the model presuming zwitterionic cluster formation in the segments between the chemical junction points. The zwitter-ionic clusters, produced at low chemical crosslinking density only, act as temperature- and salt concentration-dependent physical junction points. An irreversible temperature-stimulated swelling-shrinking behaviour of the polyzwitter-ionic hydrogels (swelling ratio-temperature hysteresis loop) at low chemical cross-linking density is also observed and analysed.
    Macromolecular Symposia 02/2001; 164(1):301 - 312. DOI:10.1002/1521-3900(200102)164:1<301::AID-MASY301>3.0.CO;2-P
  • Ts. Petrova · N. Manolova · I. Rashkov · Z. Mincheva · V. Kalcheva
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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(9-9):1561-1572. DOI:10.1080/10601329808007316 · 0.81 Impact Factor
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    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. DOI:10.1295/polymj.30.758 · 1.65 Impact Factor
  • Z. Mincheva · N. Stambolieva · K. Petrova · B. Galunsky
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    ABSTRACT: Penicillin amidase (EC 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. DOI:10.1007/BF00222555
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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 07/1994; 30(7):761-765. DOI:10.1016/0014-3057(94)90002-7 · 3.01 Impact Factor
  • N Stambolieva · Z Mincheva · B Galunsky · V Kalcheva
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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. DOI:10.1016/0141-0229(92)90144-D · 2.32 Impact Factor
  • Veneta Kalcheva · Zoia Mincheva
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    ABSTRACT: Two novel cephem derivative series were synthesized: 7-(d-α-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. Synthese und antimikrobielle Wirksamkeit einiger Cephemverbindungen Zwei neue Serien von Cephem-Derivaten, abgeleitet von 7-(d-α-aminophenyl-acetamido)-3-methyl-3-cephem-4-carbonsäure-Monohydrat (Cephalexin) bzw. Derivate der 7-Amino-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carbonsäure (7-AMTCA) wurden synthesiert. Die antibakterielle Aktivität der neuen Verbindungen wurde gegenüber 12 Standardstämmen und 189 klinischen Isolaten Gram-positiver und Gram-negativer Mikroorganismen im Vergleich mit bekannten Cephalosporinen der ersten Generation geprüft. Die Derivate des Cephalexins 4a-f haben ein enges Wirkungsspektrum und sind inaktiv. Die Verbindungen 5c und 5d übertreffen in ihrer Aktivität die Antibiotika Cephalexin und Cephazolin gegen klinisch isolierte Stämme von S. aureus und S. epidermidis.
    Archiv der Pharmazie 11/1991; 324(11):847-51. DOI:10.1002/chin.199222249 · 1.53 Impact Factor