Biosynthetic Studies on Antibiotics

The intricacies of the synthetic chemistry executed by living cells in the assembly of complex organic natural products can be probed in great detail by stable-isotope labeling in conjunction with sophisticated 2D and multiple-quantum NMR methods of analysis. Mechanistic details are revealed by unraveling the “cryptic” stereochemistry of biosynthetic reactions with the aid of stereospecific isotope labeling. Analysis of blocked mutants and cloning of biosynthetic genes provides new tools for the study of biosynthetic pathways and for the exploitation of the chemical capabilities of living organisms.     

Interstrain Variability of Human Vaginal Lactobacillus crispatus for Metabolism of Biogenic Amines and Antimicrobial Activity against Urogenital Pathogens

Lactobacillus crispatus is the dominant species in the vagina of many women. With the potential for strains of this species to be used as a probiotic to help prevent and treat dysbiosis, we investigated isolates from vaginal swabs with Lactobacillus-dominated and a dysbiotic microbiota. A comparative genome analysis led to the identification of metabolic pathways for synthesis and degradation of three major biogenic amines in most strains. However, targeted metabolomic analysis of the production and degradation of biogenic amines showed that certain strains have either the ability to produce or to degrade these compounds. Notably, six strains produced cadaverine, one produced putrescine, and two produced tyramine. These biogenic amines are known to raise vaginal pH, cause malodour, and make the environment more favourable to vaginal pathogens. In vitro experiments confirmed that strains isolated from women with a dysbiotic vaginal microbiota have higher antimicrobial effects against the common urogenital pathogens Escherichia coli and Enterococcus faecium. The results indicate that not all L. crispatus vaginal strains appear suitable for probiotic application and the basis for selection should not be only the overall composition of the vaginal microbiota of the host from which they came, but specific biochemical and genetic traits.     

Crystal structure of the 2:1 acetonitrile complex of 18-crown-6

Single crystal X-ray analysis of the 2:1 acetonitrile complex of 18-crown-6 is reported. Crystals of the complex are monoclinic,P2₁/n, witha=9.123(3),b=8.524(3),c=13.676(4) Å, =104.68(3)°, andD _c =1.118 g cm^–3 forZ=2. The complex lies on a center of symmetry, with the crown in theD _3d conformation. Methyl groups of the acetonitrile molecules have weak interactions with the crown oxygen atoms, and are tilted 31.7° from the host's threefold axis. Methyl hydrogen atoms are rotationally disordered about the acetonitrile axis. Supplementary Data relating to this article are deposited with the British Library as Supplementary Publication No. SUP 82057 (12 pages).     

Metal complexes of the diuretic drug furosemide

New complexes of the formulaeM(fur)₂·2H₂O (M = Mn, Cu, Zn),M(fur)₂·3H₂O (M = Co, Ni, Cd), Hg₂(fur)₃Cl₂·2H₂O, Pd(fur)Cl·H₂O and Rh(fur)₃·3H₂O, wherefurH = 4-chloro-N-(2-furfuryl)-5-sulfamoylanthranilic acid, have been prepared and characterized by conductivity measurements, X-ray powder patterns, thermal methods, effective magnetic moments as well as by IR, ligand field,¹H-NMR and ESR spectroscopic studies. The anionfur ^– shows a chelated bidentate O(carboxylato), N(imino)-coordinating behaviour.

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Metallkomplexe der diuretischen Droge Furosemid

Zusammenfassung Neue Komplexe der Verbindungen:M(fur)₂·2H₂O (M = Mn, Cu, Zn),M(fur)₂·3H₂O (M = Co, Ni, Cd), Hg₂(fur)₃Cl₂·2H₂O, Pd(fur)Cl·H₂O und Rh(fur)₃·3H₂O, wobeifurH 4-chlor-N-(2-furfuryl)-5-sulfamoylanthanilsäure ist, wurden dargestellt. Die Komplexe wurden durch Leitfähigkeitsmessungen, Röntgen-Pulver-Aufnahmen, thermogravimetrische Analysen, Messungen des effektiven magnetischen Dipolemomentes sowie durch spektroskopische Untersuchungen (IR,¹H-NMR und ESR) charakterisiert. Das Anionfur ^– zeigt das Verhalten einer Chelat-bidentat-O(carboxylato),N(imino)-Koordination.

     

The unimolecular chemistry of [1,2-propanediol]+˙: a rationale in terms of hydrogen-bridged radical cations

By combining results from a variety of mass spectrometric techniques (metastatle ion, collisional activation, collision-induced dissociative ionization, neutralization–reionization spectrometry and appearance energy measurements) and the classical method of isotopic labelling, a unified mechanism is proposed for the complex unimolecular chemistry of ionized 1,2-propanediol. The key intermediates involved are the stable hydrogen-bridged radical cations [CH₂?C(H)? H…?O…?O(H)CH₃]⁺˙, which were generated independently from [4-methoxy, 1-butanol]⁺˙ (loss of C₂H₄) and [1-methoxyglycerol]⁺˙ (loss of CH₂O), [CH₃? C?O…?H…?O(H)CH₃]⁺˙ and the related ion-dipole complex [CH₂?C(OH)CH₃/H₂O]⁺˙. The latter species serves as the precursor for the loss of CH³˙ and in this reaction the same non-ergodic behaviour is observed as in the loss of CH³˙ from the ionized enol of acetone.     

TRANSIENT INTERMEDIATES IN INTRAMOLECULARLY PHOTOSENSITIZED PYRIMIDINE DIMER SPLITTING BY INDOLE DERIVATIVES

Abstract— Intramolecularly photosensitized pyrimidine dimer splitting can serve as a model for some aspects of the monomerization of dimers in the enzyme-substrate complex composed of a photolyase and UV-damaged DNA. We studied compounds in which a pyrimidine dimer was covalently linked either to indole or to 5-methoxyindole. Laser flash photolysis studies revealed that the normally observed photoejection of electrons from the indole or the 5-methoxyindole to solvent was diminished by an order of magnitude for indoles with dimer attached (dimer-indole and dimer-methoxyindole). The fluorescence lifetime of dimer-indole in aqueous methanol was 0.85 ns, whereas that of the corresponding indole without attached dimer (tryptophol) was 9.7 ns. Similar results were obtained for the dimer-methoxyindole (0.53 ns) and 5-methoxytryptophol (4.6 ns). The quantum yield of dimer splitting for the dimer-methoxyindole (φ₂₈₇K7 = 0.08) was only slightly greater than the value found earlier for the dimer bearing the unsubstituted indole (4>_2K7= 0.04). Transient absorption spectroscopy also revealed lower yields of indole radical cations following laser flash photolysis of dimer-indole compared to the indole without attached dimer. Dimer-methoxyindole behaved similarly. These results are interpreted in terms of an enhanced rate of radiationless relaxation of the indole and methoxyindole excited singlet states in dimer-indoles. The possible quenching of the indole and methoxyindole excited states via electron abstraction by the covalently linked dimer is discussed.     

PHOTOMODIFICATION OF HUMAN ERYTHROCYTES: EXTERNAL HEAVY ATOM EFFECT, SELECTIVE PERMEABILITY AND PROPERTIES OF THE ANION PERMEATION PATHWAY

Abstract— Anion permeability was studied in normal and photomodified erythrocytes and the role of anion species in photomodification and singlet oxygen generation was evaluated. Relative permeability to halides and nitrate was assessed using lysis rates in valinomycin-treated cells to make anion permeation rate-limiting. In non-photomodified cells the normal high temperature dependence (E:, = 67 kJ/mol; 16 kcalhol), selectivity sequence (NO, > I > Br > F > Cl) and sensitivity to block by the stilbene derivative HzDIDS were confirmed. In cells photomodified by illumination in the presence of phloxine B the anion permeability was severely perturbed. The temperature dependence was strongly reduced, the permeability to ions other than fluoride increased, leading to a reversal of the F/CI selectivity, and the capacity to be blocked by HIDIDS was lost. Pretreatment with NEM and posttreatment with DTE did not affect rates of photohemolysis. The amount of photomodification varied with species of anion present in the reaction medium, being greatest for F and smallest for I. Rates of singlet oxygen generation in aqueous solution measured by the RNO bleaching method followed the same anion sequence, suggesting a strong external heavy atom effect.     

Synthesis of 2-oxo and 2-thioxo-3(2H)-benzothiazoleethanimic acid anhydride with acetic acid and related products

The reaction of the appropriate 2-benzothiazolinone with 2-chloroacetamide under basic conditions afforded the 2-oxo-3(2H)-benzothiazolineacetamides 6–9. The 2-thioxo-3(2H)-benzothiazolineacetamide ( 10 ) was prepared by the reaction of 3-(carbethoxymethyl)benzothiazoline-2-thione with ammonium hydroxide. The reaction of acetamides 6–10 with the appropriate anhydride containing a catalytic amount of the sodium salt of the acid corresponding to the anhydride afforded the titled compounds 11–18 in excellent yields. The omission of the catalyst in the same reaction furnished a mixture containing 57% of the titled compound, 37% of the nitrile and 6% of an unknown. Possible mechanism and supporting nmr, ir and mass spectral data are discussed.     

Surface morphological and impedance spectroscopic studies on the interaction of polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) with mild steel in acid solutions

The inhibition of mild steel corrosion in aerated acid mixture of 0.5 N H₂SO₄ and 0.5 N HCl solution was investigated using potentiodynamic polarization studies, linear polarization studies, electrochemical impedance spectroscopy, adsorption, and surface morphological studies. The effect of inhibitor concentration on corrosion rate, degree of surface coverage, adsorption kinetics, and surface morphology is investigated. The inhibition efficiency increased markedly with increase in additive concentration. The presence of PEG and PVP decreases the double-layer capacitance and increases the charge-transfer resistance. The inhibitor molecules first adsorb on the metal surface following a Langmuir adsorption isotherm. Both PEG and PVP offer good inhibition properties for mild steel and act as mixed-type inhibitors. Surface analysis by scanning electron microscopy (SEM) and atomic force microscopy (AFM) shows that PVP offers better protection than PEG.