Guillermo R. Labadie

Tautomerism of representative aromatic α-hydroxy carbaldehyde anils as studied by spectroscopic methods and AM1 calculations. Synthesis of 10-hydroxyphenanthrene-9-carbaldehyde

The synthesis of 10-hydroxyphenanthrene-9-carbaldehyde and its anil are described. The structure of the latter compound has been thoroughly studied by 1H and 13C NMR, UV-visible absorption, fluorescence and IR spectroscopies. All the experimental results support the existence of this anil mainly in the keto-enamine tautomeric form. A comparison is presented with previously studied anils derived from salicylaldehyde and 2-hydroxynaphthalene-1-carbaldehyde. Semiempirical calculations (AM1) concerning the relative stability of tautomers as well as the optimized molecular geometries are in good agreement with the experimental findings

Interaction of divalent metal ions withd-gluconic acid in the solid phase and aqueous solution

Abstract The interaction of d -gluconic acid with MnII, CoII, NiII, CuII, CdII, HgII and PbII has been investigated. Compounds of the type Mn( d -gluconate)2·3H2O, Co( d -gluconate)2·3H2O, Ni( d -gluconate)2·3H2O, Cu( d -gluconate)2·3H2O, Cd( d -gluconate)2, Hg( d -gluconate)OH and Pb( d -gluconate)2 have been isolated. These metal-sugar salts were characterized by elemental, thermogravimetric analyses and FT-IR, UV-vis absorption, EPR and13C NMR spectroscopies. In addition, a quantitative study of the equilibria involved in the interaction of this sugar and the above mentioned metal ions in an aqueous medium was carried out by means of potentiometric measurements of the hydrogen ion concentrations at 20°C andμ = 0.100M (NaNO3). On the basis of spectroscopic studies, possible structures of these complex species were discussed.

Interaction of zinc(II) ion withd-aldonic acids in the crystalline solid and aqueous solution

Abstract The interaction of zinc(II) ion with d -glucoheptonic acid, d -gluconic acid, d -gulonic acid, d -galactonic acid and d -ribonic acid has been investigated and compounds of the type Zn( d -glucoheptonate)2·3H2O, Zn( d -gluconate)2·3H2O, Zn( d -gulonate)2·3H2O, Zn( d -galactonate)2·3H2O and Zn( d -ribonate)2·H2O, have been isolated. These metal-sugar salts were characterized by elemental analysis, FT IR spectroscopy, thermogravimetric analysis and13C-NMR. Spectroscopic measurements showed similar patterns between these complexes and the structurally identified Mn( d -gluconate)2·2H2O. The zinc(II) ion is binding to two ligand molecules through the car☐ylate and OH groups of each sugar, as well as to water molecules. The potentiometric measurements in aqueous solutions for the systems formed by the sugar acids investigated and the zinc(II) ion at different metal-ligand ratios showed the 1:1 complexes formation. On the basis of the13C NMR, the participation of C-1 and C-2 in this complex formation was verfiied. Due to the hydroxide precipitation, quantitative evaluation of the stability constants was not performed.

Semisynthetic Studies on the Manzamine Alkaloids

Chemical transformation studies were conducted on (-)-8-hydroxymanzamine A ( 1), (-)-manzamine F ( 2), manzamine A ( 3), and (+)-8-hydroxymanzamine A ( 4), isolated from Indo-Pacific Acanthostrongylophora sponges. Thirteen new semisynthetic manzamine derivatives, including four Delta (34,35) manzamines ( 5, 6, 8, and 9) and the unprecedented manzamine derivative 17, are reported. The potent in vitro activities of the obtained semisynthetic manzamines against activated brain microglia and the AIDS opportunistic infection pathogen Mycobacterium tuberculosis are presented.

Click chemistry decoration of amino sterols as promising strategy to developed new leishmanicidal drugs

A series of 1,2,3-triazolylsterols was prepared from pregnenolone through reductive amination and copper(I)-catalyzed azide-alkyne cycloaddition (click chemistry). The newly generated stereocenter of the key propargylamino intermediate provided a mixture of diastereomers which were separated chromatographically, and the configuration of the R isomer was determined by X-ray crystallography. Ten triazolyl sterols were prepared, and the products and intermediates were screened in vitro against different parasites, with some compounds presenting IC50 values in the low micromolar range against Leishmania donovani.

Regioselective covalent immobilization of catalytically active glutathione s-transferase on glass slides

The high selectivity of protein farnesyltransferase was used to regioselectively append farnesyl analogues bearing bioorthogonal alkyne and azide functional groups to recombinant Schistosoma japonicum glutathione S-transferase (GSTase) and the active modified protein was covalently attached to glass surfaces. The cysteine residue in a C-terminal CVIA sequence appended to N-terminally His(6)-tagged glutathione S-transferase (His(6)-GSTase-CVIA) was post-translationally modified by incubation of purified protein or cell-free homogenates from E. coli M15/pQE-His(6)-GSTase-CVIA with yeast protein farnesyltransferase (PFTase) and analogues of farnesyl diphosphate (FPP) containing ω-azide and alkyne moieties. The modified proteins were added to wells on silicone-matted glass slides whose surfaces were modified with PEG units containing complementary ω-alkyne and azide moieties and covalently attached to the surface by a Cu(I)-catalyzed Huisgen [3 + 2] cycloaddition. The wells were washed and assayed for GSTase activity by monitoring the increase in A(340) upon addition of 1-chloro-2,4-dinitrobenzene (CDNB) and reduced glutathione (GT). GSTase activity was substantially higher in the wells spotted with alkyne (His(6)-GSTase-CVIA-PE) or azide (His(6)-GSTase-CVIA-AZ) modified glutathione-S-transferase than in control wells spotted with farnesyl-modified enzyme (His(6)-GSTase-CVIA-F).

Protective effect of glutathione (GSH) over glutathione monoethyl-ester (GSH-E) on cold preservation of isolated rat liver cells

Hepatocyte suspensions provide a rapid method to determine how hypothermic storage affects liver cell metabolism and viability. We investigated whether reduced Glutathione (GSH) inclusion into a modified University of Wisconsin (UW) solution, has a protective effect over Glutathione derivatives, such as Glutathione-monoethylester (GSH-E), when suspensions of hepatocytes are cold stored for several days. Isolated rat liver cells were cold preserved 96 h in UW, UW plus 3 mM GSH and UW plus 3 mM GSH-E. During the cold storage, not significant changes in cell viability were observed, but the total Glutathione content was higher in systems with extracellular GSH over those with GSH-E or without. After cold storage, the liver cells were gently resuspended in Krebs-Henseleit-1% Albumin and used for 120 min of normothermic (37 degrees C) incubation. We evaluate the functional response of the cells measuring the exclusion of Trypan Blue (TBE). This response was clearly different in preserved cells in presence of GSH. These results indicate a protective role of extracellular Glutathione, due to an accumulation of it, rather than the derivative, for hepatic cell during the cold storage in UW solutions. And also, it is possible to extend experiments with hepatocytes from a single cell isolation over 4 or more consecutive days.

Studies Toward the Total Synthesis of Saudine : Simple and Stereoselective Synthesis of a Model Caged Ketal Backbone

Abstract The synthesis of the tetracyclic mainframe containing the caged ketalic backbone of saudin was accomplished through a straight forward sequence starting from α-tetralone. The sequence included the stereoselective preparation of a key epoxy alcohol that allowed, by means of an intramolecular radical cyclisation, the total control of the relative stereochemistry of four consecutive chiral centers.

TDP-L-Megosamine Biosynthesis Pathway Elucidation and Megalomicin A Production in Escherichia coli

ABSTRACT In vivo reconstitution of the TDP-l-megosamine pathway from the megalomicin gene cluster of Micromonospora megalomicea was accomplished by the heterologous expression of its biosynthetic genes in Escherichia coli. Mass spectrometric analysis of the TDP-sugar intermediates produced from operons containing different sets of genes showed that the production of TDP-l-megosamine from TDP-4-keto-6-deoxy-d-glucose requires only five biosynthetic steps, catalyzed by MegBVI, MegDII, MegDIII, MegDIV, and MegDV. Bioconversion studies demonstrated that the sugar transferase MegDI, along with the helper protein MegDVI, catalyzes the transfer of l-megosamine to either erythromycin C or erythromycin D, suggesting two possible routes for the production of megalomicin A. Analysis in vivo of the hydroxylation step by MegK indicated that erythromycin C is the intermediate of megalomicin A biosynthesis.

Chemobiosynthesis of new antimalarial macrolides.

ABSTRACT We have synthesized new derivatives of the macrolide antibiotics erythromycin and azithromycin. Novel deoxysugar moieties were attached to these standard antibiotics by biotransformation using a heterologous host. The resulting compounds were tested against several standard laboratory and clinically isolated bacterial strains. In addition, they were also tested in vitro against standard and drug-resistant strains of human malaria parasites (Plasmodium falciparum) and the liver stages of the rodent malaria parasite (Plasmodium berghei). Antibacterial activity of modified erythromycin and azithromycin showed no improvement over the unmodified macrolides, but the modified compounds showed a 10-fold increase in effectiveness after a short-term exposure against blood stages of malaria. The new compounds also remained active against azithromycin-resistant strains of P. falciparum and inhibited growth of liver-stage parasites at concentrations similar to those used for primaquine. Our findings show that malaria parasites have two distinct responses to macrolide antibiotics, one reflecting the prokaryotic origin of the apicoplast and a second, as-yet uncharacterized response that we attribute to the eukaryotic nature of the parasite. This is the first report for macrolides that target two different functions in the Plasmodium parasites.