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PubMed2006

Versatile and practical chiral shift reagent with hydrogen-bond donor/acceptor sites in a macrocyclic cavity.

[structure: see text] Bifunctional macrocycle 1 with C2 symmetry was newly synthesized. NMR studies demonstrated that receptor 1 functions as a chiral shift reagent (solvating agent) that is highly effective for a wide range of chiral compounds having a carboxylic acid, oxazolidinone, lactone, alcohol, sulfoxide, sulfoximine, isocyanate, or epoxide functionality. Binding constants were determined to investigate the binding behavior of 1.

Journal Article↗

PubMed2005

Chemical models for aspects of the photosynthetic reaction centre: synthesis and photophysical properties of tris- and tetrakis-porphyrins that resemble the arrangement of chromophores in the natural system.

Tris-porphyrin and tetrakis-porphyrin arrays 1 and 2 are proposed as models for the arrangement of the chromophores that constitute photosynthetic reaction centres (PRC's). Their porphyrinic chromophores are similar in distance apart to the key chromophores of PRC's and the C2 symmetric arrangement of the macrocycles that constitute the 'special pair' where charge separation occurs is also incorporated. The use of zinc(II) and gold(III) chelation establishes an energy gradient for photoinduced electron transfer across each compound. Synthesis was achieved in good yields through a strategy that used the construction of biquinoxalinyl and Tröger's base linkages between the porphyrinoid components. Compounds which are bis-porphyrin molecular components of the arrays were also synthesised. Photophysical analyses indicate that long-range photoinduced energy and electron transfer processes occur in the extended arrays in addition to those occurring in the component bis-porphyrins. Evidence for step-wise electron transfer between terminal zinc(II)-chelated and gold(III)-chelated porphyrins has been detected in both porphyrins 1 and 2 in polar solvents, representing charge transfer across 35 A and 50 A, respectively. At 298 K, in deaerated benzonitrile, the lifetime of the charge transfer state of the tris-porphyrin 1 is 150 ns and the lifetime of the charge transfer state of tetrakis-porphyrin 2 is 59.4 micros; very long when compared to simpler chemical model systems, but still much shorter than the 1 s lifetime of the charge separated state of natural PRC's in cell membranes.

Gold↗

PubMed2004

1,14-dioxa-5,10-diaza-2,3:12,13-dibenzocyclooctadeca-2,12-diene monohydrate.

The title compound, C(22)H(30)N(2)O(2).H(2)O, is an 18-membered diaza-crown ether ligand containing two ether O and two aza N atoms. In the macrocyclic ring, the mean N.O distance is 4.526 (4) A. The macrocyclic inner-hole size, estimated as twice the mean distance of the donor atoms from their centroid, is approximately 2.29 A.

Journal Article↗

PubMed2005

Stress-induced inhibition of the NF-kappaB signaling pathway results from the insolubilization of the IkappaB kinase complex following its dissociation from heat shock protein 90.

Activation of the stress response attenuates proinflammatory responses by suppressing cytokine-stimulated activation of the NF-kappaB signaling pathway. In this study, we show that the activation of the cellular stress response, either by heat shock treatment or after exposure to sodium arsenite, leads to a transient inhibition of IkappaBalpha phosphorylation. Inhibition of IkappaBalpha phosphorylation after stress was associated with the detergent insolubilization of the upstream kinases, IkappaB kinase alpha (IKKalpha) and IkappaB kinase beta, components involved in IkappaBalpha phosphorylation. Pretreatment of cells with glycerol, a chemical chaperone that reduces the extent of stress-induced protein denaturation, reduced the stress-dependent detergent insolubility of the IKK complex and restored the cytokine-stimulated phosphorylation of IkappaB. The stress-dependent insolubility of the IKK complex appeared reversible; as the cells recovered from the heat shock treatment, the IKK complex reappeared within the soluble fraction of cells and was again capable of mediating the phosphorylation of IkappaBalpha in response to added cytokines. Treatment of cells with geldanamycin, an inhibitor of heat shock protein 90 (Hsp90) function, also resulted in IKK detergent insolubility and proteasome-mediated degradation of the IKK complex. Furthermore, while IKKalpha coprecipitated with Hsp90 in control cells, coprecipitation of the two proteins was greatly reduced in those cells early after stress or following exposure to geldanamycin. Stress-induced transient insolubilization of the IkappaB kinase complex following its dissociation from Hsp90 represents a novel mechanism by which the activation of the stress response inhibits the NF-kappaB signaling pathway in response to proinflammatory stimuli.

Animals↗

PubMed2004

Metabolic profile of pigs fed feed containing zearalenone destructor.

Zearalenone (ZEA) is a member of macrocyclic lactons family. It is a toxin--phytosteride produced by fungi of Fusarium ssp. genus. Zearalenone contaminates food and animal feeding stuffs and its destruction is difficult. It requires application of particular compounds that would bind zearalenone in the feed or feeding stuff or in the gastrointestinal tract and decrease its bio-accessibility. It should also fulfil all the safety requirements regarding the plant supplements and animals that are fed with this feed. The aim of the study was to estimate if the feed supplemented with different doses of zearalenone and zearalenone destructor causes changes of the metabolic profile in gilts. The results obtained show that applied destructor did not cause negative haematological and biochemical changes in the blood of the gilts examined. It can be suggested that it is a safe feed supplement pigs in prevention of zearalenone micotoxicosis.

Animal Feed↗

PubMedDate not supplied

Mass spectral investigations on trichothecene mycotoxins. II. Detection and quantitation of macrocyclic trichothecenes by gas chromatography/negative ion chemical ionization mass spectrometry.

A general, sensitive gas chromatographic/negative ion chemical ionization mass spectrometric (GC/NICIMS) method of analysis was developed for the detection and quantitation of several polar, thermally labile, toxic macrocyclic trichothecenes. The procedure involves the conversion of the molecules to their corresponding alcohols (verrucarols) by alkaline hydrolysis, followed by derivatization of the hydrolysate with heptafluorobutyrylimidazole and analysis by GC/MS technique under negative ion chemical ionization conditions. Nanogram (250 ng) quantities of several macrocyclic trichothecenes with different verrucarol and ester moieties were analyzed successfully with good precision by this procedure. The method was applicable for the accurate determination of at least low ppb levels of these macrocyclic trichothecenes in environmental samples, such as fungal products, fermentation broths, and plant samples. This is the first reported, well developed, sensitive, and applicable method for the detection and quantitation of these compounds in naturally occurring samples.

Fermentation↗

PubMed1995

19-Allylaminoherbimycin A, an analog of herbimycin A that is stable against treatment with thiol compounds or granulocyte-macrophage colony-stimulating factor in human leukemia cells.

Herbimycin A, a benzoquinonoid ansamycin antibiotic, reduces intracellular phosphorylation by some protein tyrosine kinases and inhibits the proliferation of malignant cells which express high tyrosine kinase activity. Herbimycin A inhibited the proliferation of human monoblastic leukemia U937 cells, but this inhibition was abrogated by the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF). On the other hand, a derivative of herbimycin A, 19-allylaminoherbimycin A, inhibited the proliferation of such cells without interference by the addition of GM-CSF. Phosphorylation of MAP kinase and c-myc expression induced by GM-CSF in U937 cells were inhibited by both herbimycin A and 19-allylaminoherbimycin A. The time courses of growth inhibition showed that the growth-inhibitory activity of herbimycin A in U937 cells was initially potent, but gradually decreased in the presence of GM-CSF. Thiol compounds, glutathione (GSH) and 2-mercaptoethanol, abrogated the inhibition of the growth of U937 cells by herbimycin A, but not by 19-allylaminoherbimycin A, like GM-CSF. Intracellular GSH content in U937 cells was increased by treatment with GM-CSF, and decreased with herbimycin A, but returned to the control level with the addition of GM-CSF to herbimycin A. In thin-layer chromatography, after in vitro incubation with herbimycin A and GSH, nothing could be detected at the position of intact herbimycin A, while 19-allylaminoherbimycin A was stably detected. These findings suggest that changes in the intracellular concentration of GSH play a role in the abrogation of the inhibition of U937 cell growth by herbimycin A. In the presence of GSH, 19-allylaminoherbimycin A inhibited the proliferation of U937 cells and Philadelphia chromosome-positive K562 cells more effectively than herbimycin A. Since GSH plays a role in detoxicating several anticancer drugs, 19-allylaminoherbimycin A may have therapeutic advantages over herbimycin A against some types of leukemia.

Antibiotics, Antineoplastic↗

PubMed1992

Design, synthesis and solution structure of a renin inhibitor. Structural constraints from NOE, and homonuclear and heteronuclear coupling constants combined with distance geometry calculations.

A macrocyclic renin inhibitor was designed using molecular modeling and a model of human renin. The synthesized molecular displayed poor binding affinity. To investigate the reasons for the observed inactivity, the structure of the compound has been studied by NMR spectroscopy and distance geometry. Structural constraints for distance geometry calculations were derived from nuclear Overhauser effects and homonuclear and heteronuclear three bond coupling constants. Homonuclear coupling constants were measured directly from the resolution-enhanced proton spectra and heteronuclear coupling constants were measured from the natural abundance 15N- and 13C-edited TOCSY experiments. One phi angle was determined uniquely by this method and two were reduced to two possible values each. By using a statistical analysis of 400 structures generated with distance geometry, two families of structures were found to be consistent with the NMR data. The solution structures so derived were different from the originally designed structure, including an internal hydrogen bond. This provides a possible explanation for the lack of effectiveness of this compound.

Humans↗

PubMed2006

The metal complexes of N-confused porphyrin as heme model compounds.

Recently, metal complexes of the isomers and analogs of porphyrin have become important model compounds for heme enzymes and proteins. While the chemistry of metalloporphyrins as heme models still attracts attention, the isomers and analogs of porphyrins provide insight into the biological choice of porphine as the macrocycle of choice and also help model reactive intermediates, such as high valent oxidation states. In this mini-review, we discuss the heme-relevant chemistry of N-confused porphyrin, an isomer of porphyrin with an inverted pyrrole ring, and focus on the chemistry of manganese, iron, and cobalt. The metallation chemistry of this macrocycle is more diverse than normal porphyrin, and involves tautomerization, C-H bond activation, the Lewis basicity of the external nitrogen, and issues with nucleophilic sensitivity. Despite the challenges posed by N-confused porphyrin, significant progress has been made toward generating heme-model complexes with this macrocycle.

Cobalt↗

PubMed1999

Spectrophotometric method for determination of bifunctional macrocyclic ligands in macrocyclic ligand-protein conjugates.

A simple spectrophotometric assay for determination of bifunctional polyazacarboxylate-macrocyclic ligands of different sizes that are conjugated to proteins has been developed for: 12-membered macrocycle DOTA (2-[4-nitrobenzyl]-1, 4, 7, 10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) and analogs, the 15-membered PEPA macrocycle (2-[4-nitrobenzyl]-1,4,7,10,13-pentaazacyclopentadecane-N,N',N'',N ''',N''''-pentaacetic acid), and the large 18-membered macrocycle HEHA (1,4,7,10,13,16-hexaazacyclooctadecane-N,N',N'',N''',N'''',N'''''- hexaacetic acid). The method is based on titration of the blue-colored 1:1 Pb(II)-Arsenazo II (AAIII) complex with the polyazacarboxylate macrocyclic ligand in the concentration range of 0-2.5 microM, wherein color change occurring upon transchelation of the Pb(II) from the AAIII to the polyazamacrocyclic ligand is monitored at 656 nm. The assay is performed at ambient temperature within 20 min without any interfering interaction between the protein and Pb(II)-AA(III) complex. Thus, this method also provides a ligand-to-protein ratio (L/P ratio) that reflects the effective number of ligands per protein molecule available to radiolabeling. The method is not suitable for 14-membered TETA macrocycle (2-[4-nitrobenzyl]-1, 4, 8, 11-tetraazacyclotetradecane N,N',N'',N'''-tetraacetic acid) because of low stability constant of Pb(II)-TETA complex. The method is rapid, simple and may be customized for other polyazacarboxylate macrocyclic ligands.

Antibodies, Monoclonal↗

PubMed2002

Cyclitol-based metal-complexing agents. Effect of the relative orientation of oxygen atoms in the ionophoric ring on the cation-binding ability of myo-inositol-based crown ethers.

myo-Inositol-derived crown ethers having varying relative orientations (1,3-diaxial, 1,2-diequatorial, and 1,2-axial-equatorial) of the oxygen atoms in the ionophoric ring were synthesized and the extent of their binding with picrates of alkali metals, ammonia, and silver were estimated. These crown ethers bind very well with potassium and silver picrates and show good to moderate binding toward lithium, sodium, cesium, and ammonium picrates. These myo-inositol-derived crown ethers exhibit very strong binding for silver, even though they do not have sulfur or nitrogen coordinating sites in them, which are known to have high affinity for silver. The ratio of binding constants for silver to other ions tested varies from 10(2) to 10(5). The ion selectivity and the strength of binding are dependent on the relative orientation of the oxygen atoms in the ionophoric ring as well as on the size of the macrocyclic ring.

Ammonia↗

PubMed2003

Bidentate ligands capable of variable bond angles in the self-assembly of discrete supramolecules.

Flexible donor ligands like 1,2-bis(3-pyridyl)ethyne or 1,4-bis(3-pyridyl)-1,3-butadiyne self-assemble into discrete supramolecules instead of infinite networks upon combination with organoplatinum 90, 120, and 180 degree acceptor units. These systems are unique examples of versatile pyridine donors adjusting their bonding directionality to accommodate rigid platinum acceptors in the formation of closed macrocycles.

Alkynes↗

PubMed1999

An expeditious procedure for the isolation of ingenol from the seeds of euphorbia lathyris

A short and practical process for the isolation of ingenol (1a) from an agricultural commodity (the seeds of Euphorbia lathyris) is described. Macrocyclic diterpene esters are obtained as byproducts, and the esterification pattern of the Euphorbia factors L2 (3), L3 (4a), and L8 (4b) was established by 2D NMR measurements. Full spectroscopic data for these compounds are reported.

Journal Article↗

PubMed1999

Interspecies complementation in Saccharopolyspora erythraea : elucidation of the function of oleP1, oleG1 and oleG2 from the oleandomycin biosynthetic gene cluster of Streptomyces antibioticus and generation of new erythromycin derivatives.

Two glycosyltransferase genes, oleG1 and oleG2, and a putative isomerase gene, oleP1, have previously been identified in the oleandomycin biosynthetic gene cluster of Streptomyces antibioticus. In order to identify which of these two glycosyltransferases encodes the desosaminyltransferase and which the oleandrosyltransferase, interspecies complementation has been carried out, using two mutant strains of Saccharopolyspora erythraea, one strain carrying an internal deletion in the eryCIII (desosaminyltransferase) gene and the other an internal deletion in the eryBV (mycarosyltransferase) gene. Expression of the oleG1 gene in the eryCIII deletion mutant restored the production of erythromycin A (although at a low level), demonstrating that oleG1 encodes the desosaminyltransferase required for the biosynthesis of oleandomycin and indicating that, as in erythromycin biosynthesis, the neutral sugar is transferred before the aminosugar onto the macrocyclic ring. Significantly, when an intact oleG2 gene (presumed to encode the oleandrosyltransferase) was expressed in the eryBV deletion mutant, antibiotic activity was also restored and, in addition to erythromycin A, new bioactive compounds were produced with a good yield. The neutral sugar residue present in these compounds was identified as L-rhamnose attached at position C-3 of an erythronolide B or a 6-deoxyerythronolide B lactone ring, thus indicating a relaxed specificity of the oleandrosyltransferase, OleG2, for both the activated sugar and the macrolactone substrate. The oleP1 gene located immediately upstream of oleG1 was likewise introduced into an eryCII deletion mutant of Sac. erythraea, and production of erythromycin A was again restored, demonstrating that the function of OleP1 is identical to that of EryCII in the biosynthesis of dTDP-D-desosamine, which we have previously proposed to be a dTDP-4-keto-6-deoxy-D-glucose 3, 4-isomerase.

Chromatography, High Pressure Liquid↗

PubMed2004

Pubescenes, jatrophane diterpenes, from Euphorbia pubescens, with multidrug resistance reversing activity on mouse lymphoma cells.

The macrocyclic jatrophane diterpene polyesters, pubescenes A - D ( 1 - 4) were isolated from the whole dried plant of Euphorbia pubescens, and evaluated for multidrug resistance (MDR) reversing activity on mouse lymphoma cells. All the compounds displayed very strong activity compared with the positive control verapamil. Pubescene D ( 4) is a new compound, whose structure was established as 3beta,9alpha,-diacetoxy-7beta-benzoyloxy-15beta-hydroxy-14-oxo-2beta H-jatropha-5 E,12 E-diene by spectroscopic methods, including (1)H- (1)H COSY, HMQC, HMBC and NOESY.

Animals↗

PubMed2004

Difurazano[3,4-b:3',4'-f]-4,5-diaza-1,8-dioxacyclododecine and an acyclic analogue.

The novel title furazan-containing macrocycle (systematic name: 6,9,14,17-tetraoxa-2,3,5,7,16,18-hexaazatricyclo[13.3.0.0(4,8)]octadeca-4,7,15,18-tetraene), C8H10N6O4, (I), is the first macrocycle where the furazan rings are connected via a hydrazine group. In spite of the strain in the 12-membered macrocycle of (I), the geometry of the furazan fragment is the same in (I) and in its acyclic analogue 1,8-bis(5-aminofurazan-4-yloxy)-3,6-dioxaoctane, C10H16N6O6, (II). In both compounds, the participation of the furazan rings in intermolecular hydrogen bonding equalizes the N-O bonds within the furazan rings, in contrast with rings which do not participate in such interactions.

Journal Article↗

PubMed2004

Self-inclusion in 5,11,17,23-tetra-tert-butyl-26,27,28-trihydroxy-25-(methoxycarbonylmethoxy)calix[4]arene chloroform trisolvate.

The title compound, C(47)H(60)O(6).3CHCl(3), is the first example of a lower-rim mono-ester calixarene derivative to be crystallographically characterized. The cone conformation adopted by the macrocycle is stabilized by three intramolecular hydrogen bonds. Self-inclusion of the methyl ester chain in the cavity of an adjacent molecule gives rise to infinite chains parallel to the c axis. C-H...pi interactions involving the methyl group most imbedded in the cavity contribute to the stabilization of the system.

Journal Article↗

PubMedDate not supplied

[Verrucarin A from conidia of Dendrodochium toxicum Pidopl. et Bilai].

A substance which was dyed blue by 4p-(nitrobenzyl)pyridine, that evidenced for its trichotecene nature, has been isolated in the crystalline form from conidia Dendrodochium toxicum Pidopl. et Bilai--roridine H producer. Thin-layer chromatography of the substance in three different systems, the well-known macrocyclic trichotecenes being used as standards, permitted it to be identified with verrucarine A. The substances possessed high biological activity with respect to the indicator test-culture Candida kefyr 900. No other compounds of trichotecene nature were found. Possible role of verrucarine A is discussed.

Chromatography, Thin Layer↗