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PubMed1992

A biological assay for the detection of Myrothecium spp. produced macrocyclic trichothecenes.

A rapid, inexpensive bioassay to detect Myrothecium spp.-produced macrocyclic trichothecenes was developed. Media containing Myrothecium isolates were inoculated with Chlorella vulgaris, Ustilago maydis and Trichoderma viride. Based on width of the inhibition zone, isolates could be classified as highly toxigenic, non-toxigenic and intermediate. Whereas, C. vulgaris and U. maydis showed significant differences in their response to toxigenic and non-toxigenic isolates, T. viride did not. Production of roridins and verrucarins by the toxigenic isolates (by bioassay) was confirmed by thin layer chromatography and high performance liquid chromatography. This bioassay system, combined with confirmation chemical analyses, increases our ability to detect toxigenic fungal isolates.

Biological Assay↗
PubMedDate not supplied

Effects of macrocyclic trichothecene mycotoxins on the murine immune system.

Macrocyclic trichothecenes are a class of mycotoxins, some of which exhibit substantial antileukemic properties. These compounds vary in their toxicity by approximately 100 fold and are suspected immunotoxins. We studied 11 of these mycotoxins: roritoxin B, myrotoxin B, roridin A, verrucarin A, 16-hydroxyverrucarin A, verrucarin J, baccharinoid B12, roridin D, roridin E, baccharinoid B4 and baccharinoid B5 for their immunotoxicity in CD-1 mice. An equitoxic dose was prepared in 1% DMSO in saline and administered i.p. at half the LD50. Organ weights, WBC, RBC, differentials of blood cell counts, blastogenesis of splenic lymphocytes in response to concanavalin A (Con A), lipopolysaccharide (LPS), phytohemagglutinin (PHA) and pokeweed mitogen (PWM), and mixed lymphocyte reaction (MLR) were studied on day 4 after administration of each mycotoxin. Organ weights showed significant differences between the controls and the baccharinoids with a decrease in spleen weight in baccharinoid B12 and an increased liver weight in B4 and B5 treated animals. Administration of myrotoxin B, roridin A, verrucarin J and roridin E had total WBC counts statistically different from controls, while mice administered myrotoxin B shoed a decrease in numbers of RBC. Differentials of WBC were unremarkable regardless of the mycotoxin. Roritoxin B and baccharinoid B5 increased Con A stimulation of splenic lymphocytes. Roridin A and baccharinoid B12 increased LPS stimulation of splenic lymphocytes while baccharinoid B5 decreased the LPS response. Stimulation of splenic lymphocytes with PHA was significantly increased by roridin A and baccharinoid B5. Stimulation of splenic lymphocytes with PWM was not altered significantly by any mycotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Antimicrobial effects of the macrocyclic Cu(II)-tetraanhydroaminobenzaldehyde complex.

The Cu(II)-tetraaza macrocyclic complex exhibited antimicrobial effects on bacteria, yeasts and filamentous fungi. The highest antibacterial activity was found with B. subtilis and S. aureus, the respective IC50 values being 18 and 80 micrograms/L and the MIC values 50 and 1000 micrograms/L. A concentration of 1 mg/L exerted a bacteriocide effect on S. aureus. The MIC value for B. subtilis was 250 times lower and for P. aeruginosa 10 times lower than the corresponding values for ampicillin. The Cu-complex was inactive against all tested yeasts. The strongest antifungal effect was manifested for R. nigricans, with an IC50 value under 0.1 mg/L, whereas in A. alternata the IC50 was 13.5 mg/L.

Anti-Bacterial Agents↗
PubMed2004

153Sm and 166Ho complexes with tetraaza macrocycles containing pyridine and methylcarboxylate or methylphosphonate pendant arms.

A set of tetraaza macrocycles containing pyridine and methylcarboxylate (ac(3)py14) or methylphosphonate (MeP(2)py14 and P(3)py14) pendant arms were prepared and their stability constants with La(3+), Sm(3+), Gd(3+) and Ho(3+) determined by potentiometry at 25 degrees C and 0.10 M ionic strength in NMe(4)NO(3). The metal:ligand ratio for (153)Sm and (166)Ho and for ac(3)py14, MeP(2)py14 and P(3)py14, as well as the pH of the reaction mixtures, were optimized to achieve a chelation efficiency higher than 98%. These radiocomplexes are hydrophilic and have a significant plasmatic protein binding. In vitro stability was studied in physiological solutions and in human serum. All complexes are stable in saline and PBS, but 20% of radiochemical impurities were detected after 24 h of incubation in serum. Biodistribution studies in mice indicated a slow rate of clearance from blood and muscle, a high and rapid liver uptake and a very slow rate of total radioactivity excretion. Some bone uptake was observed for complexes with MeP(2)py14 and P(3)py14, which was enhanced with time and the number of methylphosphonate groups. This biological profile supports the in vitro instability found in serum and is consistent with the thermodynamic stability constants found for these complexes.

Blood Proteins↗
PubMed2005

Catecholase activity of a mu-hydroxodicopper(II) macrocyclic complex: structures, intermediates and reaction mechanism.

The monohydroxo-bridged dicopper(II) complex (1), its reduced dicopper(I) analogue (2) and the trans-mu-1,2-peroxo-dicopper(II) adduct (3) with the macrocyclic N-donor ligand [22]py4pz (9,22-bis(pyridin-2'-ylmethyl)-1,4,9,14,17,22,27,28,29,30- decaazapentacyclo -[22.2.1(14,7).1(11,14).1(17,20)]triacontane-5,7(28),11(29),12,18,20(30), 24(27),25-octaene), have been prepared and characterized, including a 3D structure of 1 and 2. These compounds represent models of the three states of the catechol oxidase active site: met, deoxy (reduced) and oxy. The dicopper(II) complex 1 catalyzes the oxidation of catechol model substrates in aerobic conditions, while in the absence of dioxygen a stoichiometric oxidation takes place, leading to the formation of quinone and the respective dicopper(I) complex. The catalytic reaction follows a Michaelis-Menten behavior. The dicopper(I) complex binds molecular dioxygen at low temperature, forming a trans-mu-1,2-peroxo-dicopper adduct, which was characterized by UV-Vis and resonance Raman spectroscopy and electrochemically. This peroxo complex stoichiometrically oxidizes a second molecule of catechol in the absence of dioxygen. A catalytic mechanism of catechol oxidation by 1 has been proposed, and its relevance to the mechanisms earlier proposed for the natural enzyme and other copper complexes is discussed.

Catalysis↗
PubMed1999

Natural and synthetic double-stranded DNA binding studies of macrocyclic tetraamine zinc(II) complexes appended with polyaromatic groups.

The characteristic binding mode of zinc(II) complexes of macrocyclic tetraamines (1,4,7,10-tetraazacyclododecane, cyclen) appended with one or two arylmethyl group(s) [(4-quinolyl)methyl-, 1,7-bis(4-quinolyl)methyl-, (1-naphthyl)methyl-, 1,7-bis(1-naphthyl)methyl-, and (9-acridinyl)methyl-cyclen] to double-stranded calf thymus DNA and synthetic DNAs [poly(dA)-poly(dT), poly(dA-dT)2, poly(dI).poly(dC), poly(dI-dC)2, poly(dG) poly(dC), and poly(dG-dC)2] has been examined by spectrophotometric methods, Tm measurement, and inhibition of these DNA-directed transcriptions in vitro. Various hypochromic and bathochromic effects on the pendant aromatic absorption spectra of the complexes were observed in titration with the native and synthetic DNA. The binding constants Kapp (=[bound cyclen derivatives]/[unbound cyclen derivatives][DNA phosphates] M(-1)), at 25 degrees C in 10 mM EPPS (pH 8.0) containing 0.1 M Na+, were determined and compared with those of the corresponding Zn2+ -free ligands. The results showed that the Zn2+ -cyclen complexes interact with the DNA more strongly than the corresponding diprotonated ligands, leading to a stronger stacking of the pendant aromatic rings. The binding of Zn2+ -(9-acridinyl)methyl-cyclen to calf thymus DNA was competed by an AT-selective, minor groove binder, distamycin, but not by a major groove binder, methyl green. In an unusual interaction of excess Zn2+ -(9-acridinyl)methyl-cyclen with poly(dA).poly(dT), the Zn2+ -cyclen moiety went into the minor groove to make coordination bonds with the deprotonated imides of the thymines, resulting in disruption of the poly(dA).poly(dT) duplex. Thymine-containing DNA-directed transcription with Escherichia coli RNA polymerase in vitro was inhibited by the Zn2+ -(9-acridinyl)methyl-cyclen. The 50% inhibition concentrations of the transcription (IC50) were 22-45 microM with poly(dA).poly(dT) or poly(dA-dT)2 as templates, while with poly(dG-dC)2 as a template the IC50 value was 110 microM.

Amines↗
PubMed1992

Identification of heme macrocycle type by near-infrared magnetic circular dichroism spectroscopy at cryogenic temperatures.

The electron paramagnetic resonance (EPR) and near-infrared magnetic circular dichroism (MCD) spectra of the azide and cyanide adducts of nitrimyoglobin and hydroperoxidase II from Escherichia coli have been measured at cryogenic temperatures. For the first time, ligand-to-metal charge-transfer transitions in the near-infrared have been observed for an Fe(III)-chlorine system. It is shown that near-ultraviolet-to-visible region electronic spectra of 'green' hemes such as these are an unreliable indicator of macrocycle type. However, the combined application of EPR and near-infrared MCD spectroscopies clearly distinguishes between the porphyrin-containing nitrimyoglobin and the chlorine-containing hydroperoxidase II.

Circular Dichroism↗
PubMed1995

Highly enantioselective capillary electrophoretic separations with dilute solutions of the macrocyclic antibiotic ristocetin A.

Ristocetin A is one of a series of structurally related amphoteric, glycopeptide, macrocyclic antibiotics. These compounds have several features that make them attractive as chiral selectors. These include spatially oriented functional groups that are known to provide the types of interactions that are conducive to enantio-recognition, a somewhat rigid "pocket" that can provide a site for hydrophobic interactions and polar, flexible arms (i.e., pendent sugar moieties) that can rotate to hydrogen bond and otherwise interact with a variety of chiral analytes. In addition, these compounds are sufficiently soluble in water, aqueous buffers and aqueous-organic solvents that are commonly used in capillary electrophoresis (CE). The use and optimization of ristocetin A as a chiral selector in CE is discussed. Over 120 racemates are resolved including a variety of N-blocked amino acids, non-steroidal anti-inflammatory compounds and a large number of biologically important compounds containing carboxylic acid groups (e.g., mandelic acid derivatives, lactic acid derivatives, folinic acid, tropic acid).

Carbohydrate Sequence↗
PubMed1985

Macrocyclic trichothecenes: cause of livestock poisoning by the Brazilian plant Baccharis coridifolia.

Nine macrocyclic trichothecenes, thought to cause toxic effects in herbivors, were isolated from the Brazilian shrub Baccharis coridifolia. The structures of two new components, named miophytocene A and B, are described. Structure analysis was mainly accomplished by application of two-dimensional Fourier transform NMR techniques. The trichothecenes are most likely produced by the soil fungus Myrothecium verrucaria, which was isolated from soil samples around B. coridifolia. It is concluded that the plant is able to absorb and accumulate these mycotoxins. Histopathological studies on rabbits which received roridin E and A per os revealed mainly necrosis and hemorrhages of the mucosa of the colon and in the case of roridin A also of the caecum. Lethality in mice was generally low, intoxication proceeding slowly. It has to be considered, however, that all trichothecenes tested are practically insoluble in aqueous solutions and were applied as emulsions (i.p. and per os application). No trichothecenes or other toxic substances were detected from the Brazilian species Baccharis dracunculifolia, although slight toxic effects have been reported in cattle.

Animals↗
PubMedDate not supplied

Effects of verrucarin A and roridin A, macrocyclic trichothecene mycotoxins, on the murine immune system.

Verrucarin A (Ver A) and roridin A (Ror A), macrocyclic trichothecene mycotoxins, were examined for their immunomodulatory effects. Both mycotoxins were administered intraperitoneally at 0.35 mg/kg (1/2 the LD50) in CD-1 mice. Lymphocyte proliferation was studied on days 2, 4 and 7 after animals were dosed with Ver A. After day 2, no significant differences in [3H]thymidine (3H-TdR) incorporation were observed using concanavalin A (Con A), phytohemagglutinin (PHA), pokeweed mitogen (PWM) or lipopolysaccharide (LPS). On day 4 DNA synthesis induced by Con A, PHA and PWM was increased significantly. On day 7, PHA stimulation increased (p less than 0.001) above controls while Con A, PWM and LPS responses were not significantly different. The data indicated that Con A, PHA and PWM responses were time-dependent. Antibody production was evaluated by the hemolytic plaque assay; sheep red blood cells (SRBC) and Ver A were administered simultaneously, and Ver A was given 2 days after SRBC challenge. While spleen weights increased when Ver A was administered with SRBC or when the toxin was given 2 days after antigen, the antibody responses were not altered. In contrast, roridin A decreased PHA stimulation only on day 7 (p less than 0.05). There were no significant effects associated with the other mitogens. Antibody production did not differ significantly following administration of Ror A. Although Ver A and Ror A are equitoxic and structurally similar, their immunomodulatory properties for the given dose differ considerably. These different immunologic responses may be independent of other systemic toxic effects.

Adjuvants, Immunologic↗
PubMed1990

Preliminary trials using a macrocyclic lactone against psoroptic scabies of cattle.

A macrocyclic lactone, LL-F28249 alpha, C36H52O8, was evaluated as a one- or two-injection treatment in different formulations and concentrations against cattle infested with Psoroptes ovis (Hering). One injection of 2 mg kg-1 or two injections of 1 mg kg-1 of 3% active material in either an aqueous or oil formulation failed to eliminate all of the mites. A single injection of 3 mg kg-1 as a 5% aqueous formulation eliminated all mites for 35 days post-injection. At lower dosages of the aqueous formulation (3%), the male mites appeared to be less susceptible to the acaricide than either the female or immature mites.

Animals↗
PubMed1992

Structural studies of a phosphocholine substituted beta-(1,3);(1,6) macrocyclic glucan from Bradyrhizobium japonicum USDA 110.

In our previous in vivo 31P study of intact nitrogen-fixing nodules (Rolin, D.B., Boswell, R.T., Sloger, C., Tu, S.I. and Pfeffer, P.E., 1989 Plant Physiol. 89, 1238-1246), we observed an unknown phosphodiester. The compound was also observed in the spectra of isolated bacteroids as well as extracts of the colonizing Bradyrhizobium japonicum USDA 110. In order to characterize the phosphodiester in the present study, we took advantage of the relatively hydrophobic nature of the material and purified it by elution from a C-18 silica reverse-phase chromatography column followed by final separation on an aminopropyl silica HPLC column. Structural characterization of this compound with a molecular weight of 2271 (FAB mass spectrometry), using 13C-1H and 31P-1H heteronuclear 2D COSY and double quantum 2D phase sensitive homonuclear 1H COSY NMR spectra, demonstrated that the molecule contained beta-(1,3); beta-(1,6); beta-(1,3,6) and beta-linked non-reducing terminal glucose units in the ratio of 5:6:1:1, respectively, as well as one C-6 substituted phosphocholine (PC) moiety associated with one group of (1,3) beta-glucose residues. Carbohydrate degradation analysis indicated that this material was a macrocyclic glucan, (absence of a reducing end group) with two separated units containing three consecutively linked beta-(1,3) glucose residues and 6 beta-(1,6) glucose residues. The sequences of beta-(1,3)-linked glucose units contained a single non-reducing, terminal, unsubstituted glucose linked at the C-6 position and a PC group attached primarily to an unsubstituted C-6 position of a beta-(1,3)-linked glucose.

Carbohydrate Sequence↗
PubMed1990

Effects of macrocyclic trichothecene congeners on the viability and mitogenesis of murine splenic lymphocytes.

The effects of several congeners of the macrocyclic class of trichothecene mycotoxins on murine splenic cells in vitro were investigated. The mycotoxins were roritoxin B, myrotoxin B, roridins A, D and E, baccharinoids B4, B5 and B12, 16-hydroxyverrucarin A, and verrucarins A and J. Lymphocytes from CD-1 mice were cultured with each of the mycotoxins for 48 h to assess cytotoxicity. The maximum effect of various trichothecenes produced on cells occurred at concentrations ranging from 10(-6) to 10(-4) M. Mycotoxins had no effect at concentrations ranging from 10(-12) to 10(-7) M. The mitogenic stimulants concanavalin A, lipopolysaccharide, phytohemagglutinin, and pokeweed mitogen were added to splenic lymphocyte cultures along with varying concentrations of selected mycotoxins. Blastogenesis was inhibited at concentrations 2-5 orders of magnitude lower than those which produced lethality on resting lymphocytes.

Animals↗
PubMed1994

A new nonionic macrocyclic gadolinium(III) chelate as a potential magnetic-resonance-imaging contrast agent.

A new GdIII complex of a 17-membered macrocycle with three pendant carboxymethyl groups has been synthesized; the ligand has been obtained in a single step from diethylenetriaminepentaacetic dianhydride (pentetic dianhydride) and 1,4-butanediamine (putrescine). An X-ray crystal analysis has shown that the complex is a nonionic metal chelate with a coordinated water molecule. The near-zero electrical conductivity, 1 omega-1 cm2 mol-1, of a 1 mM solution indicated that the metal chelate is essentially undissociated. The NMR T1 relaxivity is 2.5 s-1 mM-1 at a resonance field of 64 MHz, and 3.4 s-1 mM-1 at 250 MHz. This new GdIII complex is a potentially important magnetic resonance imaging contrast agent.

Chelating Agents↗
PubMed1990

Preparation, 252Cf-plasma-desorption mass spectrometry and radiometal exchange of the Pb2+ and Bi3+ complexes of a hexalactam macrocycle.

A macrocyclic tricatechol hexalactam ligand readily forms complexes with Pb2+ and Bi3+ ions. Solid samples were isolated and characterized by 252Cf-plasma-desorption mass spectroscopy (252Cf-PDMS). Radioactive metal exchange studies employing 210Pb and 210Bi showed the compounds to be kinetically inert to exchange. The feasibility of using an available source of 203Pb, a potential imaging agent, with this class of compound was shown by synthesis of the labelled hexalactam complex.

Bismuth↗
PubMed1995

Biosynthesis of porphyrins and related macrocycles, Part 43. Isolation and characterization of intermediates of coenzyme B12 biosynthesis, a cobyrinic acid triamide, the a,c-diamide and their Co-(5'-deoxy-5'-adenosyl) derivatives, from Propionibacterium shermanii.

BACKGROUND: Vitamin B12 is synthesized by many different organisms, for example Pseudomonas denitrificans (aerobic) and Propionibacterium shermanii ('microaerophilic', or essentially anaerobic). The biosynthetic pathways in these two organisms show strong similarities but also some differences. There have been conflicting reports on where differences between these two organisms lie in the stages beyond the formation of the corrin macrocycle. Characterization of intermediates in the pathway will help resolve these conflicts. RESULTS: A single cobyrinic acid diamide and a single triamide have been isolated from Pr. shermanii. The diamide was shown to be the a,c-isomer. The triamide is not the a,c,g-isomer but it is indistinguishable from the single triamide isolated by other workers from Ps. denitrificans. The Co-(5'-deoxy-5'-adenosyl) derivative of the a,c-diamide was also isolated and fully characterized and the deoxyadenosyl derivative of the foregoing triamide has been shown to be present in the cells. CONCLUSIONS: Our results support a unique pathway in Pr. shermanii proceeding from cobyrinic acid towards coenzyme B12, at least as far as the adenosylated triamide intermediate. No evidence was found for multiple alternative pathways. The order of amidations of the carboxyl side-chains of cobyrinic acid up to the triamide stage is the same in Pr. shermanii and Ps. denitrificans.

Chromatography, High Pressure Liquid↗
PubMed2006

Synthesis and DNA cleavage activities of mononuclear macrocyclic polyamine zinc(II), copper(II), cobalt(II) complexes which linked with uracil.

Mononuclear macrocyclic polyamine zinc(II), copper(II), cobalt(II) complexes, which could attach to peptide nucleic acid (PNA), were synthesized as DNA cleavage agents. The structures of these new mononuclear complexes were identified by MS and (1)H NMR spectroscopy. The catalytic activities on DNA cleavage of these mononuclear complexes with different central metals were subsequently studied, which showed that copper complex was better catalyst in the DNA cleavage process than zinc and cobalt complexes. The effects of reaction time, concentration of complexes were also investigated. The results indicated that the copper(II) complexes could catalyze the cleavage of supercoiled DNA (pUC 19 plasmid DNA) (Form I) under physiological conditions to produce selectively nicked DNA (Form II, no Form III produced) with high yields. The mechanism of the cleavage process was also studied.

Cobalt↗
PubMed2006

Apoptosis induction and modulation of P-glycoprotein mediated multidrug resistance by new macrocyclic lathyrane-type diterpenoids.

The macrocyclic lathyrane diterpenes, latilagascenes D-F (1-3) and jolkinol B (4), were isolated from the methanol extract of Euphorbia lagascae, and evaluated for multidrug resistance reversing activity on mouse lymphoma cells. All compounds displayed very strong activity compared with that of the positive control, verapamil. The structure-activity relationship is discussed. The evaluation of compounds 1 and 4, and of latigascenes A-C (5-7), isolated from the same species, as apoptosis-inducers was also carried out. Compound 1 was the most active. Furthermore, in the model of combination chemotherapy, the interaction between the doxorubicine and latilagascene B (6) was studied in vitro, on human MDR1 gene transfected mouse lymphoma cells, showing that the type of interaction was synergistic. Latilagascenes D-F (1-3) are new compounds whose structures were established on the basis of spectroscopic methods, including 2D NMR experiments (COSY, HMQC, HMBC and NOESY).

ATP Binding Cassette Transporter, Subfamily B, Mem↗