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PubMed2006

Synthesis of new enantiomerically pure macrocycles containing phenanthroline subunits.

New enantiomerically pure macrocycles have been prepared by combining 1,10-phenanthroline 2,9-dicarboxylic acid and two alpha-amino-acids linked through spacers. Different diamine linkers have been employed in order to modify the dimensions and the properties of the macrocycles whose structures have been studied by 1H and 13C NMR spectroscopy. The ability of the (L)-valine containing macrocycles to bind metal ions and phenolic molecules has been investigated by 1H NMR experiments and Molecular Mechanics calculations.

Journal Article↗
PubMed1989

Evaluation of polyaza macrocyclic methylene phosphonate chelates of Gd3+ ions as MRI contrast agents.

Gd(DTPA)2- (diethylenetriaminepentaacetic acid) and the polyaza macrocyclic Gd(DOTA)- (1,4,7,10-tetraazacyclododecane-N,N',N'',N''') are paradigms of general purpose paramagnetic complexes useful for enhancing contrast in magnetic resonance imaging (MRI). It is of both fundamental and practical interest to determine how one might modify the chemical structure of these chelate complexes to improve their utility for MRI in specific circumstances. In the present work, we investigated polyaza methylene phosphonate complexes of Gd3+ ions to compare their NMRD profiles with those of their carboxylate analogs and with Gd(DTPA)2-. We find that the number q of exchangeable water molecules coordinated directly to the Gd3+ ions tends to be smaller in the phosphonates, in principle reducing their utility in MRI. However, these phosphonates have a tendency to oligomerize, and the resulting decrease in rotational mobility of the paramagnetic oligomers increases their relaxivity at higher fields, offsetting the effect of decreases in q. In particular, Gd(DOTRP)3- (1,5,9-triazacyclododecane-N,N',N'',-tris(methylenephosphonic++ + acid] would be an increasingly effective contrast agent above approximately 10 MHz if the oligomerization was stable in vivo (and the Gd3+ ions were sufficiently well bound). At lower fields, the relaxivity of these small chelate complexes is dominated by tau S0, the relaxation time of the spin moments of the paramagnetic ions. We find this to be favorably long for complexes of Gd3+ with the macrocyclic phosphonate ligands, as was found earlier by us for Gd(DOTA)-. This situation, ostensibly related to the relatively high symmetry and rigidity of the macrocyclic complexes, can increase the low-field relaxivity of the phosphonates almost a factor of 2 beyond that of Gd(DTPA)2-.

Chelating Agents↗
PubMed1991

Macrocyclic trichothecenes produced by Stachybotrys isolated from Egypt and eastern Europe.

Twenty seven isolates of Stachybotrys chartarum, S. albipes, S. kampalensis and S. microspora from Egypt and Eastern Europe were tested for production of macrocyclic trichothecenes. Twenty of the 27 isolates, grown on rice seeds, were toxic to brine shrimp larvae. Based on TLC and HPLC analyses, 5 macrocyclic trichothecenes (verrucarin J, roridin E, satratoxins F, G & H) as well as trichoverrols were identified. When grown in liquid culture on rice extract medium, only 3 isolates were toxic and produced verrucarin J, roridin E and satratoxins G & H. Extracts from mycelial mats were more toxic than culture filterates of two isolates grown on rice extract and both contained the same macrocyclic trichothecenes (285.5 mg/4 L), in addition to trichoverrols A & B (31 mg/4 L) found in mycelial mats only. When grown on 3% sucrose Czapek's medium supplemented with peptone and yeast extract (still cultures), all isolates were non-toxic to brine shrimp and no trichothecenes could be detected in the extracts.

Animals↗
PubMed2003

Separation of the enantiomers of substituted dihydrofurocoumarins by HPLC using macrocyclic glycopeptide chiral stationary phases.

Enantiomer separations by HPLC using the macrocyclic glycopeptides teicoplanin (Chirobiotic T), teicoplanin aglycon (Chirobiotic TAG), and ristocetin A (Chirobiotic R) chiral stationary phases (CSP) have been achieved on a unique series of potentially biologically active racemic analogues of dihydrofurocoumarin. The macrocyclic glycopeptides have proven to be very selective for this class of compound. All of the 28 chiral analogues examined afforded baseline separation on at least one of the macrocyclic glycopeptide CSP. The teicoplanin CSP showed the broadest enantioselectivity with 24 of the compounds baseline separated. The TAG and the R CSP produced 23 and 14 baseline separations respectively. All three mobile phase modes, i.e. normal phase (NP), reversed phase (RP), and new polar organic modes (PO), have been evaluated. The NP mode proved to be most effective for the separation of chiral dihydrofurocoumarins on all CSP tested. In the reversed phase (RP) mode, all three CSP separated a similar number of compounds. It was observed that the structural characteristics of the analytes and steric effects are very important factors leading to chiral recognition. Hydrogen bonding was found to play a secondary role in chiral discrimination in the normal phase and polar organic modes. Hydrophobic interactions are important for chiral separation in the reversed-phase mode. Chromatographic retention data does not provide information on the absolute configuration of these chiral dihydrofurocoumarin derivatives. However, when coupled with circular dichroism using the exciton coupling chirality method, the enantiomer elution order and the absolute configuration of some chiral dihydrofurocoumarins were successfully determined.

Chromatography, High Pressure Liquid↗
PubMed2002

In vivo behavior of copper-64-labeled methanephosphonate tetraaza macrocyclic ligands.

Copper-64 ( T(1/2)=12.7 h; beta(+): 0.653 MeV, 17.4%; beta(-): 0.578 MeV, 39%) is produced in a biomedical cyclotron and has applications in both imaging and therapy. Macrocyclic chelators are widely used as bifunctional chelators to bind copper radionuclides to antibodies and peptides owing to their relatively high kinetic stability. In this paper, we evaluated three tetraaza macrocyclic ligands with two, three, and four pendant methanephosphonate functional groups. DO2P [1,4,7,10-tetraazacyclododecane-1,7-di(methanephosphonic acid)], DO3P [1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid)], and DOTP [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methanephosphonic acid)] were all radiolabeled with (64)Cu in high radiochemical yields. Copper-64-labeled DO2P and DOTP were highly stable in rat serum out to 24 h, while (64)Cu-DO3P remained 73% intact, with the remainder possibly forming a (64)Cu(.)2DO3P dimer by 24 h. The biodistribution experiments were performed in normal Sprague-Dawley rats. Of the three complexes, (64)Cu-DO2P demonstrated the most optimal clearance through the blood and liver. Copper-64-DO3P and (64)Cu-DOTP exhibited higher liver uptake and longer retention of liver activity, possibly because of the large negative charge of the complexes under physiological conditions. All three (64)Cu-labeled complexes showed high accumulation in bone, likely due to the binding of the methanephosphonate groups to hydroxyapatite. These results suggest that this series of methanephosphonate macrocyclic ligands may be useful as potential bone-imaging agents. The thermodynamic stability constants of the Cu(II) complexes with these three ligands were determined, and were found to be significantly higher than those of their acetate analogues. The Cu(II)-DO2P complex exhibited the highest stability constant among divalent transition metal ion DO2P complexes. Metabolism studies of (64)Cu-DO2P in rat liver suggest that the DO2P ligand may be used as a bifunctional chelator for copper radionuclides in radiodiagnostic or radiotherapeutic studies.

Animals↗
PubMed1991

A PAC study of the binding of 111In to a monoclonal antibody via the macrocyclic molecule 1,4,7-triazacyclononanetriacetic acid.

Time integral and time differential PAC measurements have been made from samples of 111In bound to the functionalized 9N3 macrocycle, and 111In bound to the monoclonal antibody AUA1 via the macrocycle, over the temperature range 80-350 K. Values obtained for the integrated perturbation coefficient G22 (infinity) clearly illustrate the effects which the antibody has on the angular correlation of the gamma-rays emitted by the 111In decay. Measurements of the quadrupole frequency in the 111In-9N3-AUA1 samples show a transition temperature between 250 and 275 K which was not detected in the 111In-9N3. An arrhenius plot of the temperature dependence of the correlation time for the 111In-9N3 yielded a value of 0.10 +/- 0.01 eV for the activation energy associated with molecular re-orientation, whilst a Debye plot indicated an effective volume of (10 +/- 1) x 10(-27) m3 for the same sample. Extrapolation of the Debye plot suggests a high relaxation constant which may be attributed to internal vibrational modes in the macrocycle. Comparisons are made with similar work on the plasma protein transferrin.

Antibodies, Monoclonal↗
PubMed2004

Protective effect of macrocyclic binuclear oxovanadium complex on oxidative stress in pancreas of streptozotocin induced diabetic rats.

Chronic hyperglycemia in diabetes is a major causative factor of free radical generation which further leads to many secondary diabetic complications via the damage to cellular proteins, membrane lipids, nucleic acids and eventually to cell death. Recently we have reported on the hypoglycemic efficacy of a new macrocyclic binuclear oxovanadium complex and its non-toxic nature. This study focuses on the effect of the above complex in ameliorating oxidative stress in the pancreas of diabetic rats. Streptozotocin induced diabetic rats were treated orally with the vanadium complex (5 mg/kg/body weight) for 30 days and the level of pancreatic antioxidants and lipid peroxides were determined. Treatment with the macrocyclic binuclear oxovanadium complex decreased the lipid peroxides and the antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase to near control levels. Histological examinations also revealed the protective effect of the complex on pancreatic beta cells. The results demonstrate the protective effect of the macrocyclic binuclear oxovanadium complex on the pancreatic antioxidant status.

Administration, Oral↗
PubMed2006

Synthesis and evaluation of a radiometal-labeled macrocyclic chelator-derivatised thymidine analog.

Several radiolabeled thymidine analogs as metabolic probes of cell proliferation were developed specifically addressing DNA synthesis. Thymidine analogs containing carboranylalkyl groups for neutron capture therapy at the N-3 position were found to be good substrates for cytosolic thymidine kinase 1 (TK1). According to this approach, a DO3A macrocycle in N-3 position was attached to thymidine. The 3-DO3A thymidine analog was labeled with 68Ga and 111In. Different lipophilicities of the corresponding radiometal-thymidines were detected via RP-HPLC. [111In]DO3A-thymidine ([111In]D3T) was evaluated for cellular uptake in different cell lines (HL60 and DoHH2). Cellular uptake was low in both cell lines. Phosphorylation of the radioconjugates by TK1 was negligible. Although stable complexation of radiometals to thymidine was obtained, introduction of the macrocycle DO3A reduced the affinity to cytosolic TK1 drastically. Low cellular uptake can be ascribed to missing substrate specificity of [111In]DO3A-thymidine for TK1. The absence of substrate specificity may be due to the bulky macrocyclic chelator and partial charges remaining on the coordination sphere due to a more complex solution structure.

Chelating Agents↗
PubMed2005

Spectroscopic, cyclic voltammetric and biological studies of transition metal complexes with mixed nitrogen-sulphur (NS) donor macrocyclic ligand derived from thiosemicarbazide.

The complexation of new mixed thia-aza-oxa macrocycle viz., 2,12-dithio-5,9,14,18-tetraoxo-7,16-dithia-1,3,4,10,11,13-hexaazacyclooctadecane containing thiosemicarba-zone unit with a series of transition metals Co(II), Ni(II) and Cu(II) has been investigated, by different spectroscopic techniques. The structural features of the ligand have been studied by EI-mass, (1)H NMR and IR spectral techniques. Elemental analyses, magnetic moment susceptibility, molar conductance, IR, electronic, and EPR spectral studies characterized the complexes. Electronic absorption and IR spectra of the complexes indicate octahedral geometry for chloro, nitrato, thiocyanato or acetato complexes. The dimeric and neutral nature of the sulphato complexes are confirmed from magnetic susceptibility and low conductance values. Electronic spectra suggests square-planar geometry for all sulphato complexes. The redox behaviour was studied by cyclic voltammetry, show metal-centered reduction processes for all complexes. The complexes of copper show both oxidation and reduction process. The redox potentials depend on the conformation of central atom in the macrocyclic complexes. Newly synthesized macrocyclic ligand and its transition metal complexes show markedly growth inhibitory activity against pathogenic bacterias and plant pathogenic fungi under study. Most of the complexes have higher activity than that of the metal free ligand.

Anions↗
PubMed1987

New approaches to synthetic receptors. Studies on the synthesis and properties of macrocyclic C-glycosyl compounds as chiral, water-soluble cyclophanes.

In an approach for the preparation of macrocyclic C-glycosyl compounds, the C-glycosyl residue is synthesized by acid-assisted reduction of a cyclic hemiacetal with sodium cyanoborohydride. Macrocycle formation is effected by the reaction of a symmetrical bis(C-glycosyl)derived diamine with a dicarboxylic acid dichloride. The product macrocycles are presented as the first examples of a new type of chiral, water-soluble cyclophane. Molecules of this type are of interest as synthetic receptors for lipophilic substrates.

Alkenes↗
PubMed1999

Selection for anthelmintic resistance by macrocyclic lactones in Haemonchus contortus.

Two morphologically marked strains of Haemonchus contortus, CAVRS (smooth-macrocyclic lactone resistant) and McMaster (linguiform-macrocyclic lactone susceptible), were used to investigate the selection for anthelmintic resistance following exposure to ivermectin (IVM), a non-persistent anthelmintic. and a more persistent anthelmintic, oral moxidectin (MOX). Three types of selection were investigated: (1) selection of resident worms at the time of treatment (Head selection); (2) selection of incoming-larvae post-treatment (Tail selection); and (3) selection of both resident population and incoming larvae (Head + Tail selection). The experimental animals were adult sheep and lambs. In the controls where there was no anthelmintic selection, the proportion of CAVRS in the adult worm population was the same as the proportion in larvae given to both adults and lambs indicating that CAVRS and McMaster H. contortus were equally infective. There was a significant effect of anthelmintic on total worm numbers in adult sheep with MOX treated adults having less worms, but selection type was non-significant. Anthelmintic type had a significant effect on numbers of resistant worms in adult sheep with less resistant worms in the MOX treated groups, but selection type had no effect. Analysis of variance of arcsine-transformed proportions of resistant worms found that the type of anthelmintic had a highly significant effect, with MOX treated adults having a higher proportion of resistant worms, while type of selection was not significant. In the lambs, nil treated controls and IVM Head + Tail and Tail selected groups had similar geometric mean total worm burdens while Head selected had less total worms. In the MOX treated lamb groups the worm burdens were similar within selection type but less than the IVM treated groups. In the lambs, the types of selection that resulted in more resistant worms were IVM Tail, MOX Head + Tail and MOX Tail. Resistant worm numbers were similar in both adult and lamb groups with Head selection by either MOX or IVM. Moxidectin selected out higher proportions of resistant worms than did IVM in the lambs, with Tail and Head + Tail being stronger selectors than Head. Computer simulations were used to estimate the rate at which resistance developed in the field using the information generated in the present study. The anthelmintic treatments used in the simulation followed a strategic parasite control program for H. contortus in which all sheep receive three Closantel (CLS) treatments in summer. all sheep receive a broad-spectrum (BS) drench or capsule at weaning and lambs receive an additional two BS drenches insummer or no further treatment in the case of the capsule. Moxidectin, IVM-capsule and IVM were the broad spectrum anthelmintics simulated. All simulations were run four times assuming high or low efficacy against resident resistant worms and in the presence or absence of CLS resistance. The simulations indicated that the presence of CLS resistance hastened selection for macrocyclic lactone (ML) resistance. While the IVM-capsule will select most rapidly for ML resistance, IVM oral is expected to be least selective. Moxidectin treatment is intermediate, except in simulations with no CLS resistance and when MOX is assumed to be highly effective against resident ML-resistant worms, in which case MOX can be expected to select more slowly than IVM oral treatments.

Animals↗
PubMed1989

Mass spectral investigations on trichothecene mycotoxins. VII. Liquid chromatographic-thermospray mass spectrometric analysis of macrocyclic trichothecenes.

Thermally labile, polar toxic roridins and biologically active, isomeric baccharinoids were separated on a reversed-phase high-performance liquid chromatography column and effectively ionized under thermospray ionization conditions. The mass spectra indicated the formation of corresponding molecular ion-ammonium adducts in great abundance. Experiments designed for monitoring specific ions of these analytes at predesignated intervals were utilized for the accurate analysis of these macrocyclic trichothecenes in real, crude samples. A synthetically modified macrocyclic trichothecene, 8-ketoverrucarin A, was used as the internal standard for the detection and quantification of these compounds. Minimum detectable limits, during this first reported method for the unambiguous analysis of these structurally related macrocyclic trichothecenes, were determined to be 2-5 ng.

Chemical Phenomena↗
PubMed2002

Separation of chiral sulfoxides by liquid chromatography using macrocyclic glycopeptide chiral stationary phases.

A set of 42 chiral compounds containing stereogenic sulfur was prepared. There were 31 chiral sulfoxide compounds, three tosylated sulfilimines and eight sulfinate esters. The separations were done using five different macrocyclic glycopeptide chiral stationary phases (CSPs), namely ristocetin A, teicoplanin, teicoplanin aglycone (TAG), vancomycin and vancomycin aglycone (VAG) and seven eluents, three normal-phase mobile phases, two reversed phases and two polar organic mobile phases. Altogether the macrocyclic glycopeptide CSPs were able to separate the whole set of the 34 sulfoxide enantiomers and tosylated derivatives. Five of the eight sulfinate esters were also separated. The teicoplanin and TAG CSPs were the most effective CSPs able to resolve 35 and 33 of the 42 compounds. The three other CSPs each were able to resolve more than 27 compounds. The normal-phase mode was the most effective followed by the reversed-phase mode with methanol-water mobile phases. Few of these compounds could be separated in the polar organic mode with 100% methanol mobile phases. Acetonitrile was also not a good solvent for the resolution of enantiomers of sulfur-containing compounds, neither in the reversed-phase nor in the polar organic mode. The structure of the chiral molecules was compared to the enantioselectivity factors obtained with the teicoplanin and TAG CSP. It is shown that the polarity, volume and shape of the sulfoxide substituents influence the solute enantioselectivity factor. Changing the oxidation state of the sulfur atom from sulfoxides to sulfinate esters is detrimental to the compound's enantioselectivity. The enantiomeric retention order on the teicoplanin and TAG CSPs was very consistent: the (S)-(+)-sulfoxide enantiomer was always the less retained enantiomer. In contrast, the (R)-(-)-enantiomer was less retained by the ristocetin A, vancomycin and vancomycin aglycone columns, showing the complementarity of these CSPs. The macrocyclic glycopeptide CSPs provided broad selectivity and effective separations of chiral sulfoxides.

Chromatography, Liquid↗
PubMed2003

Antifertility, antibacterial, antifungal and percent disease incidence aspects of macrocyclic complexes of manganese(II).

Macrocyclic complexes of Mn(II) were synthesized by template condensation using 2,6-diaminopyridine and diethylenetriamine with malonic, succinic, glutaric and adipic acids. The reaction proceeded smoothly to completion. These 16- to 24-membered N(6), but behaving as tetradentate, macrocyclic complexes were characterized by elemental analyses, molecular weight determinations, infrared, electronic, mass and X-ray spectral analyses. The elemental analyses are consistent with the formation of complexes [Mn(N(6)L(n))Cl(2)]. All the complexes are stable and monomeric in nature, as indicated by the molecular weight determinations. The spectral studies confirmed the proposed framework of the new macrocyclic complexes and indicated an octahedral geometry around the central metal atom. The complexes were screened in vitro against a number of pathogenic fungi and bacteria to assess their growth-inhibiting potential. The testicular sperm density, sperm morphology, sperm motility, density of cauda epididymis, spermatozoa and fertility in mating trials and the biochemical parameters of the reproductive organs of the rat were examined and are discussed.

Animals↗
PubMed2001

Macrocyclization in the design of a conformationally constrained Grb2 SH2 domain inhibitor.

Grubbs' olefin metathesis reaction was utilized to prepare a macrocyclic variant of a linear Grb2 SH2 domain antagonist in an attempt to induce a beta-bend conformation known to be required for high affinity binding. In extracellular Grb2 SH2 domain binding assays, the macrocyclic analogue exhibited an approximate 100-fold enhancement in binding potency relative to its linear counterpart. The macrocycle was not as effective in whole cell binding assays as would be expected based on its extracellular binding potency.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Insights into channel architecture and substrate specificity from crystal structures of two macrocycle-forming thioesterases of modular polyketide synthases.

Modular polyketide synthases (PKSs) synthesize the polyketide cores of pharmacologically important natural products such as erythromycin and picromycin. Understanding PKSs at high resolution could present new opportunities for chemoenzymatic synthesis of complex molecules. The crystal structures of macrocycle-forming thioesterase (TE) domains from the picromycin synthase (PICS) and 6-deoxyerythronolide B synthase (DEBS) were determined to 1.8-3.0 A with an R(crys) of 19.2-24.4%, including three structures of PICS TE (crystallized at pH 7.6, 8.0, and 8.4) and a second crystal form of DEBS TE. As predicted by the previous work on DEBS TE [Tsai, S. C., et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14808-14813], PICS TE contains an open substrate channel and a hydrophobic dimer interface. Notwithstanding their similarity, the dimer interfaces and substrate channels of DEBS TE and PICS TE reveal key differences. The structural basis for the divergent substrate specificities of DEBS TE and PICS TE is analyzed. The size of the substrate channel increases with increasing pH, presumably due to electrostatic repulsion in the channel at elevated pH. Together, these structures support previous predictions that macrocycle-forming thioesterases from PKSs share the same protein fold, an open substrate channel, a similar catalytic mechanism, and a hydrophobic dimer interface. They also provide a basis for the design of enzymes capable of catalyzing regioselective macrocyclization of natural or synthetic substrates. A series of high-resolution snapshots of a protein channel at different pHs is presented alongside analysis of channel residues, which could help in the redesign of the protein channel architecture.

Amino Acid Motifs↗
PubMedDate not supplied

Assessment of the macrocyclic effect for the complexation of crown-ethers with alkali cations using the Substructural Molecular Fragments method.

The Substructural Molecular Fragments method (Solov'ev, V. P.; Varnek, A. A.; Wipff, G. J. Chem. Inf. Comput. Sci. 2000, 40, 847-858) was applied to assess stability constants (logK) of the complexes of crown-ethers, polyethers, and glymes with Na+, K+, and Cs+ in methanol. One hundred forty-seven computational models including different fragment sets coupled with linear or nonlinear fitting equations were applied for the data sets containing 69 (Na+), 123 (K+), and 31 (Cs+) compounds. To account for the "macrocyclic effect" for crown-ethers, an additional "cyclicity"descriptor was used. "Predicted" stability constants both for macrocyclic compounds and for their open-chain analogues are in good agreement with the experimental data reported earlier and with those studied experimentally in this work. The macrocyclic effect as a function of cation and ligand is quantitatively estimated for all studied crown-ethers.

Journal Article↗