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PubMed2003

Complexation of silver and co-recovered metals with novel aza-crown ether macrocycles by electrospray ionization mass spectrometry.

Electrospray ionization mass spectrometry (ESI-MS) is used to evaluate the metal binding selectivities of an array of novel caged macrocycles for silver, gold, copper, nickel, zinc, iron, lead, manganese and alkali metal ions. It is found that five of the new compounds display silver selectivity, and their relative affinities for various metals depend on the type, number, and arrangement of heteroatoms (N, O), the cavity size, and the presence of aromatic substituents. Alkali metal cation binding studies are used to evaluate the size-selectivities of the cavities of the macrocycles. Electronic structure calculation by B3LYP density function theory methods were used to model the metal complexes. The presence of nitrogen atoms in the macrocyclic ring is essential for silver selectivity over other transition metals and alkali metal ions, and the presence of aromatic groups also enhances silver avidity. Macrocycle 3, a triaza-18-crown-6 analog modified with two phenyl groups and a cage group, is capable of selective extraction of Ag+ from aqueous solutions in the presence of other transition metal ions and the most common alkali and alkaline earth metal ions.

Crown Ethers↗

PubMed2003

Electrochemically switchable hydrogen-bonded molecular shuttles.

A series of [2]rotaxanes containing succinamide and naphthalimide hydrogen-bonding stations for a benzylic amide macrocycle is described. Electrochemical reduction and oxidation of the naphthalimide group alters its ability to form hydrogen bonds to the macrocycle to such a degree that redox processes can be used to switch the relative macrocycle-binding affinities of the two stations in a rotaxane by over 8 orders of magnitude. The structure of the neutral [2]rotaxane in solution is established by (1)H NMR spectroscopy and shows that the macrocycle exhibits remarkable positional integrity for the succinamide station in a variety of solvents. Cyclic voltammetry experiments allow the simultaneous stimulation and observation of a redox-induced dynamic process in the rotaxane which is both reversible and cyclable. Model compounds in which various conformational and co-conformational changes are prohibited demonstrate unequivocally that the redox response is the result of shuttling of the macrocycle between the two stations. At room temperature in tetrahydrofuran the electrochemically induced movement of the macrocycle between the two stations takes approximately 50 micros.

Journal Article↗

PubMed2001

Screening metal binding selectivities of macrocycle mixtures by HPLC--ESI-MS and postcolumn reactions.

A rapid method for the screening of metal binding selectivities of host compounds in mixtures is presented. This method involves the separation of mixtures of hosts by HPLC, followed by postcolumn complexation with one or more metals, then analysis by mass spectrometry. The intensities of the host-guest complexes in the mass spectra correlate with the binding selectivities of the hosts. The method was applied to a series of lariat ethers that were synthesized as ion-selective reagents for ion-selective electrodes. The compounds most selective for Na+ vs Li+ and K+ were identified. Additionally, a mixture of substituted calixarenes was screened for alkali-metal-binding selectivity. These compounds were determined to be selective for Cs+ over Rb+, K+, and Na+.

Journal Article↗

PubMed2006

Preparation and characterization of mononuclear Co, Ni, and Zn complexes of dinucleating macrocyclic hexaaza-dithiophenolate ligands and their open-chain derivatives.

The preparation and characterization of mononuclear complexes of the dinucleating 24-membered hexazadithiophenolate macrocycles H2L2 and H2L3 and their open-chain N3S2 analogues H2L4 and H2L5 are reported. The highly crystalline compounds [Ni(L4)] (4), [Ni(L5)] (5), [Co(L5)] (6), [NiH2(L2)]2+ (7), [ZnH2(L2)]2+ (8), and [NiH2(L3)]2+ (9) could be readily prepared by stoichiometric complexation reactions of the hydrochlorides of the free ligands with the corresponding metal(II) dichlorides and NEt3 in methanolic solution. All complexes were characterized by X-ray crystallography. Monometallic complexes 4-6 of the pentadentate ligands H2L4 and H2L5 feature distorted square pyramidal MN3S2 structures (tau = 0.01 to 0.44). Similar coordination geometries are observed for the macrocyclic complexes 7-9 of the octadentate ligands H2L2 and H2L3. The two hydrogen atoms in 7-9 are attached to the noncoordinating benzylic amine functions and are hydrogen bonded to the metal-bound thiophenolate functions. A comparison of the structures of 4-9 reveals that the macrocycles L2 and L3 have a rather flexible ligand backbone that do not confer unusual coordination geometries on the metal ions. We also report on the ability of the monometallic complexes 7 and 8 to serve as starting materials for the preparation of dinuclear complexes.

Journal Article↗

PubMed2006

Synthesis and structural characterization of lanthanide(III) nitrate complexes of a tetraiminodiphenol macrocycle in the solid state and in solution.

The lanthanide(III) complexes [Ln(LH2)(NO3)3] 1-11(La-Er), 15(Y) and [Ln(LH2)(NO3)2(H2O)](NO3) 12-14 (Tm-Lu) of the tetraiminodiphenolate macrocycle L2- have been prepared by the transmetallation reaction between [Pb(LH2)(NO3)2] and Ln(NO3)3.nH2O. In these compounds, the uncoordinated imino nitrogens are protonated and are hydrogen bonded to the phenolate oxygens. The X-ray crystal structures of the La (1), Ho (10) and Lu (14) compounds have been determined. Compounds 1 and 10, in which all the three nitrates are bound in bidentate fashion, are isostructural with distorted bicapped square antiprism geometry for the metal centre. In [Lu(LH2)(NO3)2(H2O)](NO3) 14, of the two metal bound nitrates one is bidentate and the other is unidentate, while the metal centre obtains a distorted square antiprism coordination environment. Proton NMR spectra of the paramagnetic lanthanide complexes have been studied in detail. Contributions of contact and pseudo-contact shifts to the lanthanide induced isotropic shifts (LIS) of the macrocycle protons have been separated and good agreement has been obtained between the calculated LIS values and the experimentally observed values. Analysis of the NMR data has led us to conclude that all the complexes in dimethyl sulfoxide solution attain similar configurations. The absorption and emission spectral characteristic of several compounds have been investigated. The complexes of samarium (5) and europium (6) on photoexcitation at 400 nm exhibit well-resolved luminescence spectra at 77 K both in the solid state and a methanol-ethanol (1 : 4) glassy matrix. For the terbium (8) and dysprosium (9) complexes, however, the observed luminescence peaks are less resolved and weak in intensity.

Journal Article↗

PubMed2002

Extreme electronic modulation of the cofacial porphyrin structural motif.

The synthesis, electrochemistry, and optical spectroscopy of an extensive series of cofacial bis[(porphinato)zinc(II)] compounds are reported. These species were synthesized using sequential palladium-catalyzed cross-coupling and cobalt-mediated [2+2+2] cycloaddition reactions. This modular methodology enables facile control of the nature of macrocycle-to-macrocycle connectivity and allows unprecedented modulation of the redox properties of face-to-face porphyrin species. We report the synthesis of 5,6-bis[(5',5''-10',20'-bis[4-(3-methoxy-3-methylbutoxy)phenyl]porphinato)zinc(II)]indane (1), 5,6-bis[(2'-5',10',15',20'-tetraphenylporphinato)zinc(II)]indane (2), 5-([2'-5',10',15',20'-tetraphenylporphinato]zinc(II))-6-[(5"-10'',20''-bis[4-(3-methoxy-3-methylbutoxy)phenyl]porphinato)zinc(II)]indane (3), 5-([2'-5',10',15',20'-tetrakis(trifluoromethyl)porphinato]zinc(II))-6-[(5' '-10' ',20' '-bis[4-(3-methoxy-3-methylbutoxy)phenyl]porphinato)zinc(II)]indane (4), 5-(2'-5',10',15',20'-[tetrakis(trifluoromethyl)porphinato]zinc(II))-6-[(2''-5'',10'',15'',20''-tetraphenylporphinato)zinc(II)]indane (5), 5,6-bis([2'-5',15'-diphenyl-10',20'-(trifluoromethyl)porphinato]zinc(II))indane (6), and 5,6-bis([2'-5',10',15',20'-tetrakis(trifluoromethyl)porphinato]zinc(II))indane (7); 4-7 define the first examples of cofacial bis[(porphinato)metal] compounds in which sigma-electron-withdrawing perfluoroalkyl groups serve as macrocycle substituents, while 2, 6, and 7 constitute the first such structures that possess a beta-to-beta linkage topology. Cyclic voltammetric studies show that the electrochemically determined HOMO and LUMO energy levels of these cofacial bis(porphinato) complexes can be lowered by 780 and 945 mV, respectively, relative to the archetypal members of this class of compounds; importantly, these orbital energy levels can be modulated over well-defined increments throughout these wide potentiometric domains. Analyses of these cofacial bis[(porphinato)metal] potentiometric data, in terms of the absolute and relative frontier orbital energies of their constituent [porphinato]zinc(II) building blocks, as well as the nature of macrocycle-to-macrocycle connectivity, provide predictive electronic structural models that rationalize the redox behavior of these species.

Electrochemistry↗

PubMed2004

Calix[4]pyrrole Schiff base macrocycles. Novel binucleating ligands for mu-oxo iron complexes.

New bimetallic mu-oxo diferric complexes of several previously reported calix[4]pyrrole Schiff base macrocycles are described. The synthesis of a new member of this class of macrocycles is also reported; it was prepared via an acid-catalyzed condensation between 1,9-bisformyl-5,5-dipropyldipyrromethane and o-phenylenediamine. Reactions of the free base macrocycles or their bis-HCl salts with Fe(II) mesitylene, followed by air oxidation, gave the binuclear mu-oxo bis-Fe(III) compounds 6-10 in moderate yield. X-ray crystallography data reveal two different coordination environments for the Fe-O-Fe subunit in 6-10 that it is suggested can be controlled by altering the reaction conditions. Structural properties of these metalated pyrrolic macrocycles are also compared to those of mu-oxo diferric porphyrins and mu-oxo diferric texaphyrin. Complexes 6-10 exhibit two distinct types of M-N bonds that are similar in length to the bonds observed in metallotexaphyrin complexes. However, the electronics of the present systems are very different from those of texaphyrins and porphyrins in that no delocalized bonding patterns are observed within the ligands as a whole.

Benzene Derivatives↗

PubMed1986

Metabolism and toxicity of synthetic analogues of macrocyclic diester pyrrolizidine alkaloids.

Seven macrocyclic diesters analogous to hepatotoxic pyrrolizidine alkaloids have been tested in male weanling Wistar rats. The compounds were the succinate (VII), 2,3-dimethylsuccinate (VIII), phthalate (IX), glutarate (X), 2,4-dimethylglutarate (XI), 3,3-dimethylglutarate (XII) and 3,3-pentamethyleneglutarate (XIII) of the synthetic amino dialcohol, synthanecine A. Single doses of these compounds were given i.p. to rats, and liver levels of pyrrolic metabolites were measured 2 h later. For these experiments both normal rats and rats pretreated with the esterase inhibitor tri-orthocresylphosphate (TOCP) were used. In normal rats, low levels of pyrrolic metabolites were formed from compounds VII, IX, X and XI, but these levels were greatly enhanced in rats with inhibited esterase activity. Much higher pyrrole levels were formed from compounds VIII, XII and XIII in normal rats, and esterase inhibition had relatively little effect on their metabolic conversion to pyrroles. This indicated that the last mentioned compounds were relatively resistant to enzymic hydrolysis, whereas VII, IX, X and XI were easily hydrolysed in normal rats, providing an alternative metabolic path which limited their conversion to pyrrolic metabolites. Comparison of results obtained using the 2,4-dimethylglutarate (XI), the 3,3-dimethylglutarate (XII) and the 3,3,-pentamethyleneglutarate (XIII) showed that 3,3-disubstitution but not 2,4-disubstitution in the glutaric acid moiety conferred high resistance to esterase attack. Toxicity tests using four of the compounds confirmed that acute hepatotoxicity was dose related, and associated with the formation of pyrrolic metabolites in the liver. The 3,3-dimethylglutarate (XII) was highly toxic both in normal and in TOCP treated rats, doses of 25-30 mg/kg causing moderate to severe centrilobular necrosis of the liver. In contrast the toxicity of the unsubstituted succinate (VII), glutarate (X) and 2,4-dimethylglutarate (XI) was very low in normal rats but high in rats with inhibited esterase activity. Thus, the glutarate (X) was non-toxic at 200 mg/kg in normal rats, but in TOCP treated rats, in which pyrrolic metabolite formation was enhanced by a factor of 17.5, a 50 mg/kg dose of this compound was severely hepatotoxic. Kidney damage, which was generally limited to the presence of isolated necrotic cells, sometimes accompanied the liver damage caused by these compounds, but acute toxic effects were not observed in any other tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2003

Synthesis and characterization of a macrocyclic near-infrared optical scaffold.

Macrocyclization of a bioactive peptide with a bifunctional near-infrared fluorescent optical probe gives a compound that retained the receptor binding affinity of the peptide and the photophysical properties of the optical probe. The robust nature of the new compound provides a structural framework for optimizing the activity of bioactive molecules and for monitoring chemical or biological processes in vivo and in vitro by near-infrared optical methods.

Cyclization↗

PubMed2003

Disposition of doramectin milk residues in lactating dairy sheep.

Doramectin (DRM) is a broad spectrum macrocyclic lactone antiparasitic drug not approved for use in dairy animals. However, DRM and other endectocide compounds are widely used extra-label to control endo- and ectoparasites in dairy sheep. The plasma disposition kinetics and the pattern of DRM excretion in milk were characterized following its subcutaneous administration to lactating dairy sheep. DRM concentration profiles were measured in plasma and milk samples after validation of a specific HPLC-based methodology. DRM was detected between 1 h and 30 days post-treatment. DRM concentrations of 0.48 ng.mL(-1) (plasma) and 1.03 ng.mL(-1) (milk) were measured at 30 days post-treatment. DRM was extensively distributed from the bloodstream to the mammary gland, and large concentrations were excreted in milk. The peak concentrations and total amount of DRM recovered in milk (expressed as area under the concentration versus time curve) were 3-fold higher than those measured in plasma; 2.44% of the total DRM dose was excreted in milk. The long persistence of DRM milk residues should be seriously considered before its extra-label use in dairy animals is recommended.

Animals↗

PubMed2003

Three new jatrophane-type diterpenes from Euphorbia pubescens.

Three new macrocyclic jatrophane diterpene polyesters, named pubescenes A ( 1), B ( 2), and C ( 3), and the known compounds indole-3-aldehyde and scopoletin have been isolated and characterised from the whole dried plant of Euphorbia pubescens. The structures of the new compounds were established by spectroscopic means including 2D-NMR techniques such as COSY, HMQC, HMBC and NOESY experiments. Compounds 1 - 3 were evaluated for their in vitro effect on the growth of three human cancer cell lines MCF-7 (breast), NCI-H460 (lung) and SF-268 (CNS) as well as for their capacity to interfere with the proliferation of human peripheral blood lymphocytes. They exhibited a moderate growth inhibitory effect on the cancer cell line NCI-H460. No effect was observed on the mitogenic response of human lymphocytes to PHA.

Antineoplastic Agents↗

PubMed1994

Integrin alpha v beta 3 differentially regulates adhesive and phagocytic functions of the fibronectin receptor alpha 5 beta 1.

The plasma protein fibronectin is an important opsonin in wound repair and host defense. To better understand the process of fibronectin-mediated phagocytosis, we have transfected K562 cells, which endogenously express alpha 5 beta 1, with alpha v beta 3. In these transfectants, antibodies to alpha v beta 3 block phagocytosis of fibronectin-opsonized beads completely, even though half the ingestion occurs through endogenous alpha 5 beta 1 receptors. alpha 5 beta 1-mediated adhesion to fibronectin-coated surfaces is unaffected by alpha v beta 3 ligation. Neither alpha v beta 5 nor alpha M beta 2 ligation affects alpha 5 beta 1 phagocytic function in transfectants expressing these receptors. Pharmacologic data suggest that alpha v beta 3 ligation suppresses the phagocytic competence of high affinity alpha 5 beta 1 receptors through a signal transduction pathway, perhaps involving protein kinase C. In addition to its significance for phagocytosis, alpha v beta 3 regulation of alpha 5 beta 1 function may be significant for its roles in cell migration, metastasis, and angiogenesis.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2003

The CoIII-C bond in (1-thia-4,7-diazacyclodecyl-kappa3N4,N7,C10)(1,4,7-triazacyclononane-kappa3N1,N4,N7)cobalt(III) dithionate hydrate.

In the title compound, [Co(C(6)H(15)N(3))(C(7)H(15)N(2)S)]S(2)O(6).H(2)O, the Co-C bond distance is 1.9930 (13) A, which is shorter than for related compounds with the linear 1,6-diamino-3-thiahexan-4-ide anion in place of the macrocyclic 1-thia-4,7-diazacyclodecan-8-ide anion. The coordinated carbanion produces an elongation of 0.102 (7) A of the Co-N bond to the 1,4,7-triazacyclononane N atom in the trans position. This relatively small trans influence is presumably a result of the triamine ligand forming strong bonds to the Co(III) atom.

Journal Article↗

PubMed1996

Lutetium texaphyrin (PCI-0123): a near-infrared, water-soluble photosensitizer.

Lutetium texaphyrin, PCI-0123, is a pure, water-soluble photosensitizer with a large broad absorption band centered at 732 nm. The compound was tested for photodynamic therapy (PDT) effectiveness in a murine mammary cancer model. The texaphyrin macrocycle as illustrated by magnetic resonance imaging and 14C-radiolabeled texaphyrin studies was shown to be tumor selective; a tumor-to-muscle ratio of 10.55 was seen after 5 h. Lutetium texaphyrin, at a drug dose of 20 mumol/kg with irradiation 5 h postinjection at 150 J/cm2 and 150 mW/cm2, had significant efficacy (P < 0.0001) in treating neoplasms of moderate size (40 +/- 14 mm3) and also had significant efficacy (P < 0.0001) in treating larger neoplasms (147 +/- 68 mm3). The PDT efficacy was correlated with the time interval between PCI-0123 administration and light exposure. A 100% cure rate was achieved when photoirradiation took place 3 h postinjection compared to 50% for 5 h using 10 mumol/kg and 150 J/cm2 at 150 mW/cm2. The PDT efficacy was attributable to the selective uptake/retention of the texaphyrin photosensitizer in addition to the depth of light penetration achievable at the 732 nm laser irradiation.

Animals↗

PubMed1999

Unusual antimicrotubule activity of the antifungal agent spongistatin 1.

Spongistatin 1, a macrocyclic lactone from the marine sponge Hyrtios erecta, has broad-spectrum antifungal activity. Since this compound is a potent antimicrotubule agent in mammalian cells, we examined its effects on the filamentous fungus Aspergillus nidulans to determine if its antifungal effects are due to antimicrotubule activity. At 25 microg/ml (twice the MIC), spongistatin 1 caused a greater-than-twofold elevation of the chromosome and spindle mitotic indices. Immunofluorescence microscopy revealed that mitotic spindles were smaller and shorter than in control germlings. However, late-anaphase and telophase nuclei were seen occasionally, and this suggests that the spindles are capable of segregating chromosomes. Spongistatin 1 had more dramatic effects on cytoplasmic microtubules. At 30 min after initiation of treatment, 83% of germlings contained fragmented microtubules and after 2 h of treatment, microtubules had disappeared completely from 82% of germlings. In contrast, microtubules disappeared rapidly and completely from germlings treated with benomyl. We conclude that spongistatin 1 has antimicrotubule activity in A. nidulans and that its mechanism of action may involve a novel microtubule-severing activity.

Antifungal Agents↗

PubMed2005

Tungstate-induced color-pattern modifications of butterfly wings are independent of stress response and ecdysteroid effect.

Systemic injections of sodium tungstate, a protein-tyrosine phosphatase (PTPase) inhibitor, to pupae immediately after pupation have been shown to efficiently produce characteristic color-pattern modifications on the wings of many species of butterflies. Here we demonstrated that the tungstate-induced modification pattern was entirely different from other chemically-induced ones in a species of nymphalid butterfly Junonia (Precis) orithya. In this species, the systemic injections of tungstate produced characteristic expansion of black area and shrinkage of white area together with the move of parafocal elements toward the wing base. Overall, pattern boundaries became obscure. In contrast, an entirely different modification pattern, overall darkening of wings, was observed by the injections of stress-inducing chemicals, thapsigargin, ionomycin, or geldanamycin, to pupae under the rearing conditions for the adult summer form. On the ventral wings, this darkening was due to an increase of the proportion of peppered dark scales, which was reminiscent of the natural fall form of this species. Under the same rearing conditions, the injections of ecdysteroid, which is a well-known hormone being responsible for the seasonal polyphenism of nymphalid butterflies, yielded overall expansion of orange area especially around eyespots. Taken together, we conclude that the tungstate-induced modifications are clearly distinguishable from those of stress response and ecdysteroid effect. This conclusion then suggests that the putative PTPase signaling pathway that is sensitive to tungstate uniquely contributes to the wing-wide color-pattern development in butterflies.

Animals↗

PubMed1995

Herbimycin A inhibits phorbol ester-induced morphologic changes, adhesion, and megakaryocytic differentiation of the leukemia cell line, MEG-01.

12-O-Tetradecanoylphorbol 13-acetate (TPA) induces rapid changes in the morphology of the human megakaryoblastic leukemia cell line, MEG-01, as well as changes in adhesion and megakaryocytic differentiation. To investigate the signal transduction pathway of these three phenomena, we studied the effect of herbimycin A, an inhibitor of tyrosine kinase (TK) and the effects of calphostin C, a specific inhibitor protein kinase C (PKC) on TPA treated MEG-01 cells. Both herbimycin A and calphostin C inhibited all three TPA-induced phenomena, suggesting that both pathways are required for these phenomena. Herbimycin A but not calphostin C blocked the tyrosine phosphorylation of cellular proteins. Immunohistochemical staining of PKC using an anti-PKC monoclonal antibody showed that herbimycin A did not interfere with the translocation and subsequent down regulation of PKC induced by TPA, suggesting that the TPA-induced effect on PKC (translocation and probably its activation) is not dependent on TK. Induction of c-fos and c-jun expression by TPA was inhibited by both herbimycin A and calphostin C, suggesting that both PKC and TK pathways are necessary for the induction of the TPA-induced transcription factor AP1, which is a known TPA-inducible early immediate gene product. Taken together, our results show that the tyrosine kinase signal transduction system as well as the PKC pathway is indispensable for the TPA-induced phenomena of morphologic change, cell attachment, early immediate gene expression, and lineage-specific phenotypic expression in the MEG-01 cell line.

Benzoquinones↗

PubMed1991

Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors.

Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65 microM, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.

Amino Acid Sequence↗