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PubMed1999

FK506 and the role of the immunophilin FKBP-52 in nerve regeneration.

In summary, FKBP-12 does not mediate the neurite outgrowth-promoting properties of neuroimmunophilin ligands (e.g., FK506). Instead, the neurotrophic properties of neuroimmunophilin ligands (FK506) and steroid hormones are mediated by disruption of steroid-receptor complexes. It remains unclear which component mediates neurite outgrowth, although the most likely candidates are FKBP-52, hsp-90, and p23 [42]. Regardless of the underlying mechanism involved, the FKBP-52 antibody data reveal that it should be possible to design, based on the structure of FK506, non-FKBP-12-binding (nonimmunosuppressant) compounds selective for FKBP-52 and test these new libraries for their ability to augment nerve regeneration. It may also be possible to exploit the structure of geldanamycin to develop a new class of hsp-90-binding compounds for use in nerve regeneration.

Animals↗
PubMed2006

Effect of N-methylation of macrocyclic amine ligands on the spin state of iron(III): a tale of two fluoro complexes.

Syntheses and characterization of [(cyclamacetate)FeF]PF6 (1) and the corresponding N-methylated complex [(trimethylcyclamacetate)FeF]PF6 (3) are presented. Compound 1 is prepared in good yields from the analogous chloro complex, whereas 3 is prepared by hydrolysis of the oxo-bridged diiron compound (Me3cyclam-acetate)Fe-O-FeCl3 (2) in the presence of PF(6) anions. Magnetic susceptibility and spectroscopic data including electron paramagnetic resonance and Mössbauer spectra indicate that 1 contains low-spin Fe(III) (S = 1/2), while 3 is high spin (S = 5/2). Both octahedral fluoro complexes were investigated theoretically by density functional theory in order to determine why the spin states of the two molecules are different. Energies calculated using the B3LYP functional correctly predict 1 to have a low-spin S = 1/2 ground state and 3 to be high spin, regardless of whether a solvation model is included. The difference between 1 and 3 is most likely a combination of steric effects caused by the N-methyl groups, which compel the Fe-N bond distances to be longer in 3 than they ordinarily would be, and also electronic effects, which cause the N-methylated ligand to be a weaker sigma donor than its nonmethylated counterpart.

Amines↗
PubMed1989

Comparison of the toxicity of two trichothecenes applied topically to brain and liver of rats.

T-2 toxin has been found previously to be markedly more toxic upon intracerebral than upon systemic administration. In order to study the generality of this difference, we have applied to brain and liver of albino rats two different types of trichothecenes: T-2 toxin as a representative of 'simple' and myrotoxin B as a representative of 'macrocyclic' members of this series. Myrotoxin B, when applied intracerebrally, was about 100 times more poisonous than T-2 toxin. In contrast, upon intrahepatic injection both compounds exhibited similar degrees of toxicity. The different behavior of the two trichothecenes in the organs tested may be due to local metabolic factors.

Animals↗
PubMed2005

Identification of synthetic compounds active against VRE: the role of the lipidated aminoglucose and the structure of glycopeptide binding pocket.

A modified vancomycin binding pocket (D-O-E ring) incorporating an alpha-hydroxy-beta-amino acid at the AA4 position is designed and synthesized. Some of these compounds display potent bioactivities against both sensitive- and resistant-strains (8 microg/ml against VREF). Both the lipidated aminoglucose and the structure of the 16-membered macrocycle are found to be important for the anti-VRE activities. The polyamine appendage at the C-terminal, on the other hand, improved the activity against vancomycin-sensitive strains.

Anti-Bacterial Agents↗
PubMed2001

Cobalt(III) complexes of [3(5)] adamanzane, 1,5,9,13-tetraazabicyclo[7.7.3]nonadecane. Report of an inert, chelate hydrogen carbonate ion.

Three cobalt(III) complexes of the macrocyclic tetraamine [3(5)]adamanzane (1,5,9,13-tetraazabicyclo[7.7.3]nonadecane) were isolated as salts. The X-ray crystal structures were solved for the compounds [Co([3(5)]adz)(CO(3))]AsF(6) (1b), [Co([3(5)]adz)(HCO(3))]ZnBr(4).H(2)O (2a), and [Co([3(5)]adz)(SO(4))]AsF(6).H(2)O (3a). The coordination geometry around the cobalt(III) ion is a distorted octahedron with the inorganic ligands at cis-positions. Complex 2 is the second example of a cobalt(III) complex for which the X-ray structure shows a chelate binding mode of the hydrogen carbonate entity. The pK(a) value of the [Co([3(5)]adz)(HCO(3))](2+) ion (2) was determined spectrophotometrically to be 0.27 (25 degrees C, I = 5.0 M). The protonation appears to occur at the noncoordinated carbonyl oxygen atom of the carbonate group, with hydrogen bonding to the crystal water molecule. Evidence is presented for this oxygen atom as the site of protonation in solution as well. In 5.0 M CF(3)SO(3)H a slow reaction of the carbonato complex, quantitatively yielding the [Co([3(5)]adz)(H(2)O)(2)](3+) ion, was observed. k(obs) = 7.9(1) x 10(-)(6) s(-)(1) at 25 degrees C.

Journal Article↗
PubMed1998

The Intra- and Intermolecular Oxidative Coupling of Ni(II)-meso-Octaethyl Mono(pyridine)-Tris(pyrrole) Complex Leading to C-C Bonds: Pathways to Oligomeric Porphyrinogens.

This paper reports the oxidative transformations of the unprecedented meso-octaalkyl mono(pyridine)-tris(pyrrole) macrocycle [Et(8)(C(5)H(3)N)(C(4)H(2)NH)(3)], 1, which was obtained by a homologation of the corresponding porphyrinogen, [Et(8)(C(4)H(2)NH)(4)], A. The metallation of 1 was obtained via its deprotonation with LiBu, followed by the reaction with MCl(2).thf(n)(), leading to the bimetallic complexes: [Et(8)(C(5)H(3)N)(C(4)H(2)N)(3)M{Li(thf)(2)}] [M = Fe, 3; M = Co, 4; M = Ni, 6; M = Cu, 7]. The cobalt derivative occurs also in the separated ion-pair form [Et(8)(C(5)H(3)N)(C(4)H(2)N)(3)Co](-)[{Li(thf)(4)}](+), 5. The reaction of 4 and 6 with an excess of Cp(2)FeBPh(4) led to the oxidation of the macrocycle with the formation of a cyclopropane functionality [Et(8)(C(5)H(3)N){(C(4)H(2)N)(3)(Delta)}Ni](+)BPh(4)(-), 8. The cyclopropane unit underwent reductive cleavage back to the initial macrocycle using lithium metal. The use of a Ni/Cp(2)Fe(+) 1:1 ratio allowed the identification of a dimer derived formally from the monoelectronic oxidation of the macrocycle 1, which formed a radical coupling to 9, [Et(8)(C(5)H(3)N)(C(4)H(2)N)(3)Ni](2). The same compound formed from a disproportionation redox reaction occurring between 6 and 8. The C-C bond across the two metallamacrocycles involved the beta position of the pyrrole. Deprotonation of 9 by LiBu led to a dianionic form 10 [Et(8)(C(5)H(3)N)(C(4)H(2)N)(3)Ni{Li(thf)(2)}]. The formation of the cyclopropane functionality was also achieved via the oxidation of [Et(8)(C(5)H(3)N)(C(4)H(2)N)(3)Li(3)(thf)(2)}], 2, forming [Et(8)(C(5)H(3)N){(C(4)H(2)N)(3)(Delta)}Li(thf)], 11, which was ready to be used in metallation reaction. The proposed structures were supported by X-ray analyses on 4, 7, 8, 9, and 11.

Journal Article↗
PubMed2005

Catalytically active mu-Oxodiiron(IV) oxidants from Iron(III) and dioxygen.

The reaction between an Fe(III) complex and O(2) to afford a stable catalytically active diiron(IV)-mu-oxo compound is described. Phosphonium salts of orange five-coordinated Fe(III)-TAML complexes with an axial aqua ligand ([PPh(4)]1-H(2)O, tetraamidato macrocyclic Fe(III) species derived from 3,3,6,6,9,9-hexamethyl-3,4,8,9-tetrahydro-1H-1,4,8,11-benzotetraazacyclotridecine-2,5,7,10(6H,11H)-tetraone) react rapidly with O(2) in CH(2)Cl(2) or other weakly coordinating solvents to produce black mu-oxo-bridged diiron(IV) complexes, 2, in high yields. Complexes 2 have been characterized by X-ray crystallography (2 cases), microanalytical data, mass spectrometry, UV/Vis, Mossbauer, and (1)H NMR spectroscopies. Mossbauer data show that the diamagnetic Fe-O-Fe unit contains antiferromagnetically coupled S = 1 Fe(IV) sites; diamagnetic (1)H NMR spectra are observed. The oxidation of PPh(3) to OPPh(3) by 2 was confirmed by UV/Vis and GC-MS. Labeling experiments with (18)O(2) and H(2)(18)O established that the bridging oxygen atom of 2 derives from O(2). Complexes 2 catalyze the selective oxidation of benzylic alcohols into the corresponding aldehydes and bleach rapidly organic dyes, such as Orange II in MeCN-H(2)O mixtures; reactivity evidence suggests that free radical autoxidation is not involved. This work highlights a promising development for the advancement of green oxidation technology, as O(2) is an abundant, clean, and inexpensive oxidizing agent.

Journal Article↗
PubMed2006

Rotaxanes with fluorocarbon blocking groups.

A novel [2]-rotaxane has been prepared in which perfluoropropyl stoppers have been utilized as electronic blocking groups. To further investigate this capability, a linear compound that was precapped with perfluoropropyl groups was also prepared. This compound did not demonstrate rotaxane formation when mixed with dibenzo-24-crown-8, providing further evidence that the perfluoropropyl groups were effective electronic stoppers for the macrocycle. [structure: see text]

Crown Ethers↗
PubMed2004

Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors.

The development of therapeutic inhibitors of key signaling pathways has been hampered by the inability to assess the effect of a drug on its target in the patient. 17-allylaminogeldanamycin (17-AAG) is the first Hsp90 inhibitor to be tested in a clinical trial. It causes the degradation of HER2 and other Hsp90 targets, and has antitumor activity in preclinical models. We have developed a method for imaging the inhibition of Hsp90 by 17-AAG. We labeled an F(ab')2 fragment of the anti-HER2 antibody Herceptin with 68Ga, a positron emitter, which allows the sequential positron-emission tomographic imaging of HER2 expression. We have used this method to quantify as a function of time the loss and recovery of HER2 induced by 17-AAG in animal tumors. This approach allows noninvasive imaging of the pharmacodynamics of a targeted drug and will facilitate the rational design of combination therapy based on target inhibition.

Animals↗
PubMedDate not supplied

Molecular recognition of quadruplex DNA by quinacridine derivatives.

The interaction of monomeric and dimeric quinacridines with quadruplex DNA has been investigated using a variety of biophysical methods. Both series of compounds were shown to exhibit a high affinity for the G4 conformation with two equivalent binding sites. As shown from the SPR and dialysis experiments the macrocyclic dimer appears more selective than its monomeric counterpart.

Base Sequence↗
PubMed1998

Involvement of the tyrosine phosphorylation pathway in induction of human heme oxygenase-1 by hemin, sodium arsenite, and cadmium chloride.

The effect of a tyrosine kinase inhibitor, herbimycin A, on the induction of heme oxygenase-1 (HO-1) mRNA in HeLa cells upon exposure to hemin, sodium arsenite and cadmium chloride was examined. The induction of HO-1 mRNA by hemin was inhibited when the cells were pretreated with herbimycin A. Herbimycin also inhibited arsenite- and cadmium-dependent induction of HO-1 mRNA in a dose-dependent manner, but less inhibition was observed in cadmium-treated cells than in ones treated with hemin- or arsenite. Genistein (50 microM), another tyrosine kinase inhibitor, also inhibited the induction of HO-1 mRNA by hemin, arsenite, and cadmium. Nuclear runoff assays revealed that herbimycin blocked the hemin-induced transcription of the HO-1 gene. The induction of HO-1 mRNA by hemin in human peripheral blood mononuclear cells was inhibited by herbimycin. The tyrosine phosphorylation of a protein with a molecular mass of 66 kDa in the cells was increased by hemin- or arsenite-treatment, and this increase was inhibited by treatment with 5 microM herbimycin. When HeLa cells were treated with a specific inhibitor of the mitogen-activated protein kinase (MAPK)/extracellular-signal regulated kinase cascade, PD58059 (100 microM), suppression of the cadmium-dependent HO-1 induction was not observed, but the hemin- or arsenite-dependent induction was slightly inhibited. SB203580, an inhibitor of p38 MAPK, did not affect the HO-1 induction. These results indicated that signal transduction involving tyrosine kinase rather than the MAPK family regulates the induction of human HO-1 gene expression by stress inducers.

Arsenites↗
PubMed1998

Effects of macrocyclic lactones on ingestion in susceptible and resistant Haemonchus contortus larvae.

The effects of ivermectin and ivermectin aglycone on pharyngeal uptake of a carbohydrate substrate (3H-inulin) were measured in larvae of a macrocyclic lactone (ML)-susceptible isolate and 2 ML-resistant isolates of Haemonchus contortus. The resistant isolates showed a tolerance (in terms of the concentration of compound required to reduce feeding to 50%) toward ivermectin of approximately 4.5- and 9-fold and toward ivermectin aglycone of approximately 14-fold, compared to the susceptible isolate. This indicates that susceptible and resistant isolates can be readily distinguished on the basis of the sensitivity of pharyngeal uptake to MLs. The use of various metabolic inhibitors in this assay system did not reveal the nature of the resistance mechanism. Pretreatment of resistant larvae with inhibitors of multidrug resistance mechanisms (P-glycoprotein and multidrug resistance protein) and detoxification enzymes (monooxygenases, esterases, and glutathione transferases) did not reduce their level of tolerance to the ivermectin aglycone.

Animals↗
PubMed2006

Dinuclear cyano-bridged CoIII-FeII complexes as precursors for molecular mixed-valence complexes of higher nuclearity.

The preparation and characterization of a series of trinuclear mixed-valence cyano-bridged Co(III)-Fe(II)-Co(III) compounds derived from known dinuclear [[L(n)Co(III)(mu-NC)]Fe(II)(CN)(5)](-) complexes (L(n)() = N(5) or N(3)S(2) n-membered pendant amine macrocycle) are presented. All of the new trinuclear complexes were fully characterized spectroscopically (UV-vis, IR, and (13)C NMR). Complexes exhibiting a trans and cis arrangement of the Co-Fe-Co units around the [Fe(CN)(6)](4-) center are described (i.e., cis/trans-[{L(n)Co(III)(mu-NC)](2)Fe(II)(CN)(4)](2+)), and some of their structures are determined by X-ray crystallography. Electrochemical experiments revealed an expected anodic shift of the Fe(III/II) redox potential upon addition of a tripositively charged [Co(III)L(n)] moiety. The Co(III/II) redox potentials do not change greatly from the di- to the trinuclear complex, but rather behave in a fully independent and noncooperative way. In this respect, the energies and extinction coefficients of the MMCT bands agree with the formal existence of two mixed-valence Fe(II)-CN-Co(III) units per molecule. Solvatochromic experiments also indicated that the MMCT band of these compounds behaves as expected for a class II mixed-valence complex. Nevertheless, its extinction coefficient is dramatically increased upon increasing the solvent donor number.

Journal Article↗
PubMed2001

Crown compounds for anions: sandwich and half-sandwich complexes of cyclic trimetric perfluoro-o-phenylenemercury with polyhedral closo-[B10H10]2- and closo-[B12H12]2- anions.

It has been shown by IR and NMR spectroscopy that cyclic trimeric perfluoro-o-phenylenemercury (o-C6F4-Hg)3 (1) is capable of binding closo-[B10H10]2- and closo-[B12H12]2- anions to form complexes [[(o-C6F4Hg)3](B10-H10)]2- (2), [[(o-C6F4Hg)3]2(B10H10)]2-(3), [[(o-C6F4Hg)3](B12H12)]2- (4), and [[(o-C6F4Hg)3]2(B12H12)]2- (5). According to IR data, the bonding of the [B10H10]2- and [B12H12]2- ions to the macrocycle in these complexes is accomplished through the formation of B-H-Hg bridges. Complexes 2, 3, and 5 have been isolated in analytically pure form and have been characterized by spectroscopic means. X-ray diffraction studies of 3 and 5 have revealed that these compounds have unusual sandwich structures, in which the polyhedral di-anion is located between the planes of two molecules of 1 and is bonded to each of them through two types of B-H-Hg bridges. One type is the simultaneous coordination of a B-H group to all three Hg atoms of the macrocycle. The other type is the coordination of a B-H group to a single Hg atom of the cycle. According to X-ray diffraction data, complex 2 has an analogous but half-sandwich structure. The obtained complexes 2-5 are quite stable; their stability constants in THF/acetone (1:1) at 20 degrees C have been determined as 1.0 x 10(2)Lmol(-1), 2.6 x 10(3)L(2)mol(2), 0.7 x 10(2)Lmol(-1), and 0.98 x 10(3)L(2)mol(-2), respectively.

Journal Article↗
PubMed2000

A systematic evaluation of molecular recognition phenomena. 1. Interaction between phosphates and nucleotides with hexaazamacrocyclic ligands containing m-xylylic spacers.

The host-guest interactions between ortho- (Ph), pyro- (Pp), and tripolyphosphate (Tr) anions together with ATP (At), ADP (Ad), and AMP (Am) nucleotides and the hexaazamacrocyclic ligand 3,7,11,19,23,27-hexaazatricyclo[27311(13,17)]triaconta- 1(32),13,15,17(34),29(33),30-hexaene (Bn) have been investigated by potentiometric equilibrium methods. Ternary complexes are formed in aqueous solution as a result of hydrogen bond formation and Coulombic attraction between the host and the guest. Formation constants for all the species obtained are reported. The selectivity of the Bn ligand with regard to the phosphate and nucleotide substrates is discussed and illustrated with species distribution diagrams. A comparison of the present results with those obtained for the similar but smaller macrocyclic ligand 3,6,9,17,20,23- hexaazatricyclo[23311(11,15)]triaconta-1(29),11(30),12,14,25,27-hexaene (Bd) is also discussed. It is found that the competition of the Bd and Bn ligands for the formation of ternary species with a specific substrate is strongly dependent on the p[H]. The crystal structure of the compound [(H6Bn)(H2PO4)6]2H2O with empirical formula C28H68N6O26P6 has been solved by means of X-ray diffraction analysis. The compound belongs to the triclinic P1 space group with Z = 1, a = 8892(2) A, b = 9369(4) A, c = 16337(8) A, alpha = 7372(4) degrees, beta = 8301(4) degrees, and gamma = 6481(3) degrees. The phosphate counterions are found to bridge adjacent layers of macrocyclic molecules through an extensive hydrogen-bonding network

Journal Article↗
PubMed2007

Controlled metalation of self-assembled porphyrin nanoarrays in two dimensions.

We report a bottom-up approach for the fabrication of metallo-porphyrin compounds and nanoarchitectures in two dimensions. Scanning tunneling microscopy and tunneling spectroscopy observations elucidate the interaction of highly regular porphyrin layers self-assembled on a Ag(111) surface with iron monomers supplied by an atomic beam. The Fe is shown to be incorporated selectively in the porphyrin macrocycle whereby the template structure is strictly preserved. The immobilization of the molecular reactants allows the identification of single metalation events in a novel reaction scheme. Because the template layers provide extended arrays of reaction sites, superlattices of coordinatively unsaturated and magnetically active metal centers are obtained. This approach offers novel pathways to realize metallo-porphyrin compounds, low-dimensional metal-organic architectures and patterned surfaces which cannot be achieved by conventional means.

Metalloporphyrins↗