Crystal structure of {4-[10,15,20-tris-(4-meth-oxy-phen-yl)porphyrin-5-yl]benzyl 2-diazo-acetato}-zinc(II).

In the title compound, [Zn(C50H36N6O5)], the ZnII cation is chelated by four pyrrole N atoms of the porphyrinate anion and coordinated by a symmetry-generated keto O atom of the diazo-ester group in a distorted square-pyramidal geometry. The mean Zn-N(pyrrole) bond length is 2.058 Šand the Zn-O(diazo-ester) bond length is 2.179 (4) Å. The zinc cation is displaced by 0.2202 (13) Šfrom the N4C20 mean plane of the porphyrinate anion toward the O atom; the involvement of this atom leads to a [100] polymeric chain in the crystal.

Halterman Corroles and Their Use as a Probe of the Conformational Dynamics of the Inherently Chiral Copper Corrole Chromophore.

Halterman corroles have been synthesized for the first time from pyrrole and Halterman's aldehyde via Gryko's "water-methanol method". These were derivatized to the corresponding copper complexes and subsequently to the ß-octabromo complexes. Electronic circular dichroism spectra were recorded for the enantiopure copper complexes, affording the first such measurements for the inherently chiral Cu corrole chromophore. Interestingly, for a given configuration of the Halterman substituents, X-ray crystallographic studies revealed both P and M conformations of the Cu-corrole core, proving that the substituents, even in conjunction with ß-octabromination, are unable to lock the Cu-corrole core into a given chirality. The overall body of evidence strongly indicates a dynamic equilibrium between the P and M conformations. Such an interconversion, which presumably proceeds via saddling inversion, provides a rationale for our failure so far to resolve sterically hindered Cu corroles into their constituent enantiomers by means of chiral HPLC.

Crystal structure of di-aqua-[5,10,15,20-tetra-kis-(4-bromo-phen-yl)porphyrinato-κ(4) N]magnesium.

The title compound, [Mg(C44H24Br4N4)(H2O)2] or [Mg(TBrPP)(H2O)2], where TBrPP is the 5,10,15,20-tetra-kis-(4-bromo-phen-yl)porphyrinato ligand, was obtained unintentionally as a by-product of the reaction of the [Mg(TBrPP)] complex with an excess of di-methyl-glyoxime in di-chloro-methane. The entire mol-ecule exhibits point group symmetry 4/m. In the asymmetric unit, except for two C atoms of the phenyl ring, all other atoms lie on special positions. The Mg(II) atom is situated at a site with symmetry 4/m, while the N and the C atoms of the porphyrin macrocycle, as well as two C atoms of the phenyl ring and the Br atom lie in the mirror plane containing the porphyrin core. The H atoms of the axially bonded water mol-ecule are incompatible with the fourfold rotation axis and are disordered over two sites. In the crystal, mol-ecules are packed in rows along [001]. Weak inter-molecular C-H⋯π and C-H⋯Br inter-actions, as well as O-H⋯Br hydrogen bonds, stabilize the crystal packing.

Enantioselective manganese-porphyrin-catalyzed epoxidation and C-H hydroxylation with hydrogen peroxide in water/methanol solutions.

The asymmetric epoxidation of alkene and hydroxylation of arylalkane derivatives by H(2)O(2) to give optically active epoxides (enantiomeric excess (ee) up to 68%) and alcohols (ee up to 57%), respectively, were carried out in water/methanol solutions using chiral water-soluble manganese porphyrins as catalysts.

Dynamics of heme in hemoproteins: proton NMR study of myoglobin reconstituted with iron 3-ethyl-2-methylporphyrin.

The asymmetric 3-ethyl-2-methylporphyrin iron complex was synthetized and inserted into apomyoglobin. UV-visible spectroscopic studies demonstrated the capacity of iron to coordinate different exogenous axial ligands in ferrous and ferric forms. The position of synthetic heme into the hydrophobic pocket of the reconstituted myoglobin was investigated by ((1))H NMR spectroscopy. In absence of exogenous ligand, signals of the synthetic prosthetic group were not detected, suggesting a rotational disorder of the synthetic porphyrin into the heme pocket. This direct interconversion behavior is favored since site-specific interactions between the poorly substituted heme and protein in the chiral hydrophobic cavity were weak. Complexion of cyanide to the iron allowed to quench partially the heme reorientation and two interconvertible forms, around the meso-Cα-Cγ axis, were detected in solution.

First enantioselective iron-porphyrin-catalyzed sulfide oxidation with aqueous hydrogen peroxide.

The asymmetric oxidation of sulfides by H(2)O(2) to give optically active sulfoxides (ee up to 90%) was carried out in methanol and water using chiral water-soluble iron porphyrins as catalysts.

Direct electron transfer of hemoglobin and myoglobin at the bare glassy carbon electrode in an aqueous BMI.BF4 ionic-liquid mixture.

Direct and remarkably fast electron transfers between a bare glassy carbon electrode and heme proteins (hemoglobin or myoglobin) are obtained by using an aqueous 1-butyl-3-methyl imidazolium tetrafluoroborate (BMI.BF(4)) ionic-liquid mixture as electrolyte. The ionic liquid is observed to play a key role in the achievement of the electron transfer. The experimental data show that the proteins are not strongly adsorbed onto the electrode surface while giving rise to sharp and well-defined redox responses. Such a finding contrasts with most of the reported works found in literature and-beyond the fundamental aspect--it may be of interest in applications where adsorption is critical. Moreover, the electrocatalytic activity of the proteins toward the reduction of oxygen and nitrite in the aqueous BMI.BF(4) mixture is evidenced, showing the potential of this simple approach for bioelectroanalytical devices.

Self-assembled molecular wires from organoiron metalloligands and ruthenium tetramesitylporphyrin.

A trinuclear assembly of two (η(2)-dppe)(η(5)-C(5)Me(5))FeC≡C(4-Py) (Py = pyridyl) metalloligands apically coordinated to a ruthenium(II) tetramesitylporphyrin is demonstrated to behave as a molecular wire in the monooxidized state.

Biological and biophysical properties of the histone deacetylase inhibitor suberoylanilide hydroxamic acid are affected by the presence of short alkyl groups on the phenyl ring.

Inhibition of histone deacetylases (HDACs) leads to growth arrest, differentiation, or apoptosis of tumor cell lines, suggesting HDACs as promising targets for cancer therapy. At present, only one HDAC inhibitor (HDACi) is used in therapy: suberoylanilide hydroxamic acid (SAHA). Here, we describe the synthesis and biological evaluation of a new series of compounds derived from SAHA by substituting short alkyl chains at various positions of the phenyl ring. Such modifications induced variable effects ranging from partial loss of activity to increased potency. Through molecular modeling, we describe a possible interaction between HDAC7 proline 809, a residue that is strictly conserved within class 2 enzymes only, and the amide group of HDACi, while nuclear magnetic resonance experiments indicated that dimethyl m-substitution may stabilize the inhibitor in the active site. Our data provide novel information on the structure-activity relationship of HDACi and suggest new ways for developing second generation SAHA-like molecules.

Identification of small molecule regulators of the nuclear receptor HNF4alpha based on naphthofuran scaffolds.

Nuclear receptors are ligand-activated transcription factors involved in all major physiological functions of complex organisms. In this respect, they are often described as drugable targets for a number of pathological states including hypercholesterolemia and atherosclerosis. HNF4alpha (NR2A1) is a recently 'deorphanized' nuclear receptor which is bound in vivo by linoleic acid, although this natural ligand does not seem to promote transcriptional activation. In mouse, HNF4alpha is a major regulator of liver development and hepatic lipid metabolism and mutations in human have been linked to diabetes. Here, we have used a yeast one-hybrid system to identify small molecule activators of HNF4alpha in a library of synthetic compounds and found one hit bearing a methoxy group branched on a nitronaphthofuran backbone. A collection of molecules deriving from the discovered hit was generated and tested for activity toward HNF4alpha in yeast one-hybrid system. It was found that both the nitro group and a complete naphthofuran backbone were required for full activity of the compounds. Furthermore, adding a hydroxy group at position 7 of the minimal backbone led to the most active compound of the collection. Accordingly, a direct interaction of the hydroxylated compound with the ligand binding domain of HNF4alpha was detected by NMR and thermal denaturation assays. When used in mammalian cell culture systems, these compounds proved to be highly toxic, except when methylated on the furan ring. One such compound was able to modulate HNF4alpha-driven transcription in transfected HepG2C3A cells. These data indicate that HNF4alpha activity can be modulated by small molecules and suggest new routes for targeting the receptor in humans.

Photodynamic effects of SIM01, a new sensitizer, on experimental brain tumors in rats.

BACKGROUND: Glioblastomas are the third most common cause of cancer death in patients between 15 and 35 years old. Literature suggests that PDT could represent a promising treatment, providing that sensitizers could accumulate within the cancer tissues despite the blood-brain barrier. METHODS: Distribution and PDT effect of SIM01, a promising photosensitizer, have been evaluated on orthotopic C6 tumor model in rats by comparison with HPD and m-THPC. Pharmacokinetics had been analyzed with fluorescence and ROS. Photodynamic treatment was done using a 630-nm light with an energy density of 100 J cm(-2) for HPD and a 652-nm light with an energy density of 20 J cm(-2) for m-THPC and SIM01. RESULTS: The correlation between fluorescence and ROS dosimetry was found to be excellent. An optimal concentration was found after 12 hours for SIM01 (4 mg/kg), 24 hours for HPD (10 mg/kg), and 48 hours for m-THPC (4 mg/kg). The best normal tissue/cancer ratio of concentration had been found after 12 hours for SIM01 and 48 hours for HPD and m-THPC. Pathological examinations after PDT showed that the criteria for histology of glioblastic origin were absent in SIM01-treated rats 12 hours after injection but were present in 50% of rats treated 24 hours after injection and in all after a 48-hour delay. Mean survival of rats treated 12 or 24 hours after SIM01 injection was significantly improved compared with controls, HPD-, or m-THPC-treated groups. Survival of rats treated 12 or 24 hours after SIM01 injection reached 20 days but decreased for longer delays. On the contrary, survival reached 18 days at the maximum for rats treated 48 hours after m-THPC or HPD injection. CONCLUSIONS: Our results confirm that PDT is a promising treatment for glioblastomas. SIM01 efficacy is as efficient as m-THPC but with much more favorable pharmacokinetics.

13C NMR studies of the electronic structure of low-spin iron(III) tetraphenylchlorin complexes.

A series of low-spin six-coordinate (tetraphenylchlorinato)iron(III) complexes [Fe(TPC)(L)2]+/- (L = 1-MeIm, CN-, 4-CNPy, and (t)BuNC) have been prepared, and their (13)C NMR spectra have been examined to reveal the electronic structure. These complexes exist as the mixture of the two isomers with the (d(xy))2(d(xz), d(yz))3 and (d(xz), d(yz))4(d(xy))1 ground states. Contribution of the (d(xz), d(yz))4(d(xy))1 isomer has increased as the axial ligand changes from 1-MeIm, to CN(-) (in CD2Cl2 solution), CN- (in CD(3)OD solution), and 4-CNPy, and then to tBuNC as revealed by the meso and pyrroline carbon chemical shifts; the meso carbon signals at 146 and -19 ppm in [Fe(TPC)(1-MeIm)2]+ shifted to 763 and 700 ppm in [Fe(TPC)(tBuNC)2]+. In the case of the CN- complex, the population of the (d(xz), d(yz))4(d(xy))1 isomer has increased to a great extent when the solvent is changed from CD2Cl2 to CD3OD. The result is ascribed to the stabilization of the d(xz) and d(yz) orbitals of iron(III) caused by the hydrogen bonding between methanol and the coordinated cyanide ligand. Comparison of the 13C NMR data of the TPC complexes with those of the TPP, OEP, and OEC complexes has revealed that the populations of the (d(xz), d(yz))4(d(xy))1 isomer in TPC complexes are much larger than those in the corresponding TPP, OEC, and OEP complexes carrying the same axial ligands.

Proton NMR study of myoglobin reconstituted with 3, 7-diethyl-2, 8-dimethyl iron porphyrin: remarkable influence of peripheral substitution on heme rotation.

The iron complex of 3,7-diethyl-2,8-dimethylporphyrin was incorporated into horse heart apomyoglobin to investigate the influence of peripheral substitution on artificial heme rotation. The hyperfine-shifted 1H NMR spectrum of the reconstituted deoxymyoglobin (rMb) revealed the proximal imidazole N-H resonance at 82.5 ppm to indicate the formation of the Fe--N (His93) bond. The pyrrole-protons of the hemin of myoglobin in the absence of external ligand appeared as four resonances between -10 and -18 ppm, indicating a mainly low-spin ferric hemin, with a ligated distal histidine (His64). This also indicates the lost of the symmetry of the hemin, according to an absence of free rotation of the prosthetic group. The 1H NMR spectrum of reconstituted rMbCO revealed a set of four pyrrole-protons and a set of four meso-protons. Accordingly, the prosthetic group without acid side chains interacts specifically with the surrounding globin showing a unique heme orientation in the 1H NMR time-scale, despite the presence of only four alkyl substituents on the porphine ring. This also suggests that two ethyl groups are large enough to avoid the free rotation movement of the heme.

Highly enantioselective synthesis of cyclopropylphosphonates catalyzed by chiral ruthenium porphyrins.

[reaction: see text] The asymmetric addition of diisopropyl diazomethylphosphonate to styrene derivatives was carried out by using chiral ruthenium porphyrins as catalysts. The reaction proceeded under mild conditions and gave trans-cyclopropylphosphonates with good yields and high ee's (up to 92%). A progressive increase for stereochemical effectiveness exists between enantiomeric excess and the number of chiral goups linked to ruthenium porphyrins.

Organic cross-linked electropolymers as supported oxidation catalysts: poly((tetrakis(9,9'-spirobifluorenyl)porphyrin)manganese) films.

Anodic oxidation of free base and manganese complexes of tetraspirobifluorenylporphyrins leads to the coating of the working electrode by insoluble electroactive poly(9,9'-spirobifluorene-free and manganese porphyrin) films which electrochemical behavior and physicochemical properties are described. After removal from the electrode, the manganese-complexed polymers were evaluated as catalysts for the oxidation of alkenes by iodobenzene diacetate or iodosylbenzene. The results show that the reactions proceeded very efficiently at room temperature with good yields. The electrosynthesized polymer catalysts can be recycled by simple filtration and reused even up to the eighth cycle without loss of activity and selectivity. These results represent an important improvement over those previously described for manganese-porphyrin-catalyzed epoxidation reactions.

Cytochrome c and SDS: a molten globule protein with altered axial ligation.

Saccharomices cerevisiae (yeast iso-1) cytochrome c has been investigated in the presence of 100 mM SDS in order to simulate the interaction of cytochrome c with membrane. Under these circumstances, a high spin species with detached methionine axial ligand is observed through NMR, in analogy to findings on the horse heart protein. However, at variance with the latter system, for the yeast protein also a low spin species is detected, which appears to be present with a concentration of about 40% with respect to that of the high spin species. The R(1), R(2), [1H]-15N NOE of backbone amides which are not affected by paramagnetism are homogeneous and allow a simultaneous analysis of the data for the two species. The result is that the rotational correlation time is larger than in water and larger than expected on the basis of viscosity of the SDS-containing solution. This finding suggests interactions of cytochrome c with SDS. Furthermore, it appears that there is subnanosecond backbone mobility, which also accounts for the decreased intensity of NOE cross-peaks and may be associated with equilibria between helical and random coil structure. The dynamic behavior appears to be a common feature of the high spin and low spin species and is consistent with the presence of a molten globule state. The molten globule nature of the protein could account for the presence of the different axial coordination of the heme iron. Such findings are meaningful with respect to the physiology of cytochrome c as electron transfer protein and as promoter of apoptosis.

Poly(ruthenium carbonyl spirobifluorenylporphyrin): a new polymer used as a catalytic device for carbene transfer.

Oxidative electropolymerization of tetraspirobifluorenyl porphyrin ruthenium(II) carbonyl complexes can be used to coat Pt electrodes with polymeric films; after being removed from the electrode, these polymeric materials are able to catalyze the heterogeneous cyclopropanations and 2,3 sigmatropic rearrangements with ethyl diazoacetate.

Poly(9,9'-spirobifluorene-manganese porphyrin): a new catalytic material for oxidation of alkenes by iodobenzene diacetate and iodosylbenzene.

Anodic oxidation of tetraspirobifluorene-manganese porphyrin lead to the coating of the working electrode by insoluble electroactive poly(9,9'-spirobifluorene-manganese porphyrin) films for which electrochemical behaviour and physicochemical properties are described; these polymeric materials are able to catalyze the heterogeneous epoxidation of styrene with iodobenzene diacetate and iodosylbenzene.

Hydroporphyrins as tumour photosensitizers: synthesis and photophysical studies of 2,3-dihydro-5,15-di(3,5-dihydroxyphenyl) porphyrin.

The synthesis and characterization of 2,3-dihydro-5,15-di(3,5-dihydroxyphenyl) porphyrin is reported. The phototoxicity on C6 cell lines and the pharmacokinetics are also reported as preliminary results showing a very high tumor to skin ratio and short retention time in tissues, and thus promising activity in photodynamic therapy.