Biological activity of 4-hydroxyisophthalic acid derivatives. Hydrazones with antimicrobial activity

The following hydrazono derivatives (I-XIX) of type (A) (sequence in text) where Rn = (sequence in text ) (I-XVII); (sequence in text) (XVIII); -CCl3 (XIX); and Xn = H (I); 2-Cl (II); 3-Cl (III); 4-Cl (IV); 2-NO2 (V); 3-NO2 (VI); 4-NO2 (VII); 2-OH (VIII); 3-OH (IX); 4-OH (X); 4-F (XI); 3,4-OCH3,OH (XII); 3,4,5-OCH3,OH,J (XIII); 3,4-OCH3,OCH3 (XIV); 2,4-Cl2 (XV); 3,4-Cl2 (XVI); 2,6-Cl2 (XVII); were prepared and characterized in an attempt to make available for testing a representative selection of hitherto unreported 4-hydroxyisophthalic acid derivatives. The new compounds in question were obtained in satisfactory yield by condensation of 4-hydroxyisophthalic acid hydrazide with the appropriate aldehydes. The prepared compounds were tested for their possible activity against Gram-positive (S. epidermidis, B. subtilis, B. anthracis) and Gram-negative bacteria (P. aeruginosa, B. melitensis, S. typhi O, S. typhi H, S. infantis, S. paratyphi B, E. coli Bb, E. coli 7075), and fungi (C. albicans, A. niger, S. cerevisiae). The "in vitro" antimicrobial assays were carried out using the paper disk technique (Kirby-Bauer modified). The influence of certain structural modifications on the antimicrobial activity was evaluated.     

The axial ligand effect of oxo-iron porphyrin catalysts. How does chloride compare to thiolate?

We have performed density functional theory calculations on an oxo-iron porphyrin catalyst with chloride as an axial ligand and tested its reactivity toward propene. The reactions proceed via multistate reactivity on competing doublet and quartet spin surfaces. Close-lying epoxidation and hydroxylation mechanisms are identified, whereby in the gas phase the epoxidation reaction is dominant, while in environments with a large dielectric constant the hydroxylation pathways become competitive. By contrast to reactions with thiolate as an axial ligand all low-lying pathways have small ring-closure and rebound barriers, so it is expected that side products and rearrangements will be unlikely with Fe=O(porphyrin)Cl, whereas with Fe=O(porphyrin)SH some side products were predicted. The major differences in the electronic configurations of Fe=O(porphyrin)Cl and Fe=O(porphyrin)SH are due to strong mixing of thiolate orbitals with iron 3d orbitals, a mixing which is much less with chloride as an axial ligand. Predictions of the reactivity of ethylbenzene-h ₁₂ versus ethylbenzene-d ₁₂ are made. Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.     

Synthesis and characterization of a series of novel glutamic gamma-15N-anilide dipeptides.

The preparation of a series of novel Cbz-Gln-Gly dipeptide derivatives is reported, wherein the gamma-carboxamide groups of the glutamine side chains have been modified to gamma-15N-anilides which are substituted in the para position with -NO2, -Cl, -H, -CH3, -OCH3, and -N(CH3)2. Characterization of the free anilines (p(kappa)a values and 15N NMR chemical shifts) and corresponding gamma-anilides (15N NMR chemical shifts and FTIR wavenumbers) is also reported. Correlation of these physicochemical data to Hammett substituent parameters ((sigma)para) is discussed. These novel dipeptide derivatives should prove to be generally useful for structure-function enzymology studies of gamma-glutamyl transferring enzymes.     

Nitric oxide interaction with insect nitrophorins and thoughts on the electron configuration of the {FeNO}6 complex

The nitrophorins are NO-carrying heme proteins that are found in the saliva of two species of blood-sucking insects, the kissing bug (Rhodnius prolixus) and the bedbug (Cimex lectularius). In both insects the NO is bound to the ferric form of the protein, which gives rise to Kds in the micromolar to nanomolar range, and thus upon injection of the saliva into the tissues of the victim the NO can dissociate to cause vasodilation and inhibition of platelet aggregation. The structures of the proteins from each of these insects are unique, and each has a large component of beta-sheet structure, which is unusual for heme proteins. While the Rhodnius nitrophorins increase the effectiveness of their NO-heme proteins by also binding histamine, secreted by the victim in response to the bite, to the heme, the Cimex nitrophorin does not bind histamine but rather binds two molecules of NO reversibly, one to the heme and the other to the cysteine thiolate which serves as the heme ligand in the absence of NO. This requires homolytic cleavage of the Fe-S-Cys bond, which produces an EPR-active Fe(II)-NO complex having the {FeNO}7 electron configuration. For the Rhodnius nitrophorins, the heme of the {FeNO}6 stable NO complex could have the limiting electron configurations Fe(III)-NO+ or Fe(II)-NO+. While vibrational spectroscopy suggests the latter and Mossbauer spectroscopy cannot differentiate between a purely diamagnetic Fe(II) center and a strongly antiferromagnetically coupled Fe(III)-NO* center, the strong ruffling of the heme (with alternate meso-carbons shifted significantly above and below the mean plane of the porphyrin, and concomitant shifts of the beta-pyrrole carbons above and below the mean plane of the porphyrin ring, to produce a very nonplanar porphyrin macrocycle) may suggest at least an important contribution of the latter. The strong ruffling would help to stabilize the (dxz, dyz)4(dxy)1 electron configuration of low-spin Fe(III) (but not low-spin Fe(II)), and the dxy orbital does not have correct symmetry for overlap with the half-filled pi* orbital of NO. This Fe(III)-NO* electron configuration would facilitate reversible dissociation of NO.     

The secondary coordination sphere and axial ligand effects on oxygen reduction reaction by iron porphyrins: a DFT computational study

Oxygen reduction reaction (ORR) catalyzed by a bio-inspired iron porphyrin bearing a hanging carboxylic acid group over the porphyrin ring, and a tethered axial imidazole ligand was studied by DFT calculations. BP86 free energy calculations of the redox potentials and pK _a’s of reaction components involved in the proton coupled electron transfer (PCET) reactions of the ferric-hydroxo and -superoxo complexes were performed based on Born–Haber thermodynamic cycle in conjunction with a continuum solvation model. The comparison was made with iron porphyrins that lack either in the hanging acid group or axial ligand, suggesting that H-bond interaction between the carboxylic acid and iron-bound hydroxo, aquo, superoxo, and peroxo ligands (de)stabilizes the Fe–O bonding, resulting in the increase in the reduction potential of the ferric complexes. The axial ligand interaction with the imidazole raises the affinity of the iron-bound superoxo and peroxo ligands for proton. In addition, a low-spin end-on ferric-hydroperoxo intermediate, a key precursor for O–O cleavage, can be stabilized in the presence of axial ligation. Thus, selective and efficient ORR of iron porphyrin can be achieved with the aid of the secondary coordination sphere and axial ligand interactions.     

Ultrahigh resolution structures of nitrophorin 4: heme distortion in ferrous CO and NO complexes

Nitrophorin 4 (NP4), a nitric oxide (NO)-transport protein from the blood-sucking insect Rhodnius prolixus, uses a ferric (Fe3+) heme to deliver NO to its victims. NO binding to NP4 induces a large conformational change and complete desolvation of the distal pocket. The heme is markedly nonplanar, displaying a ruffling distortion postulated to contribute to stabilization of the ferric iron. Here, we report the ferrous (Fe2+) complexes of NP4 with NO, CO, and H2O formed after chemical reduction of the protein and the characterization of these complexes by absorption spectroscopy, flash photolysis, and ultrahigh-resolution crystallography (resolutions vary from 0.9 to 1.08 A). The absorption spectra, both in solution and in the crystal, are typical for six-coordinated ferrous complexes. Closure and desolvation of the distal pocket occurs upon binding CO or NO to the iron regardless of the heme oxidation state, confirming that the conformational change is driven by distal ligand polarity. The degree of heme ruffling is coupled to the nature of the ligand and the iron oxidation state in the following order: (Fe3+)-NO > (Fe2+)-NO > (Fe2+)-CO > (Fe3+)-H2O > (Fe2+)-H2O. The ferrous coordination geometry is as expected, except for the proximal histidine bond, which is shorter than typically found in model compounds. These data are consistent with heme ruffling and coordination geometry serving to stabilize the ferric state of the nitrophorins, a requirement for their physiological function. Possible roles for heme distortion and NO bending in heme protein function are discussed.     

Coordination modes of tyrosinate-ligated catalase-type heme enzymes: magnetic circular dichroism studies of Plexaura homomalla allene oxide synthase, Mycobacterium avium ssp. paratuberculosis protein-2744c, and bovine liver catalase in their ferric and ferrous states

Bovine liver catalase (BLC), catalase-related allene oxide synthase (cAOS) from Plexaura homomalla, and a recently isolated protein from the cattle pathogen Mycobacterium avium ssp. paratuberculosis (MAP-2744c (MAP)) are all tyrosinate-ligated heme enzymes whose crystal structures have been reported. cAOS and MAP have low (< 20%) sequence similarity to, and significantly different catalytic functions from, BLC. cAOS transforms 8R-hydroperoxy-eicosatetraenoic acid to an allene epoxide, whereas the MAP protein is a putative organic peroxide-dependent peroxidase. To elucidate factors influencing the functions of these and related heme proteins, we have investigated the heme iron coordination properties of these tyrosinate-ligated heme enzymes in their ferric and ferrous states using magnetic circular dichroism and UV-visible absorption spectroscopy. The MAP protein shows remarkable spectral similarities to cAOS and BLC in its native Fe(III) state, but clear differences from ferric proximal heme ligand His93Tyr Mb (myoglobin) mutant, which may be attributed to the presence of an Arg⁺-N^ω-H···¯O-Tyr (proximal heme axial ligand) hydrogen bond in the first three heme proteins. Furthermore, the spectra of Fe(III)-CN¯, Fe(III)-NO, Fe(II)-NO (except for five-coordinate MAP), Fe(II)-CO, and Fe(II)-O₂ states of cAOS and MAP, but not H93Y Mb, are also similar to the corresponding six-coordinate complexes of BLC, suggesting that a tyrosinate (Tyr-O¯) is the heme axial ligand trans to the bound ligands in these complexes. The Arg⁺-N^ω-H to ¯O-Tyr hydrogen bond would be expected to modulate the donor properties of the proximal tyrosinate oxyanion and, combined with the subtle differences in the catalytic site structures, affect the activities of cAOS, MAP and BLC.     

Evidence for variable metal-radical spin coupling in oxoferrylporphyrin cation radical complexes

Oxoferrylporphyrin cation radical complexes were generated by m-chloroperoxybenzoic acid oxidation of the chloro and trifluoromethanesulfonato complexes of tetramesitylporphyrinatoiron(III) [(TMP)Fe] and the trifluoromethanesulfonato complex of tetra(2,6-dichlorophenyl)porphyrinatoiron(III) [TPP(2,6-Cl)Fe]. Coupling between ferryl iron (S = 1) and porphyrin radical (S' = 1/2) spin systems was investigated by M?ssbauer and EPR spectroscopy. The oxoferrylporphyrin cation radical systems generated from the TMP complexes show strong ferromagnetic coupling. Analysis of the magnetic M?ssbauer spectra, using a spin Hamiltonian explicitly including a coupling tensor J, suggests an exchange-coupling constant J greater than 80 cm-1. The EPR spectra show non-zero rhombicity, the origin of which is discussed in terms of contributions from the usual zero-field effects of iron and from iron-radical spin-dipolar interaction. A consistent estimate of zero-field splitting parameter D approximately + 6 cm-1 was obtained by EPR and M?ssbauer measurements. EPR and M?ssbauer parameters are shown to be slightly dependent on solvent, but not on the axial ligand in the starting (TMP)Fe complex. In contrast to the TMP complex, the oxoferrylporphyrin cation radical system generated from [TPP(2,6-Cl)FeOSO2CF3] exhibits M?ssbauer and EPR spectra consistent with weak iron-porphyrin radical coupling of magnitude of J approximately 1 cm-1.     

The effect of axial ligand plane orientation on the contact and pseudocontact shifts of low-spin ferriheme proteins

 The effect of axial ligand nodal plane orientation on the contact and pseudocontact shifts of a symmetrical low-spin octamethylferriheme center has been calculated as a function of the angle of the axial ligand. Simple Hückel techniques have been used to estimate the contact contribution, and values obtained from model hemes, together with counter-rotation of the g-tensor, have been used to estimate the pseudocontact contribution, for the eight β-pyrrole methyl and four meso-H positions. It is found that the maximum and minimum contact shifts occur when the axial ligand is aligned at an angle of ±15° to the meso-H axes of the heme, rather than when the axial ligand plane lies along the porphyrin nitrogens, as assumed previously by some investigators. For systems having one planar axial ligand or two ligands in parallel planes, the contact and pseudocontact contributions at the meso-H positions are comparable in size (at least on the basis of simple Hückel estimates), while the contact contribution clearly dominates the isotropic shifts of the heme methyls. Allowing for the substituent effect of the 2,4-vinyls of protohemin, or the 2,4-thioethers of hemin c, as well as the average diamagnetic shifts of the heme methyls and meso-H, plots of the predicted shifts as a function of axial ligand nodal plane orientation have been constructed for hemin b- and c-containing proteins. Excellent agreement in the order of shifts, and reasonable agreement in the sizes of the observed shifts, is observed in the majority of the ferriheme proteins for which the methyl and meso-H resonances have been assigned and proton shifts reported. Plots have also been constructed for hemin c-containing proteins having the two axial ligand nodal planes oriented at relative angles of 40°, 70°, and 80°. Excellent agreement in the order of shifts, and reasonable agreement in the magnitudes of the observed shifts, is observed in all cases of bacterial cytochromes which do not fit the plots that assume the ligands are in parallel planes, except one – the cytochrome c-552 of Nitrosomonas europae. Except for this case, where the order of the predicted methyl shifts at any angle of the axial ligands disagrees with the observed, the reasons can usually be attributed to a large dihedral angle between two axial ligand nodal planes, to strong H-bonding interactions involving His and/or CN^– ligands, or to off-axis binding of one (or both) axial ligand(s). Ruffling of the porphyrin ring may also contribute to the contact shift in as yet undefined ways. Hence, despite the simplicity of the calculations, the agreement with observed data is highly satisfying and the concept of the importance of axial ligand plane orientation on the observed proton shifts of heme proteins is fully confirmed. Received: 15 June 1998 / Accepted: 6 August 1998     

Specificity of reductive dehalogenation of substituted ortho-chlorophenols by Desulfitobacterium dehalogenans JW/IU-DC1.

Resting cells of Desulfitobacterium dehalogenans JW/IU-DC1 growth with pyruvate and 3-chloro-4-hydroxyphenylacetate (3-Cl-4-OHPA) as the electron acceptor and inducer of dehalogenation reductively ortho-dehalogenate pentachlorophenol (PCP); tetrachlorophenols (TeCPs); the trichlorophenols 2,3,4-TCP, 2,3,6-TCP, and 2,4,6-TCP; the dichlorophenols 2,3-DCP, 2,4-DCP, and 2,6-DCP; 2,6-dichloro-4-R-phenols (2,6-DCl-4-RPs, where R is -H, -F, -Cl, -NO2, -CO2, or -COOCH3; 2-chloro-4-R-phenols (2-Cl-4-RPs, where R is -H, -F, -Cl, -Br, -NO2, -CO2-, -CH2CO2, or -COOCH3); and the bromophenols 2-BrP, 2,6-DBrP, and 2-Br-4ClP [corrected]. Monochlorophenols, the dichlorophenols 2,5-DCP, 3,4-DCP, and 3,5-DCP, the trichlorophenols 2,3,5-TCP, 2,4,5-TCP, and 3,4,5-TCP, and the fluorinated analog of 3-Cl-4-OHPA, 3-F-4-OHPA ("2-F-4-CH2CO2- P"), are not dehalogenated. A chlorine substituent in position 3 (meta), 4 (para), or 6 (second ortho) of the phenolic moiety facilitates ortho dehalogenation in position 2. Chlorine in the 5 (second meta) position has a negative effect on the dehalogenation rate or even prevents dechlorination in the 2 position. In general, 2,6-DCl-4-RPs are dechlorinated faster than the corresponding 2-Cl-4-RPs with the same substituent R in the 4 position. The highest dechlorination rate, however, was found for dechlorination of 2,3-DCP, with a maximal observed first-order rate constant of 19.4 h-1 g (dry weight) of biomass-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coordination chemistry of iron(III)-porphyrin-antibody complexes.

An artificial peroxidase-like hemoprotein has been obtained by associating a monoclonal antibody, 13G10, and its iron(III)-alpha,alpha,alpha,beta-meso-tetrakis(ortho-carboxyphenyl)porphyrin [Fe(ToCPP)] hapten. In this antibody, about two-thirds of the porphyrin moiety is inserted in the binding site, its ortho-COOH substituents being recognized by amino-acids of the protein, and a carboxylic acid side chain of the protein acts as a general acid base catalyst in the heterolytic cleavage of the O-O bond of H2O2, but no amino-acid residue is acting as an axial ligand of the iron.We here show that the iron of 13G10-Fe(ToCPP) is able to bind, like that of free Fe(ToCPP), two small ligands such as CN-, but only one imidazole ligand, in contrast to to the iron(III) of Fe(ToCPP) that binds two. This phenomenon is general for a series of monosubstituted imidazoles, the 2- and 4-alkyl-substituted imidazoles being the best ligands, in agreement with the hydrophobic character of the antibody binding site. Complexes of antibody 13G10 with less hindered iron(III)-tetraarylporphyrins bearing only one [Fe(MoCPP)] or two meso-[ortho-carboxyphenyl] substituents [Fe(DoCPP)] also bind only one imidazole. Finally, peroxidase activity studies show that imidazole inhibits the peroxidase activity of 13G10-Fe(ToCPP) whereas it increases that of 13G10-Fe(DoCPP). This could be interpreted by the binding of the imidazole ligand on the iron atom which probably occurs in the case of 13G10-Fe(ToCPP) on the less hindered face of the porphyrin, close to the catalytic COOH residue, whereas in the case of 13G10-Fe(DoCPP) it can occur on the other face of the porphyrin. The 13G10-Fe(DoCPP)-imidazole complex thus constitutes a nice artificial peroxidase-like hemoprotein, with the axial imidazole ligand of the iron mimicking the proximal histidine of peroxidases and a COOH side chain of the antibody acting as a general acid-base catalyst like the distal histidine of peroxidases does.     

The coordination of imidazole and substituted pyridines by the hemeoctapeptide N-acetyl-ferromicroperoxidase-8 (FeIINAcMP8)

The N-terminus acetylated ferric hemeoctapeptide from cytochrome c, N-acetylmicroperoxidase-8 (Fe(III)-NAcMP8) can be reduced by dithionite in aqueous solution to produce Fe(II)-NAcMP8. The UV-Vis spectrum has a broad Soret band and relatively poorly defined Q bands which is consistent with a mixture of a five-coordinate high spin species with His as the axial ligand and a six-coordinate, predominantly high spin species with His/H(2)O as axial ligands. There are two spectroscopically observable pK(a)s at 8.7+/-0.1 and 10.9+/-0.2 which are attributed to ionization of a heme propionic acid group and coordinated H(2)O, respectively; a pK(a) > or = 14 is due to ionization of the proximal His ligand. Equilibrium constants were determined by UV-Vis spectrophotometry at 25.0+/-0.2 degrees C and 0.5 M ionic strength (NaClO(4)) for the coordination of imidazole and a number of substituted pyridines, and complement available data for the ferric hemepeptide, allowing a comparison to be made of the affinity of an iron porphyrin with Fe in the +2 and +3 oxidation states towards these ligands. Imidazole is coordinated more strongly by the ferric porphyrin (log K=4.08) than by the ferrous porphyrin (log K=3.40). The equilibrium constants for coordination of pyridines by the ferric and ferrous porphyrins increase and decrease, respectively, with increasing ligand basicity. Values determined by cyclic voltammetry show the same dependence on the identity of the ligand. In the ferric porphyrin, the stability of the complex increases with the basicity of the ligand and hence its ability to donate electron density onto the metal. In the case of the more electron rich ferrous porphyrin, greater stability occurs with pyridine ligands that have an electron withdrawing group and hence can accept electron density from the metal. This is consistent with the midpoint reduction potentials E(1/2) of the pyridine complexes determined by cyclic voltammetry; E(1/2) is linearly dependent on, and becomes more negative with an increase in, ligand basicity. Log K for coordination of pyridines by the ferrous hemepeptide correlates well with the energy of the ligand frontier orbital with pi symmetry, suggesting that pi-bonding effects are significant in determining the strength of binding of pyridines by a ferrous porphyrin.     

Structure-activity relationships of hydrazono derivatives of biological interest

The following hydrazono derivatives (I-XXIII) of type (A), (formula; see text) where: X = NO2 (II, IV, VI, VIII, X, XIV-XXIII), X = H (I, III, V, VII, IX, XI, XII, XIII), and Y = H (I, II); 3-Cl (III, IV); 4-Cl (V, VI); 3,4-Cl2 (VII, VIII); 2,6-Cl2 (IX, X); 2-NO2 (XI); 3-NO2 (XII); 4-NO2 (XIII, XIV); 2-F (XV); 3-F (XVI); 4-F (XVII); 2-OH (XVIII); 4-OH (XIX); 2,4-(OH)2(XX); 2,4,6-(OH)3(XXI); 2,3-(OH,NO2) (XXII); 2,4-(NO2)2 (XXIII), were prepared and tested for antibacterial and antifungal activity. All of these compounds were prepared in satisfactory yield by reaction of aromatic aldehydes with 2-furoyl and 5-nitro-2-furoyl hydrazide. The hydrazono derivatives I-XXIII prepared in this investigation were screened for antimicrobial activity by a disk-diffusion assay (Kirby-Bauer modified). The organisms used were laboratory cultures of S. aureus, S. -haemoliticus, B. subtilis, M. paratuberculosis, E. coli, S. typhi, Ps. aeruginosa, K1. pneumoniae, A. niger, S. cerevisiae, C. albicans. The results of this study showed that a number of the prepared hydrazono derivatives exhibited varying degrees of activity against Gram-positive and Gram-negative bacteria. Compounds IV and XV possessed broad spectrum "in vitro" against Gram-positive and Gram-negative bacteria. Compounds XII greater than IV greater than XV showed inhibitory activity especially toward S. aureus. Compounds IV greater than XV greater than XVI were especially active against E. coli. Compounds XV greater than IV were especially inhibitory toward S. typhi and most of the prepared compounds inhibited considerably Ps. aeruginosa and K1. pneumoniae.     

First success of catalytic epoxidation of olefins by an electron-rich iron(III) porphyrin complex and H2O2: imidazole effect on the activation of H2O2 by iron porphyrin complexes in aprotic solvent

An electron-rich iron(III) porphyrin complex (meso-tetramesitylporphinato)iron(III) chloride [Fe(TMP)Cl], was found to catalyze the epoxidation of olefins by aqueous 30% H₂O₂ when the reaction was carried out in the presence of 5-chloro-1-methylimidazole (5-Cl-1-MeIm) in aprotic solvent. Epoxides were the predominant products with trace amounts of allylic oxidation products, indicating that Fenton-type oxidation reactions were not involved in the olefin epoxidation reactions. cis-Stilbene was stereospecifically oxidized to cis-stilbene oxide without giving isomerized trans-stilbene oxide product, demonstrating that neither hydroperoxy radical (HOO·) nor oxoiron(IV) porphyrin [(TMP)Fe^IV=O] was responsible for the olefin epoxidations. We also found that the reactivities of other iron(III) porphyrin complexes such as (meso-tetrakis(2,6-dichlorophenyl)porphinato)iron(III) chloride [Fe(TDCPP)Cl], (meso-tetrakis(2,6-difluorophenyl)porphinato)iron(III) chloride [Fe(TDFPP)Cl], and (meso-tetrakis(pentafluorophenyl)porphinato)iron(III) chloride [Fe(TPFPP)Cl] were significantly affected by the presence of the imidazole in the epoxidation of olefins by H₂O₂. These iron porphyrin complexes did not yield cyclohexene oxide in the epoxidation of cyclohexene by H₂O₂ in the absence of 5-Cl-1-MeIm in aprotic solvent; however, addition of 5-Cl-1-MeIm to the reaction solutions gave high yields of cyclohexene oxide with the formation of trace amounts of allylic oxidation products. We proposed, on the basis of the results of mechanistic studies, that the role of the imidazole is to decelerate the O–O bond cleavage of an iron(III) hydroperoxide porphyrin (or H₂O₂–iron(III) porphyrin adduct) and that the intermediate transfers its oxygen to olefins prior to the O–O bond cleavage.     

Hemodextrin: a self-assembled cyclodextrin-porphyrin construct that binds dioxygen

Synthetic hemoprotein model compounds are of great interest due to the vital roles and complexities of hemoproteins. This study reports a novel, self-assembled hemoprotein model, hemodextrin. The synthesis and characterization of py-PPCD (2(A)-monopyridylmethyl-perPEGylated-beta-cyclodextrin) (2) is described. The molecular design is based on a pegylated cyclodextrin scaffold that bears both a heme-binding pocket and an axial ligand that binds an iron porphyrin. The binding constant for Fe(III)TPPS [iron(III) meso-tetra(4-sulphonatophenyl)porphyrin] by py-PPCD (2) was determined to be 2 x 10(6) M(-1) at pH 6.0 by observing characteristic changes in the UV-Vis spectrum of the porphyrin. The pyridyl nitrogen of py-PPCD (2) was shown to ligate to the iron center by observing signal changes in the Fe(II)-porphyrin 1H-NMR spectrum. This hemodextrin ensemble was shown to bind dioxygen reversibly and to form a stable ferryl species.     

Studies on heterocyclic compounds: 1,3-thiazolidin-4-one derivatives. V. Pharmacological activity of substituted 2-phenyl-3-(N,N-dimethylaminoprophyl)-1,3-thiazolidin-4-one .

The following 2-substituted phenyl-3-(N,N-dimethylaminopropyl)-1,3-thiazolidin-4-one of general formula (A): [formula: see text] where: X = H (I), 3-F (II), 3-Cl (III), 3-Br (IV), 3-CH3 (V), 3-OCH3 (VI), 3-NO2 (VII), 4-F (VIII), 4-Cl (IX), 4-Br (X), 4-CH3 (XI), 4-OCH3 (XII), 4-NO2 (XIII) were prepared and tested for antihistamine activity. The synthetic procedure involves the cyclocondensation of the appropriate Schiff base with thioglycolic acid in refluxing dry benzene. The compounds herein presented were tested for their ability to inhibit the contraction inducted by histamine 5.10(-7) M "in vitro", on guinea pig ileum. The results are reported as contraction of test compound causing 50% of submaximal contraction induced by histamine (IC50), and related to mepyramine as control. The results of the antihistamine tests showed an interesting degree of activity of some of the new thiazolidinone-derivatives. Compounds II, III, V, X, and XI showed IC50 values near the value of the control, compound XI being the most active. These compounds seem to be worthy of further investigation.     

First success of catalytic epoxidation of olefins by an electron-rich iron(III) porphyrin complex and H2O2: imidazole effect on the activation of H2O2 by iron porphyrin complexes in aprotic solvent

An electron-rich iron(III) porphyrin complex (meso-tetramesitylporphinato)iron(III) chloride [Fe(TMP)Cl], was found to catalyze the epoxidation of olefins by aqueous 30% H₂O₂ when the reaction was carried out in the presence of 5-chloro-1-methylimidazole (5-Cl-1-MeIm) in aprotic solvent. Epoxides were the predominant products with trace amounts of allylic oxidation products, indicating that Fenton-type oxidation reactions were not involved in the olefin epoxidation reactions. cis-Stilbene was stereospecifically oxidized to cis-stilbene oxide without giving isomerized trans-stilbene oxide product, demonstrating that neither hydroperoxy radical (HOO·) nor oxoiron(IV) porphyrin [(TMP)Fe^IV=O] was responsible for the olefin epoxidations. We also found that the reactivities of other iron(III) porphyrin complexes such as (meso-tetrakis(2,6-dichlorophenyl)porphinato)iron(III) chloride [Fe(TDCPP)Cl], (meso-tetrakis(2,6-difluorophenyl)porphinato)iron(III) chloride [Fe(TDFPP)Cl], and (meso-tetrakis(pentafluorophenyl)porphinato)iron(III) chloride [Fe(TPFPP)Cl] were significantly affected by the presence of the imidazole in the epoxidation of olefins by H₂O₂. These iron porphyrin complexes did not yield cyclohexene oxide in the epoxidation of cyclohexene by H₂O₂ in the absence of 5-Cl-1-MeIm in aprotic solvent; however, addition of 5-Cl-1-MeIm to the reaction solutions gave high yields of cyclohexene oxide with the formation of trace amounts of allylic oxidation products. We proposed, on the basis of the results of mechanistic studies, that the role of the imidazole is to decelerate the O–O bond cleavage of an iron(III) hydroperoxide porphyrin (or H₂O₂–iron(III) porphyrin adduct) and that the intermediate transfers its oxygen to olefins prior to the O–O bond cleavage.     

The electronic and vibrational structures of iron-oxo porphyrin with a methoxide or cysteinate axial ligand

Hybrid density functional theory (DFT) calculations for the electronic and vibrational structures of compound I species with a methoxide (MeO-) (1) or cysteinate (CysS-) (2) axial ligand are carried out in order to elucidate the natures of a methoxide-coordinating new type of compound I species (Bull. Chem. Soc. Jpn. 71 (1998) 1343) and cysteinate-coordinating compound I species of chloroperoxidase (CPO-I) and cytochrome P450s (P450-I). DFT computations of 1 and 2 demonstrate that these "anionic" ligands are a spin carrier; 70% (80%) of a spin density resides on the O (S) atom of the axial ligand and 30% (20%) is distributed on the porphyrin ring. These results suggest that for the generation of the compound I species, one electron is removed from the iron centers and the rest of the one electron is supplied from the oxidizable axial ligands instead of the iron centers or the porphyrin ring. Vibrational analyses demonstrate that the Fe=O bond is more strongly activated in 1 compared with 2 with the stretching mode at 849 cm(-1) (878 cm(-1)) for the doublet state1a (2a) and at 814 cm(-1) (875 cm(-1)) in the quartet state 1b (2b). This reverse order of the Fe=O bond strength with respect to the axial donor strength should have relevance to the significantly oxidized character of the CysS- axial ligand. In conjunction with the recent results of the extensive resonance Raman (RR) studies, some interpretations of unsettled RR results for compound I of chloroperoxidase (CPO-I) and a synthetic compound I species [O=FeIV(TMP*+)(alcohol)] (J. Am. Chem. Soc. 113 (1991) 6542) concerning the O=Fe stretching frequencies are discussed.     

The reactions of octaethylporphyrin and its iron (II) and iron (III) complexes with free radicals

The reactions of dilute solutions of octaethylporphyrin and its iron (II) and iron (III) complexes with methyl, 2-cyanopropyl, t-butoxy, and benzoyloxy radicals are described. The results are summarized: (i) The reactivity of the porphyrin and its high-spin iron (II) and iron (III) complexes toward alkyl and t-butoxy radicals stands in the order: Fe^II > Fe^III ? free porphyrin. For benzoyloxy radicals the order is Fe^II > Porp > Fe^III. (ii) The exclusive path of reaction of high-spin iron (II) porphyrin with radicals is the rapid reduction of the radical and generation of an iron (III) porphyrin. The dominant path of reaction of high-spin iron (III) porphyrin with alkyl and (presumably) t-butoxy radicals is a rapid axial inner sphere reduction of the porphyrin. An axial ligand of iron is transferred to the radical. (iv) The reaction of benzoyloxy radicals with high or low-spin iron (III) porphyrins occurs primarily at the meso position. With the low-spin dipyridyl complex in pyridine the attendant reduction to iron (II) can be observed spectrally. Methyl radicals also reduce this complex by adding to the meso position. (v) The reaction of a radical with either an iron (II) or an iron (III) porphyrin results in the generation of the other valence state of iron and consequently oxidation and reduction products emanating from both iron species are obtained. (vi) No evidence for an iron (IV) is intermediate is apparent. (vii) Iron (II) porphyrins in solvents that impart either spin state are easily oxidized by diacyl peroxides. The occurrence of both axial and peripheral redox reactions with the iron complexes supports an underlying premise of a recent theory of hemeprotein reactivity. The relevance of the work to bioelectron transfer and heme catabolism is noted.