Heme models

Studies on the oxygen activation mechanisms by new heme enzymes using hemoprotein mutants and synthetic heme models 96YGK1046. 

As an example heme-models have been reported to catalyze the epoxidation of olefins to the corresponding epoxides in good yield [16, 17]. In particular, [Fe TPP)Cl] (TPP = 5,10,15,20-meso-tetraphenylporphyrin) was reported to oxidize naturally occurring propenylbenzenes to the corresponding epoxides up to 98% selectivity (conversion 98%) using H2O2 as oxidant [16]. The major drawback... 

These researchers also described [93] the design and synthesis of iron(II) porphyrin dendrimers with triethylene glycol monomethyl, ether surface groups (e.g., 31) which render them soluble in a wide range of organic solvents and water. The potential difference between the first (1 FeCl) and second generation (2 FeCl) Fe-porphryin dendrimers was found to increase more in water than in dichloromethane (0.42 vs 0.08 V). This remarkable potential difference between 2 FeCl and 1 FeCl in water was comparable with that found between cytochrome c and a similarly ligated, more solvent-exposed cytochrome c heme model compound. 

Figure 4.12 Distal histidine hydrogen bonding structure for hemoglobin (left) and a heme model (right). (Reprinted with permission from Figure 12 of Momenteau, M. Reed, C. A. Chem. Rev., 1994, 94, 659-698. Copyright 1994, American Chemical Society.)...

In order to prepare and isolate solid-state, crystalline, oxygenated iron-heme model complexes, chemists learned to synthesize (by self-assembly methods) and oxygenate many types of hindered porphyrins. For instance, capped porphyrins were synthesized by direct condensation of a suitable tetraaldehyde with four pyrrole molecules.37 Picket-fence porphyrins such as I e(TPP)((V-MeIm) (where TPP = meso-tetraphenylporphyrin and /V-Melm = (V-methylimidazole)... 

Synthetic models of myoglobin and hemoglobin are complex molecules that mimic the stereochemical properties of the protein active center [24] and have oxygen affinities similar to those measured for the protein [25-27]. The first heme model that reversibly binds oxygen (i.e. the picket-fence-oxygen complex Fe(TpivPP)(l,2-Melm)(02), shown in Fig. 3.3) was obtained in the early nine-teen-seventies by Collman and coworkers (TpivPP = tetrapivalami-nophenyl porphyrin 2-meIm = 2-methylimidazole) [18]. Research on synthetic models of the protein has led to a deeper understand-... 

Tab. 3.1 Main data defining the optimized structure of the FeP(AB) and FeP(lm)(AB) models investigated (AB = CO, NO, 02). Distances are given in A, angles in degrees, and energies in kcal mob1. Porphyrin nitrogens are denoted Np and Nc refers to one of the nitrogen atoms of the axial imidazole. The experimental values correspond to X-ray structures of heme models [18].

That the environment could play a major role in determining ligand binding to iron in heme models and, probably, in myoglobin also, is in agreement with the conclusions of site-directed... 

Laverman and coworkers have reported activation parameters for the aqueous solution reactions of NO with the iron(II) and iron(III) complexes of the water soluble porphyrins TPPS andTMPS (21). These studies involved systematic measurements to determine on and kQ as functions of temperature (298—318 K) and hydrostatic pressure (0.1—250 MPa) to determine values of AH, AS and AV for the on and off reactions of the ferri-heme models and for the on reactions of the ferro-heme models (Table II). Figure 2 illustrates hydrostatic pressure effects on kOTL and kQff for Fem(TPPS). 

Studies in this laboratory (69) of the water soluble ferri-heme model Fem(TPPS) in aqueous solution have shown that this species also undergoes reductive nitrosylation in solutions that are moderately acidic (pH 4-6) (Eq. (32)). The rate of this reaction includes a buffer dependent term indicating that the reaction of the Fem(TPPS)(NO) complex with H20 is subject to general base catalysis. The reaction depicted in Eq. (33) is not observable at pH values < 3, since the half-cell reduction potential for the nitrite anion (Eq. (1)) is pH dependent, and Eq. (33) is no longer thermodynamically favorable. 

Up to now, two types of iron compounds have been studied with ENDOR, namely heme compounds (hemoproteins and some heme model compounds) and iron-sulfur proteins. For comprehensive summaries of the corresponding EPR work, the reader is referred to the literature234-2371. 

To get a deeper insight into the factors which affect the electronic structure of hemopro-teins, systematic studies on heme model compounds have been undertaken by Scholes and coworkers79 247 255. The model systems used by these authors are protohemin, deuterohemin and ferric tetraphenylporphyrin with a series of axial ligands. All the published ENDOR data on high-spin heme model compounds were obtained in frozen solutions with B0 along gi = 2 which is oriented normal to the porphyrin plane. A 1 1... 

Robert and Meunier have isolated and characterized covalent adducts of metallopor-phyrins with artemisinin. Initial attempts using an iron(II) heme model were inconclusive, since the strong paramagnetism of the iron did not allow detailed characterization of the adduct and attempts at demetallation resulted in its degradation. Therefore, manganese(II) tetraphenylporphyrin (TPP) was used since it required milder demetallation conditions and the adduct 50a was formed. The suggested mechanism for the alkylation involves a pendent ethyl radical 50 (Scheme 13). 

Meunier and coworkers investigated the degradation of arteflene using manganese(II) TPP as a heme model. They were able to spin-trap the secondary C-centred radical with the piperidyl radical (TEMPO) and the adduct 64c was fully characterized following acetylation of the crude reaction mixture (Scheme 20). An arteflene-heme adduct was not observed and the authors suggest that this is attributable to steric hindrance factors. However, this could be further evidence that endoperoxide antimalarials do not target heme. 

It should be emphasized that virmaUy all of the above discussion is based on biomimetic chemistry, where the Fe(II) source varies from salts such FeS04 to the more reactive FeCla-THaO as well as heme mimetics (TPP) and ester hematin variants. When heme models are used, since porphyrin alkylation is a favoured process, end-product distributions of products can be very different from when a free ferrous ion source is employed. Furthermore, solvent has been shown to have a profound effect on the rate of reaction and product distributions obtained in iron-mediated endoperoxide degradation. Thus all of these studies are truly only approximate models of the actual events within the malaria parasites. Future work is needed to correlate the results of biomimetic chemistry with the actual situation within the parasite. In general, most workers do accept the role of carbon-centred radicals in mediating the antimalarial activity of the endoperoxides, but the key information defining (a) the chemical mechanism by which these species alkylate proteins and (b) the basis for the high parasite selectivity remains to be unequivocally established. 

The first HNO complex, Os(PPh3)2(CO)(HNO)Cl2, was reported in 1970 upon exposure of HC1 to Os(PPh3)2(CO)(NO)Cl (173), and the X-ray crystal structure was published in 1979 (174). Recent interest has resulted in isolation of additional examples of HNO complexes, and the structures of three similar complexes have been reported [(Ru(HNO)(2,6-bis(2-mercapto-3,5-di-fert-butyl-phenylthio)dimethylpyridine) (175), ReCl(CO)2(PR3)2(HNO) (176), and IrHCl2 (PPh3)2(FINO) (177)]. Preparative routes generally involve protonation, hydride addition, or reduction of a coordinated nitrosyl (175, 176, 178-186). Farmer and co-workers also described the first synthesis of an HNO complex directly as a result of exposure to a donor compound (187) while Lee and Richter-Addo recently observed the HNO adduct of a heme model complex [ruthenium porphyrin (188)]. 

Myer YP, Pande A (1978) Circular dichroism studies ofhemoproteins and heme models. The porphyrins 3 271-322... 

The N-alkylation reaction represents a bifurcation of the normal alkene epoxidation reaction cycle and, therefore, N-alkylation is a suicide event that leads to catalytic inhibition in the native system. With synthetic tetraarylporphyrins that mimic the N-alkylation reaction, the use of halogen-substituted catalysts that are stable toward oxidative degradation (26, 27) provide the most useful model systems because the heme model remains intact for a significantly greater number of turnovers than the partition number. The partition number is the ratio of epoxidation cycles to N-alkylation cycles, i.e., N-alkyl porphyrins are formed before the heme is oxidatively destroyed. 

Model Compounds Very few ferrous complexes having non-porphyrin ligands react with dioxygen to form stable adducts. Unlike the pseudo-heme model complexes, all of the adducts prepared so far appear to be peroxo rather than superoxo species. To mimic the protein fragment on the non-heme proteins multidentate... 

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