ion phase that leads to an alkyl radical coordinated to the iron-hydroxo complex by a weak OH---C hydrogen bond, labeled as CI; (ii) an alkyl (or OH) rotation phase whereby the alkyl group achieves a favorable orientation for rebound; and (iii) a rebound phase that leads to C-O bond making and the ferric-alcohol complexes, 4,2P. The two profiles remain close in energy throughout the first two phases and then bifurcate. Whereas the HS state exhibits a significant barrier and a genuine TS for rebound, in the LS state, once the right orientation of the alkyl group is achieved, the LS rebound proceeds in a virtually barrier-free fashion to the alcohol. As such, alkane hydroxylation proceeds by TSR,70-72,120 in which the HS mechanism is truly stepwise with a finite lifetime for the radical intermediate, whereas the LS mechanism is effectively concerted with an ultrashort lifetime for the radical intermediate. Subsequent studies of ethane and camphor hydroxylation by the Yoshizawa group117,181-183 arrived at basically the same conclusion, that the mechanism is typified by TSR. The differences between the results of Shaik et al.130,173,177-180 and Yoshizawa et al.117,181-183 were rationalized recently71,72 and shown to arise owing to technical problems and the choice of the mercaptide ligand,117,181-183 which is a powerful electron donor and is too far from the representation of cysteine in the protein environment. The most recent study of camphor hydroxylation, which was done at a higher quality,117 converged to the picture reported by Shaik et al.130,173,177-180 and shows a stepwise HS process with a barrier of more than 3 kcal/mol for C-O bond formation by rebound of the camphoryl radical vis-à-vis an effectively concerted LS process for which this barrier is 0.7 kcal mol-1 and is the rotational barrier for reaching the rebound position. By referring to Figure 21, it is possible to rationalize the clock data of Newcomb in a simple manner. The apparent lifetimes are based on the assumption that there is a single state that leads to the reaction, such that the radical lifetime can be quantitated from the rate constant of free radical rearrangement and the ratio of rearranged to unrearranged alcohol product. However, in TSR, the rearranged (R) product is formed only/mainly on the HS surface, while the unrearranged (U) product is formed mainly on Figure 20. Formal descriptions of iron(III)-peroxo, iron(III)-hydroperoxo, and iron(V)-oxo species with indication of the negative charges. The roles “electrophile” or “nucleophile” are assigned according to the charge type. Reprinted with permission from ref 7. Copyright 2000 Springer-Verlag Heidelberg. 3964 Chemical Reviews, 2004, Vol. 104, No. 9 Meunier et al.

Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes.

Reactions and Significance of Cytochrome P-450 Enzymes"

Two-state reactivity mechanisms of hydroxylation and epoxidation by cytochrome P-450 revealed by theory.

Photoactivated porphyrins display a potent cytotoxic activity towards a variety of Gram positive bacteria, mycoplasma and yeasts, but not Gram negative cells. The prerequisite for photosensitization of a microbial cell is the binding of porphyrin to the cytoplasmic membrane in a pH-dependent manner. On illumination, the membrane bound, and possibly, cytoplasmic porphyrin molecules generate singlet oxygen and radicals which sensitize biomolecules and lead to cell death. The immediate inhibition of cell growth on photodynamic treatment is accompanied by alterations in cell wall and membrane synthesis, leading to the formation of large mesosomes adjacent to the unaccomplished septa. Hemin bound to microbial cells exerts cytotoxic activity by peroxidative and oxidative reactions independent of light. Future research in the field may enhance the possibility of using porphyrin photosensitization for treatment of microbial infections. Such clinical use will be unrelated to the antibiotic resistance of the pathogen. Resistance of Gram negative bacteria to porphyrin photosensitization is the main impediment to its use as a broad spectrum antibacterial method.

New trends in photobiology bactericidal effects of photoactivated porphyrins — An alternative approach to antimicrobial drugs

Cytochrome P450s (P450s) are subject to inhibition/inactivation by various chemically diverse agents, which may interact directly or indirectly with either the P450 prosthetic heme or the protein moiety or with both moieties. This inhibition is clinically relevant, as it can block physiological pathways as well as result in therapeutically significant beneficial or adverse effects and clinically relevant drug–drug interactions. Herein, we discuss the various chemical agents and their chemical mechanisms that lead to such reversible, quasi-irreversible, or irreversible inhibition of these enzymes. We note that such inhibition targeted at P450-dependent physiological and/or pathological processes has been ingeniously and effectively harnessed not only in the design and development of clinically relevant therapeutic agents but also of fungicides, insecticides, and herbicides.

Inhibition of Cytochrome P450 Enzymes

Hydroxylation of aliphatic hydrocarbons with oxidants such as iodosobenzene can be effectively catalyzed with highly halogenated iron(III) porphyrins such as iron(III) tetrakis(2,6-dichlorophenyl)octabromoporphyrin. Hydroxylation of norbornane and tetraexodeuterionorbornane using this catalyst afforded good yields of products which consisted of 86:13:<1 and 84:16:<1 ratios of exo-norbornan-2-ol, endo-norbornan-2-ol, and 2-norbornanone, respectively. In the latter case both D 3 and D 4 exo and endo alcohols but only D 3 ketone were obtained

Aliphatic hydroxylation catalyzed by iron(III) porphyrins

Mechanisms of hemin-catalyzed alkene epoxidation. The effect of catalyst on the regiochemistry of epoxidation

Kinetics of iron(III) porphyrin catalyzed epoxidations

During the course of hemin-catalyzed epoxidation of norbornene and other alkenes, the hemin catalyst is converted to N-alkylhemin by addition to the alkene.

Transient formation of N-alkylhemins during hemin-catalyzed epoxidation of norbornene. Evidence concerning the mechanism of epoxidation

Iron(III) porphyrins efficiently catalyze the epoxidation of alkenes and the hydroxylation of alkanes by iodosylbenzenes and peracids, most likely by the same mechanisms utilized by cytochrome P-450 enzymes. The synthetic catalysts mimic the enzymes in product stereospecificity, 1 the accompanying rearrangements, 2 and the suicide labelling which results in N-alkylhemin formation.3

Beth E. Dunlap

Papers

Aliphatic hydroxylation catalyzed by iron(III) porphyrins

Mechanisms of hemin-catalyzed alkene epoxidation. The effect of catalyst on the regiochemistry of epoxidation

Kinetics of iron(III) porphyrin catalyzed epoxidations

Transient formation of N-alkylhemins during hemin-catalyzed epoxidation of norbornene. Evidence concerning the mechanism of epoxidation

Cytochrome P-450 Model Systems: Alkene Oxidation