As a result of the adaptation of life to an aerobic environment, nature has evolved a panoply of metalloproteins for oxidative metabolism and protection against reactive oxygen species. Despite the diverse structures and functions of these proteins, they share common mechanistic grounds. An open-shell transition metal like iron or copper is employed to interact with O2 and its derived intermediates such as hydrogen peroxide to afford a variety of metal–oxygen intermediates. These reactive intermediates, including metal-superoxo, -(hydro)peroxo, and high-valent metal–oxo species, are the basis for the various biological functions of O2-utilizing metalloproteins. Collectively, these processes are called oxygen activation. Much of our understanding of the reactivity of these reactive intermediates has come from the study of heme-containing proteins and related metalloporphyrin compounds. These studies not only have deepened our understanding of various functions of heme proteins, such as O2 storage and trans...

Oxygen Activation and Radical Transformations in Heme Proteins and Metalloporphyrins

Mechanisms of chemical carcinogenicity and mutagenicity: a review with implications for predictive toxicology.

Oxidizing species in the mechanism of cytochrome P450

Cytochrome P450 mechanisms continue to surprise and delight, although the field is growing to maturity and the completely unexpected is less frequently encountered. Experimentally, the past few years have seen major progress in characterizing the intermediates that are formed as molecular oxygen is activated to the final oxidizing species. All the intermediates, with the exception of the critical ferryl species, have now been directly observed by various spectroscopic and crystallographic methods. The ferric peroxo anion has been found to act as the oxidizing agent with a growing range of highly electrophilic substrates. In contrast, the proposed role for the ferric hydroperoxo complex as an electrophilic oxidizing agent remains a matter of debate, as the evidence advanced in support of the proposal is circumstantial and contradictory. Although the ferryl species remains elusive, it is increasingly clear that it plays the predominant role as the oxidizing agent in the P450 catalytic cycle. A second area that has recently received considerable attention is the mechanism of hydrocarbon hydroxylation, the key question being whether the radical rebound mechanism that has held sway for three decades is in fact valid. The contradictory results obtained with radical and cation probes, which have provided most of the new evidence, must be resolved by further experimentation in order for this quest ionto be settled. The development of a two-state model for the catalytic action of P450 enzymes may be one of the most important recent advances in the field, as it provides a ready explanation for a variety of otherwise contradictory data, some of which argues for concerted and some for nonconcerted oxidation mechanisms. No doubt, the next few years will uncover novel aspects of P450 function and will lead to deeper and more sophisticated understanding of the catalytic mechanisms of the amazing family of P450 enzymes.

Substrate Oxidation by Cytochrome P450 Enzymes

Drug targeting to the kidney: Advances in the active targeting of therapeutics to proximal tubular cells.

The microsomal demethylation of N,N-dimethylbenzamides. Substituent and kinetic deuterium isotope effects.

Triazene drug metabolites. Part 17: Synthesis and plasma hydrolysis of acyloxymethyl carbamate derivatives of antitumour triazenes.

http://oro.open.ac.uk/15413/1/Acylaminoacyltriazenes%2DEJMedChem2008_reviewed.pdf

Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: synthesis and stability of N-acylamino acid derivatives of triazenes.

Purpose. The synthesis of chemically stable triazene prodrugs capable of hydrolysing under physiological conditions to liberate cytotoxic monomethyltriazene alkylating agents.

Triazene drug metabolites: part 15. Synthesis and plasma hydrolysis of anticancer triazenes containing amino acid carriers.

Acyloxymethyl derivatives of secondary and tertiary amides undergo hydrolysis via. acid-catalysed, base-catalysed and pH-independent processes. The pH-independent pathway involves rate-limiting iminium ion formation and is characterised by the following: a Hammett ρ value for the substituent in the benzamide moiety of ca.–1.2 for both types of substrate; the absence of general-base or nucleophilic catalysis; a common benzoate ion effect; a solvent deuterium isotope effect, kobsH2O/kobsD2O, of ca. 1.6; ΔS‡ values of –4 and –12 J K–1 mol–1 for secondary and tertiary substrates respectively; and higher reactivity of the tertiary amides over their secondary counterparts. The acid-catalysed process involves protonation of the substrate followed by iminium ion formation, and is characterised by the following: a Hammett ρ value of ca.–1.5 for the substituent effect of the benzamide moiety; a solvent deuterium isotope effect of ca. 0.4; a monotonic rise in the pseudo-first-order rate constant kobs with increasing [H2SO4]; ΔS‡ values > 0 J K–1 mol–1; higher reactivity of the tertiary substrates over their secondary counterparts; and a value of 0.85 for the Bronsted coefficient, βIg for the carboxylate nucleofuge. The base-catalysed hydrolysis of tertiary substrates involves normal ester hydrolysis via. acyl–oxygen bond cleavage, and is characterised by a Hammett ρ value of +0.38, a solvent deuterium isotope effect, kOH–/kOD–, of 0.85, and a ΔS‡ value of –96 J K–1 mol–1. The corresponding base-catalysed process for the secondary substrates involves imine formation via an E2 elimination reaction. The secondary acyloxymethylamides are some 7 × 104 times more reactive than their tertiary counterparts in the base-catalysed region. Hammett ρ values of +1.1 and +0.6 are obtained for the substituents in the ester and amide moieties, respectively. Buffer catalysis is observed, and the value of ca. 0.5 for the Bronsted β coefficient identifies the amide proton as approximately 50% transferred to the buffer species in the transition state.Heats of formation, ΔHf, calculated using the AM1 SCF MO package reveal that iminium ion formation is thermodynamically equi-energetic for cyclic and acyclic systems. Iminium ion formation from tertiary substrates is favoured by ca. 25 kJ mol–1 over the corresponding secondary analogues.

Eduarda Rosa

Papers

The microsomal demethylation of N,N-dimethylbenzamides. Substituent and kinetic deuterium isotope effects.

Triazene drug metabolites. Part 17: Synthesis and plasma hydrolysis of acyloxymethyl carbamate derivatives of antitumour triazenes.

Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: synthesis and stability of N-acylamino acid derivatives of triazenes.

Triazene drug metabolites: part 15. Synthesis and plasma hydrolysis of anticancer triazenes containing amino acid carriers.

Acyloxymethyl as a drug protecting group. Kinetics and mechanism of the hydrolysis of N-acyloxymethylbenzamides