James R. Ames

Mechanism of antibacterial action: Electron transfer and oxy radicals

Most of the main categories of bactericidal agents, namely, aliphatic and heterocyclic nitro compounds, metal derivatives and chelators, quinones, azo dyes, and iminium-type ions, are proposed to exert their action by a unified mechanism. The toxic effect is believed to result generally from the catalytic production of reactive oxygen radicals that usually arise via electron transfer. Cyclic voltammetry was performed on a number of these agents. Reductions were for the most part reversible, with potentials in the favorable range of -0.20 to -0.58 V.

Cyclic voltammetry with cyclic iminium ions: Implications for charge transfer with biomolecules (metabolites of nicotine, phencyclidine, and spermine)

Abstract Recently, the theory was advanced that the iminium species plays a widespread role in living systems as a charge transfer agent. Cyclic voltammetry was applied to model compounds, 3,4-dihydro-1,5-dimethyl-2H-pyrrolium perchlorate 2 and 3,4-dihydro-1-methyl-5-phenyl-2H-pyrrolium chloride 3 , in order to provide reference data. Compounds 2 and 3 gave reductions with E p = −1.11 and −0.98 V, respectively, vs SCE (DMF). Reactions were also carried out in water and benzonitrile. Resonance and inductive effects are used to rationalize the data. Iminium ions 5, 12, and 18 are intermediary oxidative metabolites of nicotine 6 , the hallucinogenic drug phencyclidine 8 , and spermine 17a , respectively. Reduction potentials are −1.04, −0.93, and −1.10 V, respectively. It is suggested that electon transfer mediated by iminium moieties may be related to biological activity. Examples are presented of electrochemically reducible iminium compounds which exhibit physiological activity in a variety of areas.

Oxidative Ionic Metabolites of L-Methyl-4-Phenyl-L, 2, 3, 6-Tetrahydropy-Ridine (MPTP): Correlation of Electro-Reduction with Physiological Behavior

Electrochemical studies (reduction potential and reversibility) were performed on 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+). MPP+ gave reduction potentials in the range of -1.09 to -1.11 V in organic solvents in a process which was reversible. The reduction potential of MPDP+ was -0.64 V (irreversible). Possible relationships involving the electrochemical properties, oxy radical formation, and biological activity of these and related iminium species are discussed.

Reduction potentials of anthelmintic drugs: Possible relationship to activity

Electrochemical data were acquired for several categories of anthelmintic agents, namely, iminium-type ions, metal derivatives and chelators, quinones and iminoquinones, and nitroheterocycles. Reductions usually were in the favorable range of +0.2 to -0.7 V versus normal hydrogen electrode. The drug effect is believed to result in part from either the catalytic production of oxidative stress or disruption of helminth electron transport systems. Relevant literature results are discussed.

Conjugated and cross-conjugated mesomeric betaines. correlation of electroreduction with structure and physiological activity

Electroreduction studies were performed on several cross-conjugated mesomeric betaines containing the fused pyrazolium (2) and fused imidazolium (3) ring systems. Studies at acidic pH were of principal interest. Substituent effects for 2 were in line with prior findings, and reduction potentials were comparatively negative (-0.96 to -1.34 V). Reduction potentials fit the modified Hammett equation. Compound 3 was more readily reduced (-0.88 V). The related psi-oxatriazoles (6) gave values in the range of -0.85 to -1.22 V. The electrochemical characteristics are compared with those of the mesoionic sydnones (4) and sydnoneimines (5). These mesoionic compounds were generally reduced at more positive potentials than 2 and 3. A relationship between electroreduction and physiological activity is proposed. The overall results are in keeping with the hypothesis of widespread participation of iminium-type species in biological systems.

Mode of action of antiprotozoan agents. Electron transfer and oxy radicals

Cyclic voltammetry data were obtained for most of the main classes of antiprotozoan agents, specifically, nitroheterocycles, quinones, metal complexes and derivatives, iminium-type ions, and azo compounds. The reductions were generally reversible in the range of -0.3 to -0.9 V. Catalytic production of oxidative pressure from redox cycling involving oxygen is believed to be an important mode of action by the medicinal agents. Literature data contribute support.

A novel approach to β-lactam chemistry in vivo: Electron transfer and oxy radical formation by iminium

Abstract On binding to cell-wall enzyme, β-lactams form precursors of conjugated iminium species that apparently possess favorable reduction potentials based on studies with model compounds. The models used were iminium salts of Δ1-pyrroline-2-carboxylic acid and Δ3-thiazoline-4-carboxylic acid. Reduction potentials of −0.76 to −0.92 V increased to −0.18 to −0.37V with decrease in pH. The potentials of the iminium species are similar to those of well-known electron transfer (ET) agents, such as quinones, nitroheterocycles, and metal complexes. Catalytic ET by these cations is discussed in relation to nephrotoxicity, antibiotic action, and cell culture redox potential. Reactions of penicillin at the binding site are addressed. We propose that the bactericidal effect involves various modes of action, including inactivation of cell-wall enzyme and electrochemical interference with normal electron transfer processes.

Electron Transfer Mechanism for β-lactam Antibiotic Action via Side-Chain Imine

Abstract Evidence has been previously presented for an electron transfer (ET) component associated with the mechanism of action of β-lactam antibiotics, in addition to enzyme inactivation. For the fused-ring types, apparently the ET entity is a conjugated iminium group formed as a result of ring-opening. We now report on the feasibility of ET associated with several monocyclic and cephalosporin β-lactams that contain conjugated imine in the acyl side chain. The side chain assumes increased importance for the monobactams and nocardicins since ring scission does not generate iminium. The monocyclic agents generally reduced in the favorable range of −0.5 to −0.6 V at pH 4.1. The cephalosporin drugs potentially contain two electroactive sites, iminiums from ring-opening and from generation in the side chain. Electroreduction involving the side-chain oxime occurred at about −0.4 to −0.7 V (pH 4.1). Model compounds are used to provide additional mechanistic insight. There are various sources of hydrogen ions needed for iminium formation at the active site. Comparisons are made between reduction potential and antibiotic activity. The mode of bactericidal action is discussed with focus on ET by iminium.

Reduction potentials of antimycobacterial agents: Relationship to activity

Abstract Electrochemical studies (reduction potential and reversibility) were performed on several antimycobacterial agents to gain insight regarding the proposal that many drugs exert part of their activity via an electron transfer process which results in the production of oxidative stress or the disruption of electron transport systems. Reduction potentials provide data relevant to the feasibility of electron transfer in vivo. Categories of antimycobacterial agents include iminium-type ions from ethionamide and pyrazinamide, coordination complexes (Cu or Fe) of chelators (isoniazid, thiosemicarbazones, p -aminosalicylic acid, and ethambutol) and quinone types (clofazimine). Reduction potentials ranged from 0.26 to −0.6 V. Relevant literature data are discussed.

Anticancer Quinones and Quinolines: Mode of Action Via Electron Transfer and Oxidative Stress

General background material may be found in our companion article in these Proceedings dealing with other anticancer agents1.