Philip W. Crawford

Cyclic voltammetry of phenazines and quinoxalines including mono- and di-N-oxides. Relation to structure and antimicrobial activity

Cyclic voltammetry data were obtained for eight phenazines and phenazine-N-oxides, and eleven quinoxalines and quinoxaline-N-oxides: 1,6-phenazine-diol-5,10-dioxide (iodinin), iodinin copper complex, 6-methoxy-1-phenazinol-5,10-dioxide 1,6-dimethoxyphenazine-5-oxide, 1,6-phenazinediol, 1,6-dimethoxyphenazine, quinoxaline-1,4-dioxide, 2-methylquinoxaline-1,4-dioxide, 2,3-diphenylquinoxaline-1,4-dioxide, 2-carboxyquinoxaline-1,4-dioxide, 5-hydroxyquinoxaline-1,4-dioxide, 5-hydroxy-8-methoxyquinoxaline-1,4-dioxide, 2-methylquinoxaline, 2,3-diphenylquinoxaline, 5-hydroxyquinoxaline, 5-hydroxy-8-methoxyquinoxaline and 2-(2-quinoxalinylmethylene)hydrazine carboxylic acid methyl ester-1,4-dioxide (Carbadox). The di-N-oxides exhibit the most positive E1/2 values within each class. Reversible first wave reductions were observed for iodinin, iodinin copper complex, 1,6-dimethoxyphenazine-5-oxide, 1,6-dimethoxyphenazine, quinoxaline-1,4-dioxide, 2-methylquinoxaline-1,4-oxide and 2,3-diphenylquinoxaline-1,4-dioxide. The results are correlated with structure. Some relationships exist between reduction potential and reported antimicrobial activity. A possible mechanism of drug action is addressed.

The electrochemistry of antineoplastic furanquinones: Electrochemical properties of benzo[b]naphtho[2,3-d]furan-6,11-dione derivatives

Abstract The electrochemical reductions of 9 benzo[ b ]naphtho[2,3- d ]furan-6,11-dione derivatives in dimethylformamide were investigated. In the aprotic medium the quinones reduced in two successive one-electron steps. The influence of molecular structure on reduction potential is addressed. The reduction process involved a single irreversible two-electron process in the presence of a proton source, occurring via an ECE mechanism. A relationship is observed between reduction potential and reported inhibitory activity against various cancer cell lines. The hydroxyl substituted derivatives exhibit the most positive E 1 2 values and have generally more potent activities.

Charge transfer mechanism for benzodiazepine (BZ) action: Correlation of reduction potential of BZ iminium with structure and drug activity

Abstract A novel mechanism for BZ action is proposed in which a BZ is protonated by GABA or protein RNH3+ to yield an iminium species that is responsible for drug activity via charge transfer (c.t.). The following evidence from our work and prior studies supports this concept: • binding sites for BZs and GABA are apparently on the same protein complex; data point to possible interaction between the two ligands; • recent theoretical studies propose reaction of basic imine of BZ with cationic RNH3+ of protein at the receptor site; • BZ is protonated by weak acids, such as acetic and GABA, to give iminium ions which exhibit appreciable and favorable increases in reduction potential in vitro; • the reduction potentials are of the same order of magnitude as for a number of other biologically active compounds; • reversible electron uptake has been shown to occur with some protonated BZ drugs; |Up - Up/2| calculations from the voltammograms of some BZs indicate the potential for reversible electrochemical processes; • correlations exist involving reduction potential of BZ iminium, structure, and drug activity; • a significant number of BZ agonists, inverse agonists, and antagonists incorporate the imine-type precursor of iminium; • the postulated c.t. pathway is in keeping with a variety of bioelectrochemical phenomena arising from active site binding.

Novel quinoxaline 1,4-di-N-oxide derivatives as new potential antichagasic agents

As a continuation of our research and with the aim of obtaining new agents against Chagas disease, an extremely neglected disease which threatens 100 million people, eighteen new quinoxaline 1,4-di-N-oxide derivatives have been synthesized following the Beirut reaction. The synthesis of the new derivatives was optimized through the use of a new and more efficient microwave-assisted organic synthetic method. The new derivatives showed excellent in vitro biological activity against Trypanosoma cruzi. Compound 17, which was substituted with fluoro groups at the 6- and 7-positions of the quinoxaline ring, was the most active and selective in the cytotoxicity assay. The electrochemical study showed that the most active compounds, which were substituted by electron-withdrawing groups, possessed a greater ease of reduction of the N-oxide groups.

Electrochemical Properties of Some Biologically Active Quinone Derivatives: Furanquinones, Pyridoquinones, and Diplamine, a Cytotoxic Pyridoacridine Alkaloid

The electrochemical properties of 17 furanquinones, 5 pyridoquinones, and the iminoquinone diplamine in aprotic solvent systems were investigated. For the furanquinone and pyridoquinone derivatives, the quinone/semiquinone and semiquinone/dianion redox couples were observed as two successive one-electron transfer steps during cyclic voltammetry. For the pyridoquinones, two additional voltammetric waves attributed to nitro group reduction were observed at more negative potentials. The influence of molecular structure on quinone reduction potential is addressed. Reduction of diplamine was analogous to reduction of the quinones, occurring in two successive one-electron processes. In the presence of a proton donor, pyridoquinone reduction occurred via an ECEC mechanism. For the furanquinones, a general relationship is observed between reduction potential and reported inhibitory activity against various cancer cell lines.

844 — Charge transfer mechanism for carcinogenesis by alkylating and other agents

Abstract This study was undertaken as an outgrowth of the oxy radical-iminium theory of carcinogenesis. A conjugated iminium species is thought to act in certain cases as a charge transfer entity resulting in the generation of oxy radicals which attack DNA. The iminium ion is commonly formed from the purine constituents of nucleic acids via electrophilic attack by alkylating agents. In electrochemical studies, the protonated forms of the purines are used as models for the salts generated in vivo by alkylation. Polarographic and cyclic voltammetry data correlate remarkably well with the current picture relating carcinogenicity with site of alkylation and defect persistence. Other oncogens, e.g., quinones, metals, N-oxypurines, radiation, carbon tetrachloride, 4-nitroquinoline-1-oxide, and inert bodies, are also discussed. The general theory and accompanying experimental results are in keeping with various important facets of the cancer literature. Therefore, a charge transfer mechanism appears reasonable for the cell-transforming process resulting from the action of alkylating and certain other agents.

CHARGE TRANSFER-OXY RADICAL MECHANISM FOR ANTICANCER AGENTS: mAMSA DERIVATIVES, RHODAMINE 123, AND NICKEL SALICYLALDOXIMATE

The proposal is advanced that many anticancer agents may function via redox reactions resulting in generation of toxic oxy radicals which destroy neoplastic cells. Cyclic voltammetry was performed with some of the main types: iminium ions (protonated mAMSA derivatives), quinone derivatives (rhodamine 123) and metal complexes (nickel(II) salicylaldoximate). In addition, relevant literature data are provided. A rationale is offered that relates electrochemical data to physiological activity.

The electrochemistry and spectroelectrochemistry of sulfate complexes of iron porphyrins

The spectroscopy and electrochemistry of [Fe(TPP)]2SO4 and [Fe(OEP)]2SO4 in methylene chloride, dimethylformamide and dimethyl sulfoxide was examined. In methylene chloride, the reduction of iron(III) to iron(II) porphyrins occurs in two well-separated reduction waves. The first wave corresponds to the reduction of the sulfate-bridged dimer to Fe(P) and Fe(P)(SO4)−, where P=TPP or OEP. The second wave corresponds to the reduction of Fe(P)(SO4)− to Fe(P). The reduction of Fe(P) occurs at the normal potential for the iron(II)/iron(I) porphyrin reduction. These results were confirmed by visible spectroelectrochemistry, proton NMR and EPR spectroscopy. In coordinating solvents such as DMF or DMSO, the sulfate-bridged dimer dissociated and a single iron(III)/iron(II) wave was observed. The addition of sulfate to the sulfate-bridged complex in methylene chloride or chloroform lead to the dissociation of the complex into the sulfate monomer complexes. The NMR spectrum of Fe(TPP)(SO4)− was typical of a high-spin ferric porphyrin complex, and was almost indistinguishable from Fe(TPP)Cl. In the presence of excess sulfate, only one iron(III)/iron(II) wave was observed, and this wave occurred at the potential of the second wave for the sulfate-bridged dimer. As with the dimer itself, this wave was quite quasi-reversible, and the reduction wave occurred substantially negative of the iron(III)/iron(II) wave for Fe(TPP)Cl. The spectroelectrochemistry of the reduced product was consistent with a Fe(II)(TPP)(SO4)2− complex. The strong complex between sulfate and iron(II) is probably due to the poor solvation of sulfate in these organic solvents. In DMSO, the results were similar to methylene chloride, except that there was no evidence for complexation of sulfate with the ferrous species. In addition to the sulfate complex, the bisulfate complex of ferric OEP was also examined, as well as the reaction of bisulfate with Fe(TPP)(ClO4). The infrared, visible and NMR spectra for Fe(OEP)(HSO4) were obtained.