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Preface [Hot topic: Oxidative Stress (Guest Editor: Peter Kovacic)]

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Ingold reviews the role of charge in reactions of alkylperoxyl radicals and superoxide with DNA and other biopolymers, a topic which has received scant attention. The abilities of the peroxyl radicals to attack polyanion DNA are controlled by Coulombic forces with only the positively charged ones being able to induce cleavage. Although the anionic and neutral radical counterparts do not directly cause DNA scission, they appear to cause extensive damage by oxidation of bases. However, Coulombic control is not evident with other electrostatically charged bio-targets, e.g., low density lipoprotein. Rationale is provided for the various observations.

Acridine-based drugs are important, particularly in the anticancer domain. In an appraisal of mechanism, Baguley, Wakelin, Jacintho, and Kovacic address involvement of electron transfer (ET), reactive oxygen species (ROS), and oxidative stress. 9-Anilinoacridines appear to function as electron donors in ET reactions with DNA. On the other hand, the acridine- 4 - carboxamides are proposed to act as electron acceptors. Based on the ET-ROS mechanistic framework, other drug activities of acridines are reviewed.

Alzheimer's disease is one of the most important areas in the medical field. Butterfield puts focus on oxidative stress and amyloid-β-peptide deposition, hallmarks of the disease, as part of a comprehensive model to account for synapse loss and neurodegeneration in the brain. Discussion entails reactive oxygen species (including peroxynitrite), protein oxidation, lipid peroxidation, roles of methionine residues and metals, and fibril formation.

On the topic of liver transplantation, Hines, Harada, Wolf, and Grisham discuss therapy for protection against severe liver injury and graft failure. Much evidence points to involvement of reactive oxygen species in post - ischemic tissue injury. Recent work provides novel free radical scavengers including mutated forms of superoxide dismutase (SOD) and low molecular weight SOD mimics, which possess favorable properties. One example is the SOD mimic AEOL 10150.

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors represent a new therapy for various brain insults arising from oxidative stress. Klaidman, Yang, Chang, and Adams discuss mechanistic features. PARP-1 inhibitors block excess consumption of NAD+, preserve energy metabolism, protect mitochondrial function, and prevent necrosis, apoptosis, and Ca cycling.

Prostate cancer is the second leading cause of cancer-related mortality in men. Sikka shows that reactive oxygen species (ROS) play a significant, but paradoxical, role, acting as a “double-edged sword” in regulation of cellular processes. The review describes key signal transduction mechanisms involved n ROS-induced effects on prostate cell growth, cell-cycle checkpoints, apoptosis and transcription factors, and the role of antioxidants. Chemo-preventive and chemotherapeutic strategies are addressed.

Jacintho and Kovacic review the mode of action of nitric oxide, catecholamines, and glutamate as important neurotransmitters and as neurotoxins, based on reactive oxygen species (ROS) and electron transfer (ET). ROS and ET can provide a unifying theme for both activities, with concentration being a critical factor. Also discussed are cell signaling, electrochemistry, antioxidants, and apoptosis.

The subject of organophosphate nerve gases and pesticides has attracted considerable attention in public, scientific, and military forums. Kovacic addresses the mode of action of these agents and their antidotes. In addition to regeneration of inhibited acetylcholine esterase, other bioactivities of the pyridyl oxime antidotes are considered. The possible role of electrochermical properties of the antidotes is analyzed, along with supporting evidence. Structure - activity relationships are examined, including reduction potentials and the captodative effect.

Gossypol, a constituent of cottonseeds, has received considerable attention as a drug and toxin. From the perspective of reactive oxygen species and electron transfer, Kovacic discusses the mechanistic aspects. Main interest in the drug properties has been on male infertility and anticancer, and to a lesser degree on antiprotozoan , antiparasitic, and antiviral. In addition to carcinogenesis, gossypol exhibits toxicity in the following areas: reproductive, cardio, hepato, and membrane. The substance has potential for electron transfer either per se or as a metabolite (quinone, Schiff base or metal complex). Mechanistic discussion includes reduction potential and enzyme inhibition.

Document Type: Review Article


Affiliations: Department of Chemistry San Diego State University San Diego California 92182-1030 USA

Publication date: 2003-12-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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