Current Medicinal Chemistry - Volume 10, Issue 24, 2003

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.

The role of electrostatic forces in free radical biology is very important but it is all too often overlooked. The radicals discussed in this review include positivelycharged, negatively-charged and neutral water-soluble alkylperoxyls and superoxide. Important scientific insights have been gained by generating these radicals in known quantities by the thermal decomposition of simple, “clean”, chemical precursors in the presence of potential bio-targets. For example, the abilities of these radicals to damage double-stranded DNA, a polyanion, are dictated by Coulombic forces with only the positively-charged peroxyls being capable of directly producing single-strand breaks. The Coulombic control of the reactions and reaction rates of water-soluble peroxyl radicals which are so evident with DNA do not manifest themselves with all electrostatically charged biotargets, e.g., low density lipoprotein (LDL), probably because the charge on the surface of the LDL is not uniformly distributed.

Reactive oxygen species (ROS) are produced continuously in living cells as a by-product of respiration and other metabolic activity. Some ROS may react with DNA, and in some cases may abstract an electron from the double helix, leading to long range electron transfer (ET) reactions. Thus, the DNA of living cells may be in a continuous state of ET. We consider here whether acridine-based anticancer or antimicrobial drugs, which bind to DNA by intercalation, might either donate electrons to, or accept electrons from, the double helix, thus actively participating in ET reactions. We focus in particular on two acridine-based drugs that have been tested against human cancer in the clinic. Amsacrine is a 9-anilinoacridine derivative that appears to act as an electron donor in ET reactions on DNA, while N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) may act as an electron acceptor. Such reactions may make important contributions to the antitumor activity of these drugs.

In addition to synapse loss, neurofibrillary tangles, and neurodegeneration, oxidative stress and amyloid β-peptide [Aβ] deposition are hallmarks of Alzheimer's disease [AD] brain. Our laboratory coupled these two characteristics of AD into a comprehensive model to account for the synapse loss and neurodegeneration in AD brain. This model combines much of the extant studies on AD and is based on oxidative stress associated with amyloid β-peptide. This review presents evidence in support of this model and provides insight into the molecular basis of this devastating dementing disorder.

Cessation of blood flow to the liver is required during liver transplantation and resectional surgery. A growing body of experimental evidence suggests that restoration of blood flow to the ischemic liver initiates hepatocellular injury which may lead, in some cases, to severe liver injury and graft failure. A large number of studies have implicated reactive oxygen species as potential mediators of post-ischemic tissue injury. Recent developments in genetic engineering as well as chemical modeling, have allowed for the production of novel free radical scavengers including mutated forms of superoxide dismutase (SOD) and low molecular weight SOD mimics with extended circulating half-lives and / or significant membrane permeability's. Application of these newly developed free radical scavengers show promising results in animal models of liver I / R and may become powerful tools in the treatment of post-ischemic liver injury that occurs in liver transplantation.

Numerous pathophysiological disorders involve some element of oxidative stress and bioenergetic deficit. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been used recently as a promising new therapeutic strategy aimed at halting the bioenergetic decline associated with oxidative brain insults and other conditions. PARP-1 uses NAD+ as a substrate and is activated during stressful circumstances, mainly in the nucleus. PARP-1 inhibitors are well known for blocking the excessive consumption of NAD+, thereby preserving energy metabolism. But what is the role of mitochondria in this process? Recent investigations have begun to focus on whether mitochondrial function can also be preserved by PARP-1 inhibitors. This review will present some of the latest mechanistic evidence documenting the potential involvement of PARP-1 inhibitors in protecting mitochondrial function and preventing necrosis, apoptosis and mitochondrial calcium cycling.

Prostate cancer (PC) has become the most frequently diagnosed neoplasm and the second leading cause of cancer-related mortality in men. Its incidence rate has continued to increase rapidly during the past two decades, especially in men over the age of 50 years as they are living longer. The prostate in aging males is highly susceptible to benign and malignant proliferative changes. About two / thirds of all cancers, however, could have been prevented based upon lifestyle choices. The preventative and therapeutic options available to men prone to prostate cancer (both benign and malignant) are limited. How environment, diet and genetics interact to either induce or prevent prostate cancer (PC) is not known. Free radicals, called reactive oxygen species (ROS), play a significant but paradoxical role acting as a “double-edged sword” to regulate cellular processes. Recent in vitro studies using benign prostate hyperplasia (BPH) and PC cell lines grown under various oxidative stress conditions confirm this theory. This manuscript describes key signal transduction mechanisms involved in ROS induced effects on prostate cell growth, cell-cycle checkpoints, apoptosis and transcription factors and the role of potential dietary antioxidants on these mechanisms. It is important to understand underlying signaling mechanisms affected by oxidative stress so as to scientifically prove the efficacy and safety of potential antioxidants in PC prevention. Thus by identifying several potential preventive and therapeutic molecular targets in prostate and by devising better chemo-preventive and chemotherapeutic strategies for controlling PC progression, one can envision significant drop in number of deaths, cut down health care costs and improve the quality of life.

This review treats the mechanism of nitric oxide, catecholamines, and glutamate as important neurotransmitters and as neurotoxins, based on involvement of reactive oxygen species (ROS) and electron transfer (ET). ROS and ET can serve as a unifying framework for both transmission and toxicity, with ROS concentration being a crucial issue. Cell signaling, electrochemistry, antioxidants, and apoptosis are also discussed.

Evidence indicates that nerve gas toxins operate in ways in addition to inhibition of acetylcholine esterase. Alternative bioactivities are discussed with focus on electron transfer. The main class, including pralidoxime (2-PAM), incorporates conjugated iminium and oxime moieties that are electron affinic. Various physiological properties of iminium and oxime species are reviewed. The organophosphates encompass both nerve gases and insecticides, possessing similar properties, but different activities. Toxic manifestations are apparently due, in part, to oxidative stress. Alkylation of DNA takes place which may lead to generation of reactive oxygen species. Structure-activity relationships are examined, including reduction potentials and the captodative effect.

Gossypol, a constituent of cottonseeds, displays various drug properties, including antifertility and anticancer. Toxicity is shown against the reproductive system, heart, liver, and membranes. The compound exhibits pro- and anti-oxidant behavior. Electron transfer (ET) functionalities, present in gossypol and its metabolites, comprise conjugated dicarbonyl, a quinone derivative, Shiff bases, and metal complexes. The parent possesses a reduction potential favorable for in vivo ET. Considerable evidence points to oxidative stress (OS), formation of reactive oxygen species (ROS), and DNA scission, characteristics of redox cycling by ET in biosystems. Mechanistic aspects are addressed with OS-ROS-ET as the guiding theme, in addition to other modes of action resulting in a multifaceted scenario.

Cannabinoids comprise three classes of compounds, the active components of marijuana (Cannabis sativa), as well as endogenous and synthetic derivatives. To date, two distinct cannabinoid receptors (CB1 and CB2) have been discovered, but evidence for further receptor types has been brought forward. The potential use of cannabinoids for medicinal purposes has long been known, but the mechanisms of action of both exogenously applied and endogenous cannabinoids are only partly established. For nervous system disorders, cannabinoids may be useful by modulating neurotransmission and calcium homeostasis as well as by anti-inflammatory and antioxidant actions. Some cannabinoids can also trigger cell death, which may be of therapeutic benefit in the treatment of malignant tumours. A number of both in vitro and in vivo models have provided promising but diverse evidence for cannabinoid protection in glutamate-mediated excitotoxicity, hypoxia and glucose deprivation, brain trauma, epilepsy and MS. Subsequent to many preclinical investigations, clinical trials are now underway in a variety of the above applications. Overall, the understanding of the therapeutic relevance of cannabinoids will rely on further investigations into the neuroprotective and neurotoxic potency of cannabinoids in animal models and humans, as much as on a further advancement of our general understanding of the endocannabinoid system and the development of specific compounds devoid of unwanted psychoactive side effects.

The development of the first automated oligosaccharide synthesizer, along with new methods for screening carbohydrate ligand arrays is likely to lead to a rapid acceleration in both our ability to synthesize these molecules, and understand the roles of oligosaccharides and glycoconjugates in biology. Consequently we may uncover new avenues for therapeutic intervention more rapidly. These recent developments are very important since our understanding of the role of glycoconjugates in nature has traditionally fallen far behind that of the other biopolymers such as proteins and nucleic acids as the formation of, for example, glycosylated proteins is not template driven. The chemical synthesis of oligosaccharides and glycoconjugates has provided us with new potential cancer vaccines, antibiotics and new biotechnological tools. Glycobiologists have employed many such tools to uncover new signalling roles for oligosaccharides and glycoconjugates. In this review we aim to highlight some emerging methods for glycoconjugate assembly and screening, and discuss innovative approaches to glycoconjugate based drug design and delivery, all of which are, and will continue to be, fruitful avenues for medicinal chemistry research.