Current Medicinal Chemistry - Volume 20, Issue 36, 2013

Hydroxycinnamic acids (HCAs) are important phytochemicals possessing significant biological properties. Several investigators have studied in vitro antioxidant activity of HCAs in detail. In this review, we have gathered the studies focused on the structure-activity relationships (SARs) of these compounds that have used medicinal chemistry to generate more potent antioxidant molecules. Most of the reports indicated that the presence of an unsaturated bond on the side chain of HCAs is vital to their activity. The structural features that were reported to be of importance to the antioxidant activity were categorized as follows: modifications of the aromatic ring, which include alterations in the number and position of hydroxy groups and insertion of electron donating or withdrawing moieties as well as modifications of the carboxylic function that include esterification and amidation process. Furthermore, reports that have addressed the influence of physicochemical properties including redox potential, lipid solubility and dissociation constant on the antioxidant activity were also summarized. Finally, the pro-oxidant effect of HCAs in some test systems was addressed. Most of the investigations concluded that the presence of ortho-dihydroxy phenyl group (catechol moiety) is of significant importance to the antioxidant activity, while, the presence of three hydroxy groups does not necessarily improve the activity. Optimization of the structure of molecular leads is an important task of modern medicinal chemistry and its accomplishment relies on the careful assessment of SARs. SAR studies on HCAs can identify the most successful antioxidants that could be useful for management of oxidative stress-related diseases.

DNA mutation is a very important step in carcinogenesis and elevated levels of oxidative DNA damage have been monitored in a variety of tumors. The discovery of the role of free radicals in cancer has led to a new medical approach. Minimizing oxidative damage may be a significant advance in the prevention or treatment of these diseases, since antioxidants are able to stop the free-radical formation and prevent oxidizing chain reactions. These findings have generated great interest in therapeutic antioxidant-based cancer drug development. The design and development of synthetic compounds, able to scavenge free radicals, could present a significant therapeutic advance, in particular for treating pathological conditions such as cancer. This article will outline the state of the research on the relationship between antioxidant therapy and cancer, describing the new synthetic antioxidant molecules that have anticancer activities. Investigations and association between dietary antioxidants, oxidative stress, and cancer will be also discussed.

Antioxidants are of great interest because of their involvement in important biological and industrial processes. According to Halliwell antioxidants are substances that at low concentration significantly delay or prevent oxidation. Chemically, oxidation is a process in which a loss of electrons occurs. Oxidants play a significant role in the pathogenesis of a number of disorders leading to oxidative stress. Oxidative stress may be defined as an imbalance between cellular production of reactive oxygen species and antioxidant defense mechanisms. ROS (e.g., superoxide radical, peroxynitryl, hydroxyl radical and hydrogen peroxide) are constantly produced as a result of metabolic reactions in living systems. Oxidative damage caused by ROS is responsible for many degenerative diseases such as cancer, atherosclerosis, diabetes, cirrhosis, Alzheimer’s and inflammatory diseases. The aim of this review is to describe recent developments in the study of the antioxidant activity of thiazole and thiazolidinone derivatives, which are the core structure in a variety of pharmaceuticals with a broad spectrum of biological activity and their role in preventing the formation of ROS.

Xanthones (dibenzo-γ-pyrones) constitutes an important class of oxygenated heterocycles and occur as secondary metabolites in plants and microorganisms. They are known for various biological activities such as antioxidant, monoamine oxidase inhibitor, antihypertensive, hepatoprotective, antithrombotic, antifungal and anticancer. The tricyclic scaffold as well as the nature and/or position of the substituents present on it play an important role in displaying various biological activities. The unique structural scaffold and medicinal importance of xanthones have therefore attracted many Scientists in the past, to isolate or synthesize xanthones or their analogs as potential drug candidates. It would not be wrong to call them as close cousins to the polyphenol family that are known to possess strong antioxidant effects on the nervous system. The main two sources of xanthones are: Isolation from natural resources or synthesis. Though few reviews have been published in the past, mainly focusing on the anticancer activities of xanthone derivatives, but there is not a single review which is based on their antioxidant activities. We therefore have made efforts to briefly summarize natural and synthetic xanthones possessing antioxidant activity in this review.

Recent years have witnessed an unprecedented progress in biological applications of metal coordination compounds of biologically active ligands because of their key role in clinical therapy. Transition metals are particularly suitable for this purpose because they can adopt a wide variety of coordination numbers, geometries and oxidation states in comparison with other main group elements. One of the characteristics of metals is their potential to undergo redox processes, as determined by their redox potentials. Especially, transition metal ions are usually able to switch between several oxidation states. Due to the redox activity of metals and, therefore, a possible disturbance of the sensitive cellular redox homeostasis, a tight regulation of the metal and redox balance is crucial for health. On the other hand, over production of activated oxygen species, generated by normal metabolic process, is considered to be the main contributor to oxidative damages to biomolecules such as DNA, lipids and proteins, thus accelerating cancer, aging, inflammation, cardiovascular and neurodegenerative diseases. The potential value of antioxidants has already prompted investigators to search for the cooperative effects of metal complexes and natural compounds for improving antioxidant activity. Depending on their structure and on the source of the oxidative stress, metal complexes might act as antioxidants or prooxidants. The current review provides insight into the interaction between the reactive oxygen species and the transition metals and their complexes. It will focus on a novel approach to design synthetic antioxidant metal-based compounds and to study their activities in the oxidation processes. This work underlines some important features for the research on metal complexes of biologically active ligands as antioxidants, and supports future evaluation of some of these compounds as possible therapeutic agents.

Heavy metals are known to cause oxidative deterioration of bio-molecules by initiating free radical mediated chain reaction resulting in lipid per-oxidation, protein oxidation and oxidation of nucleic acid like DNA and RNA. The development of effective dual functioning antioxidants, possessing both metal-chelating and free radical-scavenging properties should bring into play. Administration of natural and synthetic antioxidants like, quercetin, catechin, taurine, captopril, gallic acid, melatonin, N-acetyl cysteine, α- lipoic acid and others have been recognized in the disease prevention and clinical recovery against heavy metal intoxication. These antioxidants affect biological systems not only through direct quenching of free radicals but also via chelation of toxic metal(s). These antioxidants also, have the capacity to enhance cellular antioxidant defense mechanism by regenerating endogenous antioxidants, such as glutathione and vitamin C and E. They also influence cellular signaling and trigger redox sensitive regulatory pathways. The reactivity of antioxidants in protecting against heavy metal induced oxidative stress depends upon their structural properties, their partitioning abilities between hydrophilic and lipophilic environment and their hydrogen donation antioxidant properties. Herein, we review the structural, biochemical and pharmacological properties of selected antioxidants with particular reference to their ability to (i) chelate heavy metals from its complex (ii) ameliorate free radical (iii) terminate heavy metal induced free radical chain reaction (iv) regenerate endogenous antioxidants and, (v) excretion of metal without its redistribution.

In recent years, much attention has been given to dietary antioxidants, especially polyphenols. Several peptides derived from protein molecules have also been found to show antioxidant capacity along with other biological properties and thus there is an increasing interest in these compounds as health promoters. This review summarizes and discusses the main sources of antioxidative peptides with focus on food-derived peptides (animal, plant and marine sources), methods of preparation, antioxidant capacity evaluation as well as their proposed mechanisms of action. A discussion of the potential health effects and comments on the different applications for these antioxidants and their potential research interest are also subject of this review.

Oxidative stress is implicated in the pathogenesis of different human diseases: Alzheimer, Parkinson, Huntington, amyotrophic lateral sclerosis (Lou Gehrig's disease), Down’s syndrome, atherosclerosis, vascular disease, cancer, diabetes mellitus type 1 and type 2, age – related macular degeneration, psoriatic arthritis. The aim of current study is to summarize the scientific evidences for the antioxidant and neuroprotective activity of Galantamine and some of its derivatives. Galantamine is a scavenger of reactive oxygen species and causes neuroprotective effect by lowering the oxidative neuronal damage, through the following pathways: 1) prevention of the activation of P2X7 receptors; 2) protection of mitochondrial membrane potential; 3) pre – vention of the membrane fluidity disturbances. Another mechanism is the decreasing of the overproduction of reactive oxygen species, a result from the increasing of acetylcholine level due to: 1) acethylcholinesterase inhibition; 2) allosteric potentiation of α7 – subtype of nicotinic acetylcholine receptors. A close relationship between acethylcholinesterase inhibition and reduced oxidative injury is observed. Through allosteric potentiation of the α7 – subtype of nicotinic acetylcholine receptors, the drug leads to induction of phosphorylation of serine – threonine protein kinase, stimulates phosphoinositide 3 – kinase and elevates the expression of protective protein Bcl – 2. By activation of these important neuroprotective cascades, Galantamine exerts neuroprotection against a variety of cytotoxic agents (β– amyloid peptide, glutamate, hydrogen peroxide, oxygen and glucose deprivation). The new trend in therapy of Alzheimer's disease will be the investigation and application of compounds such as Galantamine derivatives, which possess acethylcholinesterase and γ – secretase inhibitory activity and antioxidant properties.

The search for metal-derived antioxidants has received much attention and effort in order to identify the compounds having high capacity in scavenging free radicals related to various disorders and diseases associated with oxidative damage, caused by reactive oxygen species (ROS). Presently, synthetic antioxidants are widely used because they are effective and cheaper than natural antioxidants. Currently a number of Schiff-base metal complexes have been investigated as effective scavengers of ROS, acting as antioxidants. The aim of this review is to highlight specific characteristics of Schiff-based compounds capable of chelating metal ions and their antioxidant activity. Schiff bases form an important class of organic compounds with a wide variety of biological properties. Schiff bases have often been used as chelating ligands in the field of coordination chemistry, and their metal complexes have been of great interest to researchers for many years. The activity is usually increased by complexation therefore to understand the properties of both ligands and metal can lead to the synthesis of highly active compounds. The influence of certain metals on the biological activity of these compounds and their intrinsic chemical interest as multidentate ligands has prompted a considerable increase in the study of their coordination behavior. Development of a new chemotherapeutic Schiff bases and their metal complexes is now attracting the attention of medicinal chemists.

The antioxidants and antioxidant enzyme systems belong to the major protective systems of the organism. The use of retinoic acid in many animal models of carcinogenesis has also suggested that its action may depend on its antioxidant activity. Retinoids have been shown to function as effective antioxidants by inhibiting microsomal lipid peroxidation. The importance of antioxidants for the maintenance of health and for protection from oxidative stressinduced damage places them in the forefront of mechanistic approaches to genetically originated diseases related to retinoids. It is well known that cellular and subcellular membranes are susceptible to lipid oxidation because of their relatively high concentration of polyunsaturated fatty acids and their close proximity to oxygen, transition metals and peroxidases. Therefore, there has been a great deal of interest in the study of reactive oxygen species (ROS) which are associated with arteriosclerosis, nephritis and carcinogenesis. Antioxidants scavenge and prevent the formation of free radicals so they are highly important for the treatment of these kinds of diseases. For this reason, antioxidant properties of retinoidal benzimidazole or indole derivatives have been investigated in this review.

Resveratrol is a naturally occurring phytoalexin found in many plants, nuts and fruits and is abundant in grapes and red wine. Resveratrol possesses a wide range of biological activities which include antioxidant, anti-inflammatory, chemoprotective, chemopreventive etc. Resveratrol has been investigated extensively in diabetes and its complications which suggest its anti-diabetic activity and protective effect against various diabetic complications. Neurons are extremely susceptible to oxidant-induced damage which may be due to their high rate of oxygen consumption and low levels of antioxidant defence enzymes. Traditionally, it was thought that the protective actions of resveratrol in diabetic neuropathy are due to its intrinsic radical scavenger properties. However, recently many other associated or separate mechanisms like upregulation of Nrf2, SIRT1 and inhibition of NF-kB, AP-1 have been proposed for its beneficial effect against nerve dysfunction. This present review discusses the neuroprotective effects of resveratrol that have been observed in experimental diabetic neuropathy and possible mechanistic explanations, as these effects may provide directions for the development of newer therapies. Futuristic therapies can be based on either resveratrol or its analogs with better bioavailability, or combining the resveratrol with existing therapies.