Current Medicinal Chemistry (v.20, #36)

Editorial (Thematic Issue: Synthesis, Evaluation and Pharmacological Applications of Antioxidants- Part 1) by Fernanda Borges, Luciano Saso, Jorge Garrido, Sibel Suzen (4435-4435).

Antioxidant Properties of Hydroxycinnamic Acids: A Review of Structure- Activity Relationships by N. Razzaghi-Asl, J. Garrido, H. Khazraei, F. Borges, O. Firuzi (4436-4450).
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 thestudies focused on the structure-activity relationships (SARs) of these compounds that have used medicinal chemistry togenerate more potent antioxidant molecules. Most of the reports indicated that the presence of an unsaturated bond on theside chain of HCAs is vital to their activity. The structural features that were reported to be of importance to the antioxidantactivity were categorized as follows: modifications of the aromatic ring, which include alterations in the number andposition of hydroxy groups and insertion of electron donating or withdrawing moieties as well as modifications of the carboxylicfunction that include esterification and amidation process. Furthermore, reports that have addressed the influenceof physicochemical properties including redox potential, lipid solubility and dissociation constant on the antioxidant activitywere also summarized. Finally, the pro-oxidant effect of HCAs in some test systems was addressed. Most of the investigationsconcluded that the presence of ortho-dihydroxy phenyl group (catechol moiety) is of significant importance tothe antioxidant activity, while, the presence of three hydroxy groups does not necessarily improve the activity. Optimizationof the structure of molecular leads is an important task of modern medicinal chemistry and its accomplishment relieson the careful assessment of SARs. SAR studies on HCAs can identify the most successful antioxidants that could be usefulfor management of oxidative stress-related diseases.

Oxidative stress in carcinogenesis: new synthetic compounds with dual effects upon free radicals and cancer. by Betul Tekiner-Gulbas, Andrew D. Westwell, Sibel Suzen (4451-4459).
DNA mutation is a very important step in carcinogenesis and elevated levels of oxidative DNA damage havebeen 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, sinceantioxidants are able to stop the free-radical formation and prevent oxidizing chain reactions. These findings have generatedgreat interest in therapeutic antioxidant-based cancer drug development. The design and development of syntheticcompounds, able to scavenge free radicals, could present a significant therapeutic advance, in particular for treating pathologicalconditions such as cancer. This article will outline the state of the research on the relationship between antioxidanttherapy and cancer, describing the new synthetic antioxidant molecules that have anticancer activities. Investigations andassociation between dietary antioxidants, oxidative stress, and cancer will be also discussed.

Thiazoles and Thiazolidinones as Antioxidants by A.A. Geronikaki, E.P. Pitta, K.S. Liaras (4460-4480).
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 pathogenesisof a number of disorders leading to oxidative stress. Oxidative stress may be defined as an imbalance between cellularproduction 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. Oxidativedamage 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 ofthe antioxidant activity of thiazole and thiazolidinone derivatives, which are the core structure in a variety of pharmaceuticalswith a broad spectrum of biological activity and their role in preventing the formation of ROS.

Xanthones as Potential Antioxidants by S.S. Panda, M. Chand, R. Sakhuja, S.C. Jain (4481-4507).
Xanthones (dibenzo-γ-pyrones) constitutes an important class of oxygenated heterocycles and occur assecondary 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 tricyclicscaffold as well as the nature and/or position of the substituents present on it play an important role in displaying variousbiological activities. The unique structural scaffold and medicinal importance of xanthones have therefore attracted manyScientists in the past, to isolate or synthesize xanthones or their analogs as potential drug candidates. It would not bewrong to call them as close cousins to the polyphenol family that are known to possess strong antioxidant effects on thenervous system. The main two sources of xanthones are: Isolation from natural resources or synthesis. Though fewreviews have been published in the past, mainly focusing on the anticancer activities of xanthone derivatives, but there isnot a single review which is based on their antioxidant activities. We therefore have made efforts to briefly summarizenatural and synthetic xanthones possessing antioxidant activity in this review.

Metal Complexes of Biologically Active Ligands as Potential Antioxidants by Irena Kostova, Stefan Balkansky (4508-4539).
Recent years have witnessed an unprecedented progress in biological applications of metal coordination compoundsof biologically active ligands because of their key role in clinical therapy. Transition metals are particularly suitablefor this purpose because they can adopt a wide variety of coordination numbers, geometries and oxidation states incomparison 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 severaloxidation states. Due to the redox activity of metals and, therefore, a possible disturbance of the sensitive cellular redoxhomeostasis, a tight regulation of the metal and redox balance is crucial for health. On the other hand, over production ofactivated oxygen species, generated by normal metabolic process, is considered to be the main contributor to oxidativedamages to biomolecules such as DNA, lipids and proteins, thus accelerating cancer, aging, inflammation, cardiovascularand neurodegenerative diseases. The potential value of antioxidants has already prompted investigators to search for thecooperative effects of metal complexes and natural compounds for improving antioxidant activity. Depending on theirstructure and on the source of the oxidative stress, metal complexes might act as antioxidants or prooxidants. The currentreview 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 activitiesin the oxidation processes. This work underlines some important features for the research on metal complexes of biologicallyactive ligands as antioxidants, and supports future evaluation of some of these compounds as possible therapeuticagents.

Heavy metals are known to cause oxidative deterioration of bio-molecules by initiating free radical mediatedchain reaction resulting in lipid per-oxidation, protein oxidation and oxidation of nucleic acid like DNA and RNA. Thedevelopment of effective dual functioning antioxidants, possessing both metal-chelating and free radical-scavenging propertiesshould 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 andclinical recovery against heavy metal intoxication. These antioxidants affect biological systems not only through directquenching of free radicals but also via chelation of toxic metal(s). These antioxidants also, have the capacity to enhancecellular antioxidant defense mechanism by regenerating endogenous antioxidants, such as glutathione and vitamin C andE. They also influence cellular signaling and trigger redox sensitive regulatory pathways. The reactivity of antioxidants inprotecting against heavy metal induced oxidative stress depends upon their structural properties, their partitioning abilitiesbetween hydrophilic and lipophilic environment and their hydrogen donation antioxidant properties. Herein, we reviewthe structural, biochemical and pharmacological properties of selected antioxidants with particular reference to their abilityto (i) chelate heavy metals from its complex (ii) ameliorate free radical (iii) terminate heavy metal induced free radicalchain reaction (iv) regenerate endogenous antioxidants and, (v) excretion of metal without its redistribution.

Antioxidative Peptides: Trends and Perspectives for Future Research by A.C. Freitas, J.C. Andrade, F.M. Silva, T.A.P. Rocha-Santos, A.C. Duarte, A.M. Gomes (4575-4594).
In recent years, much attention has been given to dietary antioxidants, especially polyphenols. Several peptidesderived from protein molecules have also been found to show antioxidant capacity along with other biological propertiesand thus there is an increasing interest in these compounds as health promoters. This review summarizes and discusses themain sources of antioxidative peptides with focus on food-derived peptides (animal, plant and marine sources), methodsof preparation, antioxidant capacity evaluation as well as their proposed mechanisms of action. A discussion of the potentialhealth effects and comments on the different applications for these antioxidants and their potential research interest arealso subject of this review.

Antioxidant Activity of Galantamine and Some of its Derivatives by D. Tsvetkova, D. Obreshkova, D. Zheleva - Dimitrova2, L. Saso (4595-4608).
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 currentstudy is to summarize the scientific evidences for the antioxidant and neuroprotective activity of Galantamine and some ofits derivatives. Galantamine is a scavenger of reactive oxygen species and causes neuroprotective effect by lowering theoxidative neuronal damage, through the following pathways: 1) prevention of the activation of P2X7 receptors; 2) protectionof mitochondrial membrane potential; 3) pre - vention of the membrane fluidity disturbances. Another mechanism isthe 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 α 7 - subtype of nicotinic acetylcholine receptors. A closerelationship between acethylcholinesterase inhibition and reduced oxidative injury is observed. Through allosteric potentiationof the α 7 - 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 cytotoxicagents (β - amyloid peptide, glutamate, hydrogen peroxide, oxygen and glucose deprivation). The new trend in therapyof Alzheimer's disease will be the investigation and application of compounds such as Galantamine derivatives, whichpossess 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 compoundshaving high capacity in scavenging free radicals related to various disorders and diseases associated with oxidativedamage, caused by reactive oxygen species (ROS). Presently, synthetic antioxidants are widely used because they are effectiveand cheaper than natural antioxidants. Currently a number of Schiff-base metal complexes have been investigatedas effective scavengers of ROS, acting as antioxidants. The aim of this review is to highlight specific characteristics ofSchiff-based compounds capable of chelating metal ions and their antioxidant activity. Schiff bases form an importantclass of organic compounds with a wide variety of biological properties. Schiff bases have often been used as chelatingligands in the field of coordination chemistry, and their metal complexes have been of great interest to researchers formany years. The activity is usually increased by complexation therefore to understand the properties of both ligands andmetal can lead to the synthesis of highly active compounds. The influence of certain metals on the biological activity ofthese compounds and their intrinsic chemical interest as multidentate ligands has prompted a considerable increase in thestudy of their coordination behavior. Development of a new chemotherapeutic Schiff bases and their metal complexes isnow attracting the attention of medicinal chemists.

The antioxidants and antioxidant enzyme systems belong to the major protective systems of the organism. Theuse of retinoic acid in many animal models of carcinogenesis has also suggested that its action may depend on itsantioxidant activity. Retinoids have been shown to function as effective antioxidants by inhibiting microsomal lipidperoxidation. The importance of antioxidants for the maintenance of health and for protection from oxidative stressinduceddamage places them in the forefront of mechanistic approaches to genetically originated diseases related toretinoids. It is well known that cellular and subcellular membranes are susceptible to lipid oxidation because of theirrelatively high concentration of polyunsaturated fatty acids and their close proximity to oxygen, transition metals andperoxidases. Therefore, there has been a great deal of interest in the study of reactive oxygen species (ROS) which areassociated with arteriosclerosis, nephritis and carcinogenesis. Antioxidants scavenge and prevent the formation of freeradicals so they are highly important for the treatment of these kinds of diseases. For this reason, antioxidant properties ofretinoidal 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 grapesand 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 complicationswhich suggest its anti-diabetic activity and protective effect against various diabetic complications. Neurons are extremelysusceptible to oxidant-induced damage which may be due to their high rate of oxygen consumption and low levels of antioxidantdefence enzymes. Traditionally, it was thought that the protective actions of resveratrol in diabetic neuropathy aredue to its intrinsic radical scavenger properties. However, recently many other associated or separate mechanisms likeupregulation of Nrf2, SIRT1 and inhibition of NF-κ B, 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 experimentaldiabetic neuropathy and possible mechanistic explanations, as these effects may provide directions for the development ofnewer therapies. Futuristic therapies can be based on either resveratrol or its analogs with better bioavailability, or combiningthe resveratrol with existing therapies.