New glycoside derivatives of carnosine and analogs resistant to carnosinase hydrolysis: synthesis and characterization of their copper(II) complexes

Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide widely and abundantly distributed in muscle and nervous tissues of several animal species. Many functions have been proposed for this compound, such as antioxidant and metal ion-chelator properties. However, the main limitation on therapeutic use of carnosine on pathologies related to increased oxidative stress and/or metal ion dishomeostasis is associated with the hydrolysis by the specific dipeptidase carnosinase. Several attempts have been made to overcome this limitation. On this basis, we functionalized carnosine and its amide derivative with small sugars such as glucose and lactose. The resistance of these derivatives to the carnosinase hydrolysis was tested and compared with that of carnosine. We found that the glycoconjugation protects the dipeptide moiety from carnosinase hydrolysis, thus potentially improving the availability of carnosine. The copper(II) binding properties of all the new synthesized compounds were investigated by spectroscopic (UV-Visible and circular dichroism) and ESI-MS studies. Particularly, the new family of amide derivatives that are not significantly hydrolyzed by carnosinase is a very promising class of carnosine derivatives. The sugar moiety can act as a recognition element. These new derivatives are potentially able to act as chelating agents in the development of clinical approaches for the regulation of metal homeostasis in the field of medicinal inorganic chemistry.     

Stobadine: bellwether of a broader view of drug actions

Stobadine was recognized early in its development as having antioxidant properties. A number of laboratories found associations between the antioxidant properties of stobadine and its potential beneficial effects. We found that stobadine acted as an antioxidant in a modification of an oxygen radical absorbance capacity (ORAC) assay. Similar results were observed with other drugs, including tirilazad and pramipexole. We suggest that stobadine and certain other drugs exhibit antioxidant properties in both hydrophilic and hydrophobic environments. Other drugs have been developed for their antioxidant properties and some currently marketed drugs have antioxidant properties. Although they may not have been explicitly sought during development, at least some of the beneficial effects may be related to antioxidant properties and/or scavenging of free radicals. Because stobadine was one of the first drugs for which useful properties were associated with its antioxidant actions, stobadine may be seen as a bellwether of a broader view of pharmacological actions--a view that encompasses antioxidant properties as a useful basis of therapeutic effects.     

Neuroprotective and neuroregenerative properties of metallothioneins

Metallothioneins (MTs) are low-molecular weight cysteine- and metal-rich proteins with unquestionable metal binding capacity, antioxidant and anti-inflammatory properties, and a clear involvement in diverse physiological actions as inhibition of proapoptotic mechanisms, enhancement of cell survival, and tissue regeneration. Concurrent with this wide array of functions, MT-1/2 have been implicated in neuroprotection and neuroregeneration. The zinc binding capacity and antioxidant properties of MTs may account for most of their physiological features in the brain. However, some receptor-mediated actions of MT-1/2 have also been reported recently, a subject to be fully elucidated. This review analyses and updates the current knowledge on the actions of MTs related to neuroprotection and neuroregeneration in an effort to distinguish receptor-mediated actions of MTs from those arising from its zinc binding capacity and its antioxidant properties.     

Imidazole derivatives as antioxidants and selective inhibitors of nNOS.

The reperfusion of ischemic tissue often delays its physiological and functional recovery; this paradoxical effect is ascribed to increased release of free radicals including O(2)(-) and NO. For these reasons, scavenging reactive oxygen species or inhibition the NO synthesis has been shown to result in an enhanced neuronal survival after cerebral ischemia. Many authors believe that therapy for stroke patients would be a cocktail of drugs with various mechanisms of action. Combination therapy is a difficult and complicated avenue for drug development because of the possibility of drug-drug interactions. An alternative approach would be to combine multiple activities within the same compound. In consideration of the free-radical scavenging and inhibitory effect on NOS of various natural and synthetic compounds, the aim of this study was to analyze the antioxidant properties of some imidazole derivatives previously synthesized in our laboratory. Results obtained in the present study provide evidence that tested compounds exhibit interesting antioxidant properties, expressed either by their capacity to scavenge free radicals or their ability to reduce lipid peroxidation. In particular, compounds A and B represent chemical structures which can be easily modified to improve the observed antioxidant properties and to provide new therapeutic strategies focused on multiple downstream events.     

Treatment of viral and neoplastic diseases with double-stranded RNA derivatives and other new agents

Many attempts have been made to inhibit viral and neoplastic diseases by targeting the RNA system. The pathophysiologic significance of the microRNA system and the therapeutic potential of its manipulation are discussed. Studies of double-stranded RNA derivatives are reviewed. The therapeutic potential of one of these compounds, polyI:MPC, is emphasized. Studies of other related antiviral and antineoplastic agents are discussed, including 2'-deoxyoligocytidilates and telomerase inhibitors.     

Biosynthesis and biotechnological production of serotonin derivatives

Serotonin derivatives belong to a class of phenylpropanoid amides found at low levels in a wide range of plant species. Representative serotonin derivatives include feruloylserotonin (FS) and 4-coumaroylserotonin (CS). Since the first identification of serotonin derivatives in safflower seeds, their occurrence, biological significance, and pharmacological properties have been reported. Recently, serotonin N-hydroxycinnamoyl transferase (SHT), which is responsible for the synthesis of serotonin derivatives, was cloned from pepper (Capsicum annuum) and characterized in terms of its enzyme kinetics. Using the SHT gene, many attempts have been made to either increase the level of serotonin derivatives in transgenic plants or produce serotonin derivatives de novo in microbes by dual expression of key genes such as SHT and 4-coumarate-CoA ligase (4CL). Due to the strong antioxidant activity and other therapeutic properties of serotonin derivatives, these compounds may have high potential in treatment and prophylaxis, as cosmetic ingredients, and as major components of functional foods or feeds that have health-improving effects. This review examines the biosynthesis of serotonin derivatives, corresponding enzymes, heterologous production in plants or microbes, and their applications.     

The ortho hydroxy-amino group: another choice for synthesizing novel antioxidants

Four ortho hydroxy-amino derivatives have been designed based on the structures of flavonoids to explore the effect of the ortho hydroxy-amino group on the antioxidant properties of molecules, and their bond dissociation enthalpies (BDE), ionization potentials (IP), the highest occupied molecular orbitals (HOMO), and spin densities have been calculated. The results reveal that the ortho hydroxy-amino group plays an important role in promoting the antioxidant properties of molecules because of its lowering effect on BDE, IP, and spin density. The derivatives with ortho hydroxy-amino group show stronger antioxidant activity than the derivatives with mono hydroxy or ortho dihydroxy group. Thus, the ortho hydroxy-amino group can be used as another potential functional group to synthesize novel antioxidants as guessed.     

Synthesis of new N-isobutyryl-L-cysteine/MEA conjugates: evaluation of their free radical-scavenging activities and anti-HIV properties in human macrophages

Four novel N-isobutyryl-l-cysteine/2-mercaptoethylamine (MEA, cysteamine) conjugates have been designed and synthesized. The antioxidant activities of these new series were evaluated by three different free radical scavenging methods (DPPH test, ABTS test, and deoxyribose assay) and their metal binding capacity was evaluated by the ethidium bromide fluorescence binding assay. These results were compared with those obtained with their pro-GSH acetyl analogues recently developed in our laboratory. We observed that most of these compounds exhibit free radical-scavenging activities similar to those of Trolox, but always superior than NAC. While none of these new derivatives had pro-GSH activities, they displayed anti-HIV properties in human monocyte-derived macrophages infected in vitro. The present study demonstrates that these new N-isobutyryl derivatives, which are expected to have a greater bioavailability than their acetyl analogues, may have useful applications in HIV infection in respect to their antioxidant and anti-HIV activities.     

Sulfation of a polysaccharide produced by a marine filamentous fungus Phoma herbarum YS4108 alters its antioxidant properties in vitro

Free radicals and other reactive oxygen species (ROS) are generated by all aerobic cells and are widely believed to play a significant role in aging as well as a number of degenerative or pathological diseases. This study compared the free radical-scavenging properties and antioxidant activity of YCP, a polysaccharide from the mycelium of a marine filamentous fungus Phoma herbarum YS 4108 and its two chemically sulfated derivatives YCP-S1 and YCP-S2. Sulfation, which masks hydroxyl groups of YCP polysaccharide molecule, could introduce new antioxidant activity, such as superoxide and hydroxyl radicals scavenging activity, metal chelating action, lipid peroxidation and linoleic acid oxidation inhibition capability. Furthermore, sulfated YCP was more potent than YCP at protecting erythrocytes against oxidative damage hemolysis. The current data suggest for the first time that sulfation of polysaccharide significantly increases its antioxidant activity and the chemical modification of polysaccharides may allow the preparation of derivatives with new properties and a variety of applications.     

1,12-substituted tetracyclines as antioxidant agents

Novel hydroxypyrazoline derivatives of tetracycline and minocycline have been synthesized through the reaction of these tetracyclines with hydrazine. The formation of a new chiral center at C12 is stereospecific to give 12S-12-hydroxy-1,12-pyrazolinotetracycline. A reaction mechanism for the formation of these novel tetracycline derivatives has been proposed. Hydroxypyrazolinotetracyclines exhibit no binding to Mg2+ and Zn2+, features that are required for antibiotic activity and matrix metalloproteinase (MMP) inhibitions, respectively. The modification toward their hydroxypyrazolino derivatives significantly improved the antioxidant activities of tetracycline and minocycline, as shown by three commonly used assays (DPPH, ABTS+, and superoxide scavenging). 12S-Hydroxy-1,12-pyrazolinominocycline is a promising tetracycline-based antioxidant devoid of antibiotic properties and MMP inhibitory activity, which could be beneficial in the treatment of complications related to oxidative stress.     

Diminution of singlet oxygen-induced DNA damage by curcmin and related antioxidants

Curcumin, the natural antioxidant from turmeric, an Indian spice, and its derivatives have significant abilities to protect plasmid pBR322 against single-strand breaks induced by singlet oxygen (¹O₂), a reactive oxygen species with potential genotoxic/mutagenic properties. ¹O₂ was generated at 37°C in an aqueous buffer system by the thermal dissociation of the endoperoxide of 3,3′-(1,4-naphthylene)dipropionate (NDPO₂). Among the compounds, tested, curcumin was the most effective inhibitor of DNA damage followed by desmethoxycurcumin, bisdesmethoxycurcumin and other derivatives. The observed antioxidant activity was both time-and concentration-dependent. The protectice ability of curcumin was higher than that of the well-known biological antioxidants lipoate, α-tocopherol and β-carotene. However, the highest protective ability with saturating concentrations of curcumin did not exceed 50%. The ability of curcumin and its derivatives to protect DNA against ¹O₂ seems to be related to their structures and may at least partly explain the therapeutic and other beneficial effects of these compounds including anticarcinogenic and antimutagenic properties.     

Cell and molecular biology of intervertebral disc degeneration: current understanding and implications for potential therapeutic strategies

Intervertebral disc degeneration (IDD) is a chronic, complex process associated with low back pain; mechanisms of its occurrence have not yet been fully elucidated. Its process is not only accompanied by morphological changes, but also by systematic changes in its histological and biochemical properties. Many cellular and molecular mechanisms have been reported to be related with IDD and to reverse degenerative trends, abnormal conditions of the living cells and altered cell phenotypes would need to be restored. Promising biological therapeutic strategies still rely on injection of active substances, gene therapy and cell transplantation. With advanced study of tissue engineering protocols based on cell therapy, combined use of seeding cells, bio‐active substances and bio‐compatible materials, are promising for IDD regeneration. Recently reported progenitor cells within discs themselves also hold prospects for future IDD studies. This article describes the background of IDD, current understanding and implications of potential therapeutic strategies.     

Lipid biomarkers and metabolic effects of lycopene from tomato juice on liver of rats with induced hepatic steatosis

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver disorders, covering steatosis to nonalcoholic steatohepatitis (NASH). Dietary factors may modulate its evolution, and antioxidants have been proposed as therapeutic agents. Among them, lycopene has been demonstrated to prevent the development of steatohepatitis and even to inhibit NASH-promoted early hepatocarcinogenesis induced by a high-fat diet in rats. These conclusions have been related to its antioxidant activity; however, NAFLD is more complex than a simple redox imbalance state since it disturbs several metabolic systems in the liver. In consequence, there is a lack of information related to the action of lycopene beyond antioxidant biomarkers. In this work, NAFLD was induced in rats using a hypercholesterolemic and high-fat diet to evaluate the effect of lycopene consumption from tomato juice on liver metabolism. Several classical antioxidant biomarkers related to NAFLD were measured to check the state of this disease after 7 weeks of the controlled diet. Moreover, a metabolomics platform was applied to measure more than 70 metabolites. Results showed clear differences in the classical antioxidant biomarkers as well as in the metabolic pattern, attending not only to the diet but also to the intake of lycopene from tomato juice. Interestingly, tomato juice administration partially reverted the metabolic pattern from a high-fat diet to a normal diet even in metabolites not related to the redox state, which could lead to new targets for therapeutic agents against NAFLD and to achieving a better understanding of the role of lycopene in liver metabolism.     

In Silico Discovery of Novel Potent Antioxidants on the Basis of Pulvinic Acid and Coumarine Derivatives and Their Experimental Evaluation

A pigment from the edible mushroom Xerocomus badius norbadione A, which is a natural derivative of pulvinic acid, was found to possess antioxidant properties. Since the pulvinic acid represents a novel antioxidant scaffold, several other derivatives were recently synthetized and evaluated experimentally, along with some structurally related coumarine derivatives. The obtained data formed the basis for the construction of several quantitative structure-activity and pharmacophore models, which were employed in the virtual screening experiments of compound libraries and for the prediction of their antioxidant activity, with the goal of discovering novel compounds possessing antioxidant properties. A final prioritization list of 21 novel compounds alongside 8 established antioxidant compounds was created for their experimental evaluation, consisting of the DPPH assay, 2-deoxyribose assay, β-carotene bleaching assay and the cellular antioxidant activity assay. Ten novel compounds from the tetronic acid and barbituric acid chemical classes displayed promising antioxidant activity in at least one of the used assays, that is comparable to or even better than some standard antioxidants. Compounds 5, 7 and 9 displayed good activity in all the assays, and were furthermore effective preventers of oxidative stress in human peripheral blood mononuclear cells, which are promising features for the potential therapeutic use of such compounds.     

Design,Synthesis, Calculation and Biological Activity Studies Based on Privileged Coumarin Derivatives as Multifunctional Anti-AD Lead Compound

Coumarins and their derivatives possessed a variety of biological activities and some of coumarin-based drugs have been approved by the US Food and Drug Administration. Alzheimer's disease (AD) has caused great losses to human society. However, due to its complex pathogenesis, the ideal therapeutic approach has not been found yet. Free radical scavenging activity which is one of the main activities of coumarin core structure is closely related to other anti-AD activities. Therefore, in this work coumarins were chosen as privileged lead compounds for the development of anti-AD drugs based on strategy of multi-target directed ligands (MTDLs). Derivatives 1 – 3 which could modulate multiple targets simultaneously, including ROS, cholinesterase, βamyloid (Aβ) aggregation, and metal dyshomeostasis were designed and for the first time synthesized. Their anti-AD activities were studied both in vitro and in silico. Results showed that 1 – 3 possessed potent antioxidant activities and 7-OH group did change the electron distribution of the molecule and enhance the antioxidant activities. They also have good inhibition activities on acetylcholinesterase (AChE) and Aβ aggregation and compound 1 had the strongest AChE inhibitory effect among the three compounds (AChE IC₅₀=11.15 μM). Compound 1 – 3 could also selectively chelate with Cu²⁺ and Al³⁺ to regulate the metal homeostasis. In silico simulations, including molecular docking and prediction of ADMET performance, indicated that 1 – 3 could interact with target proteins and cross the blood brain barrier. In conclusion, 1 – 3 could be promising MTDLs applied as anti-AD candidate drugs.     

N-Acetylcysteine amide: a derivative to fulfill the promises of N-Acetylcysteine

Abstract

In the present human health scenario, implication of oxidative stress in numerous pathologies including neurodegenerative, cardiovascular, liver, renal, pulmonary disorders, and cancer has gained attention. N-Acetylcysteine (NAC), a popular thiol antioxidant, has been clinically used to treat various pathophysiological disorders. However, NAC therapy is routine only in paracetamol intoxication and as a mucolytic agent. Over six decades, numerous studies involving NAC therapy have yielded inconsistent results, and this could be due to low bioavailability. In order to overcome the limitations of NAC, an amide derivative N-Acetylcysteine amide (NACA) has been synthesized to improve the lipophilicity, membrane permeability, and antioxidant property. Recent studies have demonstrated the blood–brain barrier permeability and therapeutic potentials of NACA in neurological disorders including Parkinson's disease, Alzheimer's disease, Multiple sclerosis, Tardive dyskinesia, and HIV-associated neurological disorders. In addition, NACA displays protective effect against pulmonary inflammation and antibiotic-induced apoptosis. Forthcoming research on the possible therapeutic properties of NACA and its generics in the management of pathologies associated with extracellular matrix degradation and oxidative stress-related inflammation is highly exiting. Superior bioavailability of NACA is likely to fulfill the promises of NAC as well as a molecule to improve the endurance and resident time of bioscaffolds and biomaterials. Till date, more than 800 reviews on NAC have been published. However, no comprehensive review is available on the therapeutic applications of NACA. Therefore, the current review would be the first to emphasize the therapeutic potentials of NACA and its derivatives.     

Water-soluble polysaccharides as carriers of paramagnetic contrast agents for magnetic resonance imaging: synthesis and relaxation properties.

Water-soluble, carbohydrate-based, paramagnetic metal chelate derivatives have been investigated as potential organ-selective contrast media for magnetic resonance imaging (m.r.i.). The in vitro proton spin-lattice relaxation properties of compounds with different paramagnetic metals, chelating agents, and carbohydrate matrixes have been studied. Typically, these complexes were 60-260% more efficient proton-relaxation agents than the corresponding low-molecular-weight metal chelates at 10 MHz, but less efficient than the corresponding protein derivatives. As expected, carbohydrates that contained manganese or gadolinium were more effective relaxation agents than iron, copper, erbium, or nickel derivatives.     

Effects of phytic acid on the myoglobin-t-butylhydroperoxide-catalysed oxidation of uric acid and peroxidation of erythrocyte membrane lipids

Phytic acid stimulated the myoglobin-t-butylhydroperoxide (TBHP)-catalysed oxidation of uric acid, but inhibited the peroxidation of erythrocyte membrane lipids induced by the same system. Butylated hydroxy-toluene, a free radical chain reaction-terminating antioxidant, also suppressed the myoglobin-TBHP-induced lipid peroxidation. Moreover, phytic acid inhibited the hydroxyl radical-induced degradation of deoxyribose, but the extent of inhibition in this system was reduced by increasing the ferric ion concentration, suggesting that these effects of phytic acid on the myoglobin-TBHP-mediated oxidation are more likely attributable to its metal chelating properties rather than to a free radical scavenging action. The effectiveness of phytic acid, a naturally occurring antioxidant, in the inhibition of both iron- (as previously shown) and myoglobin-dependent lipid peroxidation suggests its possible therapeutic application as a non-toxic antioxidant for ameliorating the extent of oxy-radical-mediated myocardial ischemia/reperfusion damage.Abbreviations ASC Ascorbic acid - BHT Butylated Hydroxytoluene - DMSO Dimethyl Sulfoxide - TBHP t-Butylhydroperoxide - TBA Thiobarbituric Acid - TBARS Thiobarbituric Acid-reactive Substances     

Antioxidant properties of bucillamine: possible mode of action

The antioxidant properties of Bucillamine (BUC), a di-thiol compound used for treatment of rheumatoid arthritis (RA) and its possible mode of action, were investigated. BUC exhibits potent antioxidant activity similar to those of trolox and ascorbic acid. It reduces the stable free radical diphenyl-2-picrylhydrazyl (DPPH) with IC(50) of 18.5+/-0.1 micromol, its relative antioxidant activity by the ferric reducing ability (FRAP) is 2.07+/-0.01 mM and by the trolox equivalent antioxidant capacity (TEAC), 1.46+/-0.05 mM. However, its superoxide and apparent hydroxyl radical scavenging activities are low (IC(50) at millimolar concentrations). We found that BUC is a strong iron (II) and copper (II) chelator. This finding is very important since these metal ions are significantly higher in RA patients and may be involved in oxidative stress-induced damage. Our study suggests that BUC is a potent antioxidant which exerts its beneficial therapeutic activities in RA patients by metal chelation rather than by scavenging free radical species.