Current Organic Chemistry - Volume 21, Issue 20, 2017

Background & Objective: Various 1,4-dihydropyridines (DHPs) could affect basic and cell-type specific mitochondrial functions in different way and at various extent either as protectors or as harmful compounds, depending on their lipophylicity and chemical modifications of the DHP nucleus. Hence, several DHPs may affect: 1) mitochondrial bioenergetics as well as enzymatic activities including electron transport chain reactions and organic acids consumption rate; 2) mitochondrial lipid peroxidation, production of reactive oxygen species and reactive nitrogen species; 3) antioxidant enzymes: glutathione-S-transferase, superoxide dismutase, catalase; 4) mitochondrial and cellular membranotropic and/or physico-chemical properties: incorporation into mitochondrial membrane, alteration of membrane lipid organization, thermotropic phase transition profile and membrane lateral heterogeneity; 5) chemo-osmotic processes (mitochondrial permeability transition, swelling/contraction/aggregation); 6) mitochondrial viability, protecting mitochondria against toxic effects of doxorubicin, MPP+, mixture of rotenone/oligomycin, etc.); 7) implication of some DHPs in the regulation of mitochondria-mediated heme biosynthetic pathways was checked also in respect to potential differences between their effects on normal and malignant cells. The effects of DHPs on mitochondria of different cellular origin (hepatic, cardiac, neuronal, brain, muscle) were observed. Methodology: It were reported about several accepted and original methods used in the studies of mitochondrial bioenergetics (respiratory activity, respiratory control ratio – RCR and membrane potential), lipid peroxidation, detection of oxygen and nitrogen radical species, enzyme activity (activities of succinate-, malate-, glutamate-, NADH-dehydrogenases, δ(delta)-aminolevulinic acid synthetase), membrane physico-chemical properties. Conclusion: DHPs could affect mitochondria solely as well as in combination with other drugs either for the enhancement or for the weakening of their mutual effects, or even being active as one of the essential parts of large complex molecules. Accordingly, bimodal effects on mitochondria (improvement or endangerment of mitochondrial functions) obtained by various DHPs are of high importance for the overall bioactivities of DHPs.

Background: The growing interest on the redox modulation in living systems broadly involved selenium derivatives that during the last twenty years were often claimed powerful antioxidants but that were also clearly correlated to several important biological effects sometimes, unfortunately, associated to a certain toxicity. Comparing the antioxidant activity of different organoselenium structures it can be observed that sometimes quite different reaction mechanisms are involved. Method: We propose here a classification based on the nature of the selenenylated functional group. Beside the natural glutathione peroxidase-like activity, other biological interactions were proposed and we report now an overview of the state of art pointing the attention also to the testes used to evaluate and demonstrate the biological activity. Conclusion: New prospective on the use of selenium and tellurium derivatives as Redox modulators, were discussed throughout a series of selected examples. The possibility to obtain from organoselenium derivatives molecules endowed with hormetic effect or able to act as selective inhibitor of specific enzyme will be discussed.

Background: Nowadays, nitrones are the most used spin traps to characterize free radicals in biological systems due to the versatility and variety depending on the types of radicals to study and that the halflives of the species studied and/or detected increase considerably. In recent years, nitrones have been studied not only as free radical spin traps. Moreover, nitrones have been employed as therapeutic agents; in particular, those spin traps that are derived from α-phenyl-N-tert-butylnitrone (PBN). Nitrones as therapeutics agents have been used in the treatment of diseases related to oxidative stress such as neurodegeneration, cardiovascular disease and cancer. Conclusion: In this review, we focus mainly on those studies where nitrones have been used as potential therapeutic agents in diseases such as cancer, neurodegenerative, acoustic trauma and others. In addition, we have shown that they continue to be a potent and important tool as radical spin trap as well as their use as therapeutic agent

Background: All cancers are leading causes of morbidity and mortality worldwide. The urgent need for new lead compounds for the treatment of cancer is higher than ever before. Scientists search and try to discover effective but less harmful new anti-tumor agents. Surgery, chemotherapy and radiation are the bestknown methods for treating cancer, however, they continued to be limited. Rising efforts of the scientists toward success of the drug discovery is increasing. Indole ring is considered as a key molecule existing in various biologically active compounds. Indole derivatives are recognized to prevent proliferation and invasion of many cancer cells. Conclusion: This review presents the existing status and the very recent studies of indoles which have promising activities such as derivatives of indole-3-carbinol, 3,3'-diindolylmethane (DIM), isatin etc. Their chemical and biological behavior as well as a general overview of the anticancer activity is discussed.

Background: Oxidative stress (OS) arises when the balance between the production of oxidants and their removal is disturbed; OS is associated with a wide variety of health disorders. Finding strategies that efficiently reduce OS is an active area of research. Objective: This review summarizes the chemical insights concerning the antioxidant capacity (AOC) of melatonin and related compounds. Method: We consider not only naturally-occurring but also synthetic derivatives. Different chemical routes that may be involved in their AOC are analyzed and some trends in activity are provided. Conclusion: Based on the data gathered so far it can be stated that melatonin and related compounds constitute a chemical family with remarkable protective effects against OS. Their action includes both primary and secondary AOC, and -collectively- they can be considered as multifunctional protectors against OS. Current challenges and future perspectives in this area of research are discussed.

Background: Free radicals are frequently generated in vivo and their reactivity varies causing different damages to biological molecules, e.g. DNA, lipids, and proteins. Oxidative stress in the human body is due to the free radicals generation and to the reduced level of antioxidants. Antioxidants are able to reduce the risk for chronic diseases. Hence, natural and synthetic antioxidants may be predominantly significant in diminishing cumulative oxidative damage. Objective: Many novel approaches have been made and significant progress has been done in the last years. This review shows current trend in the synthesis of pyrimidines and uracils and reveals their potent structures which can be a good source for the synthesis of new derivatives with required antioxidant activity. Conclusion: These classes of compounds play an essential role in a variety of biological systems and have substantial attention in the field of pharmacology.

Background: There are two types of antioxidants -high molecular weight antioxidants like glutathione peroxidase and superoxide dismutase and low molecular weight antioxidants like ascorbic acid, glutathione, uric acid, melatonin. Both types of antioxidants are necessary in the system keeping oxidative homeostasis and protecting against reactive oxygen and nitrogen species. Objective: This review is focused on low molecular weight antioxidant assay which can serve as an important tool for various diagnoses since the antioxidant level corresponds with pathological states and can indicate oxidative stress. The assay of antioxidants is also a tool for food quality control because the antioxidant level is decreasing due to aging and poor storage conditions. Disparate protocols were established in order to judge antioxidant capacity. Conclusion: In this review, spectrophotometric tests like 2,2'-azinobis(3-ethyl-benzothiazoline-6-sulfonic acid) based assay (ABTS), 2,2-diphenyl-1-picrylhydrazyl radical (DPPH), like ferric reducing antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), electrochemical assays and instrumental analyses are described and discussed. Survey of actual literature and principle of the analyses are provided as well.

Objective: Enhanced production of reactive oxygen and/or nitrogen species in biological tissues leads to oxidative and nitrative stress, a general pathophysiological phenomenon playing a role in the development of various human diseases including cardiovascular and neurological disorders. Method: Reactive oxygen and/or nitrogen species interact with lipids, DNA and proteins via oxidative or radical- mediated reactions, potentially leading to cell damage or death. Proteoglycans are among the most important structural and functional macromolecules in most tissues. The chemical structure of these molecules consist of a core protein onto which one or more negatively charged glycosaminoglycan (GAG) chain(s) are covalently attached. Interaction of proteoglycans with oxidative/nitrative stress has been demonstrated in various experimental systems. In this review, we discuss the modulatory effects of proteoglycans on tissue oxidative/ nitrative stress and consequent cellular function especially in cardiovascular and neurological disorders. Conclusion: Proteoglycans have been implicated in both deleterious and potentially cytoprotective mechanisms. The protective mechanisms include chelation of positively charged transitional metal ions (e.g. iron and copper), scavenging superoxide anions by extracellular superoxide dismutase, building pericellular net and mediation of signal transduction pathways. Although these results may implicate proteoglycans as potential therapeutic targets, more research should be done to better explore proteoglycans as modulators of reactive oxygen/nitrogen species and to determine their possible therapeutic value in disorders accompanied by oxidative/ nitrative stress.

Background: Previously, it was demonstrated that quinoid pigments of sea urchins exhibit antioxidant properties. Objective: The work presents a comparative investigation of the antioxidant and antiaggregant action of polyhydroxy- 1,4-naphthoquinones: echinochrome A, spinochrome B, spinochrome C, spinochrome E, echinamine B, histochrome. The glycolytic enzyme glyceraldehyde-3-phospate dehydrogenase (GAPDH) was chosen as a possible natural target for the action of the quinones. GAPDH is easily affected by reaction oxygen species and prone to amyloid aggregation. Methods: Influence of polyhydroxy-1,4-naphthoquinones on the enzymatic activity of GAPDH, on the oxidation of the enzyme by hydrogen peroxide as well as on its thermal aggregation and some thermodynamic parameters of the enzyme were investigated. Results: It was demonstrated that spinochromes B and C decelerate the oxidation of GAPDH by hydrogen peroxide, but do not affect the GAPDH activity in the absence of H2O2. Echinichrome A and histochrome decelerate the oxidation of GAPDH by hydrogen peroxide and moderately inhibit the activity of GAPDH. Echinamine B and spinochrome E were shown to decrease significantly the activity of GAPDH. Spinochrome E exhibits a pronounced antiaggregant action, completely suppressing thermal aggregation of GAPDH. Echinochrome A and the spinochromes prevent chaperone hsp70 from blocking by oxidized and denatured forms of GAPDH. Conclusion: Most of the quinoid pigments of sea urchins, as well as the derived preparation histochrome exhibit antioxidant action and prevent interaction of denatured proteins with each other and with chaperones. However, echinamine B and spinochrome E inhibit GAPDH, which is in agreement with previously described cytotoxic action of some polyhydroxy-1,4-naphthoquinones.