Ashok K. Prasad

N,N,N′,N′‐Tetraoctyl Diglycolamide (TODGA): A Promising Extractant for Actinide‐Partitioning from High‐Level Waste (HLW)

Abstract N,N,N′,N′‐Tetraoctyl diglycolamide (TODGA) has been evaluated as an extractant for the partitioning of minor actinides from simulated high level nuclear waste solutions. Acid uptake studies suggested that TODGA is more basic (KH: 4.1) as compared to TRUEX and DIAMEX solvents viz. CMPO (KH: 2.0) and DMDBTDMA (KH: 0.32), respectively. TODGA molecules display a tendency toward aggregation in n‐dodecane at lower acidities. Effect of diluent on the distribution behavior of Am(III) was studied employing diluents of different dielectric constants. N,N‐dialkyl amides with different alkyl groups viz. dibutyl decanamide (DBDA), di(2‐ethylhexyl) acetamide (D2EHAA), di(2‐ethylhexyl) propionamide (D2EHPRA), di(2‐ethylhexyl) isobutyramide (D2EHIBA), dihexyl octanamide (DHOA) and dihexyl decanamide (DHDA) were evaluated as phase modifiers. Distribution behavior of various metal ions viz. Am(III), Pu(IV), U(VI), Eu(III), Fe(III), Sr(II) and Cs(I) was studied from pure nitric acid solution as well as from simulated high level waste solution.

Coumarins as Antioxidants

Coumarins, a well-known class of naturally occurring compounds, display a remarkable array of biochemical and pharmacological actions, some of which suggest that certain members of this group of compounds may significantly affect the function of various mammalian cellular systems. The development of coumarins as antioxidant agents has attracted much attention in recent years. Coumarins afford an opportunity for the discovery of new antioxidants with truly novel mechanisms of action. This review updates and expands the 2006 review by the same author. The review considers and incorporates the most recently published literature on coumarins as related to their antioxidant properties. A lot of coumarins have been identified from natural sources, especially green plants. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. Beyond doubt, a deep understanding of the mechanisms of existing synthetic and natural coumarins will build the basis for the rational design.

Naturally occurring aristolactams, aristolochic acids and dioxoaporphines and their biological activities

Aristolactams, having a phenanthrene chromophore are a small group of compounds mainly found in the Aristolochiaceae together with the aristolochic acids and 4,5-dioxoaporphines. In this report, these three important classes of natural products are reviewed and classified on the basis of their oxygenation pattern. In addition the biological activities of these compounds and their general chemistry are discussed.

7,8-Dihydroxy-4-methylcoumarin induces apoptosis of human lung adenocarcinoma cells by ROS-independent mitochondrial pathway through partial inhibition of ERK/MAPK signaling

Coumarins have attracted intense interest in recent years because they have been identified from natural sources, especially green plants and have diverse pharmacological properties. In this study, we investigated whether 7,8‐dihydroxy‐4‐methylcoumarin (DHMC) caused apoptosis in A549 human non‐small cell lung carcinoma cells (NSCLC) and, if so, by what mechanisms. Here, we show that, in A549 human NSCLC cells, DHMC induces apoptosis through mitochondria‐mediated caspase‐dependent pathway. Although an increase in the levels of reactive oxygen species (ROS) was observed, pre‐treatment with antioxidant showed no protective effect against DHMC‐induced apoptosis. In addition, our immunoblot data revealed that DHMC treatment led to down‐regulation of Bcl‐xl, Bax, p21, Cox‐2, p53 and upregulation of c‐Myc. Results in the present study for the first time suggest that DHMC induces apoptosis in human lung A549 cells through partial inhibition of ERK/MAPK signaling.

Antioxidant activity of 4-methylcoumarins

Polyphenolic coumarins are known to act as antioxidants in biological systems, but it is difficult to distinguish their antioxidant activity from the many other effects they produce in cells. We have determined the radical scavenging capacity of 22 structurally related natural and synthetic 4‐methylcoumarins, by measuring their reaction with radicals, galvinoxyl and 2,2‐diphenyl‐1‐picrylhydrazyl, using electron paramagnetic resonance spectroscopy. Efficient antioxidant activity of 4‐methylcoumarins in cells was verified using the DCF fluorescent probe assay for determination of intracellular reactive oxygen species levels. As expected, the o‐dihydroxysubstituted coumarins were found to be excellent radical scavengers and better than the m‐dihydroxysubstituted or monohydroxysubstituted analogues, but surprisingly the corresponding o‐diacetoxy derivatives also turned out to be good scavengers, even in the absence of an esterase. Another unexpected result was that the anti‐oxidant efficiency of 4‐methylcoumarins could be modulated by introducing an ethoxycarbonyl‐ethyl substituent at the C‐3 position; this effect cannot be explained by simple electron donating/withdrawing properties. Coumarin concentrations of 10 μm or less were used in all experiments, corresponding to the levels relevant for therapeutic purposes. Considering that 4‐methylcoumarins, in contrast to many other coumarins, are not metabolized to toxic epoxide intermediates, these results indicate promising new strategies for the design of non‐toxic antioxidant coumarin‐based drugs.

In vitro interactions of coumarins with iron

Coumarins are a large group of natural substances with diverse pharmacological properties that may predetermine some of them for the prevention and/or treatment of cardiovascular diseases and also other pathologies. Free iron participates in the production of reactive oxygen species (ROS) and plays an important role in the pathogenesis of cardiovascular diseases. Therefore, chelation of iron may attenuate some ROS consequences, but on the other hand, reduction of ferric ions to ferrous ones is unfavourable and leads to intensification of ROS production. In this study, we have examined the interaction of iron with coumarins which has been rarely analyzed. A series of naturally occurring and chemically synthesized 4-methylcoumarins were analyzed for their ferrous and total iron-chelating properties and compared with standard iron chelator deferoxamine. The iron chelation activity was assessed by a simple spectrophotometric approach based on the specific indicator for ferrous ions--ferrozine. The methodology was also extended for the measurement of total iron. Among the tested coumarins, ortho-dihydroxyderivatives were the most potent iron chelators and 7,8-dihydroxy-4-methylcoumarin even reached the efficiency of deferoxamine in neutral pH. However, these ortho-dihydroxycoumarins did not bind iron firmly in acidic conditions (e.g., in acute myocardial infarction) and, moreover, they reduced ferric ions that could lead to intensification of the Fenton chemistry. Other tested coumarins did not substantially chelate iron with the exception of ortho-diacetoxycoumarins. Conclusively, the use of iron-chelating coumarins in acidic conditions may be disadvantageous in contrast to neutral conditions.

Production of a novel alkaline lipase by Fusarium globulosum using neem oil, and its applications*

A low-temperature, alkaline, and detergent-compatible lipase from Fusarium globulosum (FGL) has been produced using an inexpensive source, viz. neem oil. Maximum lipase production of 12 300 U/L was achieved in 96 h on optimizing various physicochemical parameters. The lipase exhibited remarkable stability in the presence of commercial detergents, bleaching agents, and proteases. The lipase showed a novel property of marked activation on prolonged incubation at alkaline pH. Wash performance analysis of the commercial detergent for removal of fatty stains improved upon addition of this lipase.

Nucleic acid therapeutics: basic concepts and recent developments

Nucleic acid based therapeutics have an allure for medicinal chemists due to their potential for specific control of gene expression. Persistent efforts have resulted in the FDA approval of the nucleic acid based drugs Vitravene™, Macugen™ and recently Kynamro™, leading to a sudden leap in the number of active clinical trials involving the nucleic acid moieties. Beginning with antigene and antisense technology, nucleic acid therapeutics have recently gained more potent strategies, e.g. RNA interference, ribozymes, decoy oligonucleotides and aptamers. Nucleic acid based therapeutics which have opened up new frontiers in medicinal chemistry research, along with various chemical modifications undertaken to improve their utility and their mechanism of action, will be discussed in this review article.

4-methylcoumarins as antioxidants: scavenging of peroxyl radicals and inhibition of human low-density lipoprotein oxidation.

The antioxidant activity of eight synthetic 4-methylcoumarins was systematically studied. The antioxidant capacity was measured using: (i) a competition kinetic test, to measure the relative capacity to quench peroxyl radical; (ii) the in vitro oxidative modification of human low-density lipoprotein, initiated by AAPH or catalyzed by copper. In both models, the ortho-OH substitutes were found to be better antioxidant than the meta one. The most efficient antioxidant was the 7,8-dihydroxy-4-methylcoumarin and the corresponding diacetoxy-substituted was unexpectedly a good antioxidant. Finally, the presence of an ethoxycarbonylethyl substituent at the C-3 position increased the antioxidant capacity of both 7,8-dihydroxy-4-methylcoumarin and 7,8-diacetoxy-4-methylcoumarin.

Apoptogenic effect of 7,8-diacetoxy-4-methylcoumarin and 7,8-diacetoxy-4-methylthiocoumarin in human lung adenocarcinoma cell line : Role of NF-κB, Akt, ROS and MAP kinase pathway

Coumarin (1,2-benzopyrone) is a naturally occurring fragrant compound found in a variety of plants and spices. Coumarins have attracted intense interest in recent years because of their diverse pharmacological activities. This study examines the antioxidant coumarin 7,8-diacetoxy-4-methylcoumarin (DAMC) and its thiocoumarin derivative 7,8-diacetoxy-4-methylthiocoumarin (DAMTC) for their effect on human non-small cell lung cancer A549 cells. Here we show that both DAMC and DAMTC not only inhibited cell proliferation, but also induced apoptosis with an IC(50) of 160 microg/ml as confirmed by morphological examination, annexin-V assay and flow cytometric analysis. Interestingly, it was observed that these two coumarin compounds exhibited little cytotoxicity towards peripheral blood mononuclear cells but induced apoptosis in malignant cells. DAMC/DAMTC treatment also resulted in pronounced release of apoptogenic cytochrome c from mitochondria to cytosol, alteration of mitochondrial membrane potential (DeltaPsi(m)), and activation of caspase-9 and caspase-3. Although an increase in the levels of reactive oxygen species (ROS) was observed, pre-treatment with antioxidant showed no protective effect against DAMC/DAMTC-induced apoptosis. Results of present study suggest that downregulation of Bcl-xl, Cox-2 and mitogen activated protein kinase pathway and upregulation of p53, Akt and NF-kappaB pathway are involved in the underlying molecular mechanism of apoptosis induction by DAMC and DAMTC in A549 cells.