Glucosinolates are sulfur-rich, anionic natural products that upon hydrolysis by endogenous thioglucosidases called myrosinases produce several different products (e.g., isothiocyanates, thiocyanates, and nitriles). The hydrolysis products have many different biological activities, e.g., as defense compounds and attractants. For humans these compounds function as cancer-preventing agents, biopesticides, and flavor compounds. Since the completion of the Arabidopsis genome, glucosinolate research has made significant progress, resulting in near-complete elucidation of the core biosynthetic pathway, identification of the first regulators of the pathway, metabolic engineering of specific glucosinolate profiles to study function, as well as identification of evolutionary links to related pathways. Although much has been learned in recent years, much more awaits discovery before we fully understand how and why plants synthesize glucosinolates. This may enable us to more fully exploit the potential of these compounds in agriculture and medicine.

Biology and biochemistry of glucosinolates

Recent applications of the Suzuki–Miyaura cross-coupling reaction in organic synthesis

Although no randomized studies have demonstrated a positive impact of therapeutic drug monitoring (TDM) on clinical outcome in epilepsy, evidence from nonrandomized studies and everyday clinical experience does indicate that measuring serum concentrations of old and new generation antiepileptic drugs (AEDs) can have a valuable role in guiding patient management provided that concentrations are measured with a clear indication and are interpreted critically, taking into account the whole clinical context. Situations in which AED measurements are most likely to be of benefit include (1) when a person has attained the desired clinical outcome, to establish an individual therapeutic concentration which can be used at subsequent times to assess potential causes for a change in drug response; (2) as an aid in the diagnosis of clinical toxicity; (3) to assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures; (4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g., children, the elderly, patients with associated diseases, drug formulation changes); (5) when a potentially important pharmacokinetic change is anticipated (e.g., in pregnancy, or when an interacting drug is added or removed); (6) to guide dose adjustments for AEDs with dose-dependent pharmacokinetics, particularly phenytoin.

/pdf/antiepileptic-drugs-best-practice-guidelines-for-therapeutic-2fvwrwdstw.pdf

Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies

Two-dimensionally extended, polycyclic heteroaromatic molecules (heterocyclic nanographenes) are a highly versatile class of organic materials, applicable as functional chromophores and organic semiconductors. In this Review, we discuss the rich chemistry of large heteroaromatics, focusing on their synthesis, electronic properties, and applications in materials science. This Review summarizes the historical development and current state of the art in this rapidly expanding field of research, which has become one of the key exploration areas of modern heterocyclic chemistry.

Heterocyclic Nanographenes and Other Polycyclic Heteroaromatic Compounds: Synthetic Routes, Properties, and Applications

Glucosinolates present classical examples of plant compounds affecting insect-plant interactions. They are found mainly in the family Brassicaceae, which includes several important crops. More than 120 different glucosinolates are known. The enzyme myrosinase, which is stored in specialized plant cells, converts glucosinolates to the toxic isothiocyanates. Insect herbivores may reduce the toxicity of glucosinolates and their products by excretion, detoxification, or behavioral adaptations. Glucosinolates also affect higher trophic levels, via reduced host or prey quality or because specialist herbivores may sequester glucosinolates for their own defense. There is substantial quantitative and qualitative variation between plant genotypes, tissues, and ontogenetic stages, which poses specific challenges to insect herbivores. Even though glucosinolates are constitutive defenses, their levels are influenced by abiotic and biotic factors including insect damage. Plant breeders may use knowledge on glucosinolates to increase insect resistance in Brassica crops. State-of-the-art techniques, such as mutant analysis and metabolomics, are necessary to identify the exact role of glucosinolates.

Role of Glucosinolates in Insect-Plant Relationships and Multitrophic Interactions

1. The anti-inflammatory agent diclofenac sodium (o-[(2,6-dichlorophenyl)amino]phenylacetic acid sodium salt) is extensively metabolized by rat, dog, baboon and man. The main metabolites were isolated from the urine of all species and from the bile of rat and dog and identified by spectroscopy. 2. Metabolism involves direct conjugation of the unchanged drug, or oxidation of the aromatic rings usually followed by conjugation. Sites of oxidation are either position 3' or 4' of the dichlorophenyl ring or, alternatively, position 5 of the phenyl ring attached to the acetic acid moiety. 3. In the urine of rat, baboon and man conjugates of the hydroxylated metabolites predominate, but the major metabolite in dog urine is the taurine conjugate of unchanged diclofenac. 4. In the bile of rat and dog, the main metabolite is the ester glucuroniade of unchanged diclofenac.

Biotransformation of diclofenac sodium (Voltaren) in animals and in man. I. Isolation and identification of principal metabolites.

1. The disposition of the new anti-epileptic agent oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) has been studied in two healthy volunteers following an oral 400 mg dose of 14C-labelled drug. The dose was excreted almost completely in the urine (94.6 and 97.1%) within six days. Faecal excretion amounted to 4.3 and 1.9% of the dose in the two subjects.2. In the 0–6 days urine samples the biotransformation products have been isolated and identified. 10,11-Dihydro-10-hydroxycarbamazepine (GP 47 779) and its two diastereoisomeric O-glucuronides were found as main metabolites. Taken together, they accounted for 79% of urinary 14C. Unchanged oxcarbazepine, and its sulphate and glucuronide conjugates were isolated in smaller amounts only (13%). Other minor metabolites were the trans- and cis-isomers of 10,11-dihydro-10,11-dihydroxy-carbamazepine (∼4%), and a phenolic derivative of GP 47 779 (<1%).3. The biotransformation of oxcarbazepine proceeds mainly by reduction to GP 47 779, and s...

The metabolism of 14C-oxcarbazepine in man.

13C NMR spectroscopy of naturally occurring iridoid glucosides and their acylated derivatives

1. The disposition of valsartan, a potent angiotensin II receptor antagonist, was investigated in six healthy male volunteers. They each received a single oral dose of 80 mg of a 14C-labelled preparation as a neutral buffered solution. 2. Peak concentrations of radioactivity and valsartan in plasma measured 1 h after dosing showed rapid onset of absorption. The results of this study combined with other available data indicate that at least 51% of the dose was absorbed. 3. Valsartan was the predominant radioactive compound in plasma. Elimination of valsartan and radioactivity was fast and multiexponential. beta-Half-lives of 6 +/- 1 h were observed. In a terminal elimination phase, low radioactivity levels decreased with a half-life of 81 +/- 33 h. A minor, pharmacologically inactive metabolite (valeryl-4-hydroxy-valsartan; M1) was detected in the plasma at time points later than 2 h after dosing, representing approximately 11% of the AUC(24 h) of plasma radioactivity. 4. The bulk of the dose was excreted within 4 days. The total excretion within 7 days amounted to 99 +/- 1% of dose. Faecal excretion was predominant (86 +/- 5% of dose). Valsartan was largely excreted unchanged (81 +/- 5% of the dose in the excreta). The predominant clearance mechanism appeared to be direct elimination via bile. 5. An inactive metabolite, M1, was formed by oxidative biotransformation and accounted for 9 +/- 3% of the dose in the excreta.

Pharmacokinetics, disposition and biotransformation of [14C]-radiolabelled valsartan in healthy male volunteers after a single oral dose.

Recognition by rice plants (Oryza sativa) of the nonhost pathogen Pseudomonas syringae pv. syringae leads to an active response ultimately resulting in local acquired resistance against the rice blast fungus Pyricularia oryzae. An observable aspect of this defense response is the increased abundance of a set of transcripts. The accumulation of one of these transcripts, Pir7b, was dependent on the function of the bacterial lemA gene, which encodes part of a two-component regulatory system. This suggested that the lemA regulatory system controlled the production of an elicitor of Pir7b transcript accumulation. This elicitor, which we name syringolin, was purified to homogeneity and its structure was elucidated. Syringolin is a novel and unusual secreted peptide consisting of a 12-membered ring formed by the two non-proteinogenic amino acids 5-methyl-4-amino-2-hexenoic acid and 3,4-dehydrolysine. The α-amino group of the latter is connected by a peptide bond to a valine that in turn is linked to a second val...

/pdf/syringolin-a-novel-peptide-elicitor-from-pseudomonas-54jcvr819n.pdf

Tammo Winkler

Papers

Biotransformation of diclofenac sodium (Voltaren) in animals and in man. I. Isolation and identification of principal metabolites.

The metabolism of 14C-oxcarbazepine in man.

13C NMR spectroscopy of naturally occurring iridoid glucosides and their acylated derivatives

Pharmacokinetics, disposition and biotransformation of [14C]-radiolabelled valsartan in healthy male volunteers after a single oral dose.

Syringolin, a novel peptide elicitor from Pseudomonas syringae pv. syringae that induces resistance to Pyricularia oryzae in rice