Transport properties and ionicity of phosphonium ionic liquids.

Ionic liquids (ILs) are promising electrolytes and many efforts have been made in basic scientific research as well as in applied research. In this contribution, we synthesised a variety of partly novel phosphonium ILs with different anions as well as with different compositions and lengths of the side chains of the cations. We measured a variety of their important transport properties such as viscosity, conductivity and diffusivity by means of stress-controlled rheology, impedance spectroscopy and PFGSTE NMR diffusometry. The results are analysed with respect to different models for derivation from ideal behaviours such as the ionicity and the (fractional) Walden rule depending on their molecular structure. These models are well established in the literature and are herein applied to rarely investigated but promising phosphonium ILs, with a particular emphasis placed on the effect of ether side chains. In comparison, the models show a qualitative correlation but distinct deviation in the quantification especially in the temperature dependent values and with other IL systems. These results aim to facilitate a better understanding of the IL properties depending on the molecular composition and by this way help to choose the ILs with optimal properties for practical applications.

Steering the azido-tetrazole equilibrium of 4-azidopyrimidines via substituent variation - implications for drug design and azide-alkyne cycloadditions.

This paper focuses on an interesting constitutional isomerism called azido-tetrazole equilibrium which is observed in azido-substituted N-heterocycles. We present a systematic investigation of substituent effects on the isomer ratio within a 2-substituted 4-azidopyrimidine model scaffold. NMR- and IR-spectroscopy as well as X-ray crystallography were employed for thorough analysis and characterization of synthesized derivatives. On the basis of this data, we demonstrate the possibility to steer this valence tautomerism towards the isomer of choice by means of substituent variation. We show that the tetrazole form can act as an efficient disguise for the corresponding azido group masking its well known reactivity in azide-alkyne cycloadditions (ACCs). In copper(I)-catalyzed AAC reactions, substituent-stabilized tetrazoles displayed a highly decreased or even abolished reactivity whereas azides and compounds in the equilibrium were directly converted. By use of an acid sensitive derivative, we provide, to our knowledge, the first experimental basis for a possible exploitation of this dynamic isomerism as a pH-dependent azide-protecting motif for selective SPAAC conjugations in aqueous media. Finally, we demonstrate the applicability and efficiency of stabilized tetrazolo[1,5-c]pyrimidines for Fragment-Based Drug Design (FBDD) in the field of quorum sensing inhibitors.

Kaempferol-3,4'-di-O-beta-glucopyranoside-7-O-alpha-rhamnopyranoside as a new flavonoid from Iberis amara L.

A new flavonol glycoside, kaempferol-3,4'-di-O-beta-glucopyranoside-7-O-alpha-rhamno-pyranoside, was isolated from the ethanolic extract of the whole fresh plant of Iberis amara L., an European plant used in gastrointestinal medicine. The structure was established by a combination of 1D and 2D NMR techniques (COSY, HSQC, HMBC, NOESY) as well as UV, IR and mass spectral data.

Decomposition of the telomere-targeting agent BRACO19 in physiological media results in products with decreased inhibitory potential.

The stability of the acridine-based telomere-targeting agent BRACO19, a G-quadruplex stabilizing substance, was tested at different pH, temperature and in different dissolution media. Analysis was performed by HPLC. Decomposition products were examined by LC/MS and NMR. The TRAP assay was used to determine the inhibitory potential of the decomposition products on telomerase activity. The results show that the stability of BRACO19 strongly depends on pH and temperature. Decomposition was fastest at physiological pH and temperature while the type of dissolution medium had no major influence on stability. The most probable mechanism for this decomposition seems to be a hydrolysis of the amide bonds in position 3 and 6 of the acridine ring and/or a deamination of the phenyl ring. The decomposition products showed a reduced inhibitory potential compared to the parent compound BRACO19. The results demonstrate that the preparation of dosage forms and their storage conditions will have an important influence on the stability--and hence biological efficacy--of BRACO19 and related substances.

The steroid metabolite 16(ß)-OH-androstenedione generated by CYP21A2 serves as a substrate for CYP19A1.

The 21-hydroxylase (CYP21A2) is a steroidogenic enzyme crucial for the synthesis of mineralo- and glucocorticoids. It is described to convert progesterone as well as 17-OH-progesterone, through a hydroxylation at position C21, into 11-deoxycorticosterone (DOC) and 11-deoxycortisol (RSS), respectively. In this study we unraveled CYP21A2 to have a broader steroid substrate spectrum than assumed. Utilizing a reconstituted in vitro system, consisting of purified human CYP21A2 and human cytochrome P450 reductase (CPR) we demonstrated that CYP21A2 is capable to metabolize DOC, RSS, androstenedione (A4) and testosterone (T). In addition, the conversion of A4 rendered a product whose structure was elucidated through NMR spectroscopy, showing a hydroxylation at position C16-beta. The androgenic properties of this steroid metabolite, 16(ß)-OH-androstenedione (16bOHA4), were investigated and compared with A4. Both steroid metabolites were shown to be weak agonists for the human androgen receptor. Moreover, the interaction of 16bOHA4 with the aromatase (CYP19A1) was compared to that of A4, indicating that the C16 hydroxyl group does not influence the binding with CYP19A1. In contrast, the elucidation of the kinetic parameters showed an increased Km and decreased kcat value resulting in a 2-fold decreased catalytic efficiency compared to A4. These findings were in accordance with our docking studies, revealing a similar binding conformation and distance to the heme iron of both steroids. Furthermore, the product of 16bOHA4, presumably 16-hydroxy-estrone (16bOHE1), was investigated with regard to its estrogenic activity, which was negligible compared to estradiol and estrone. Finally, 16bOHA4 was found to be present in a patient with 11-hydroxylase deficiency and in a patient with an endocrine tumor. Taken together, this study provides novel information on the steroid hormone biosynthesis and presents a new method to detect further potential relevant novel steroid metabolites.

Diterpenoid alkaloids from the roots of Aconitum cochleare.

From the roots of Aconitum cochleare Woroschin, collected in Turkey, a new diterpenoid alkaloid named acochlearine has been isolated along with the known diterpenoid alkaloids talatisamine, 14-O-acetyltalatisamine, senbusine C and condelphine. The structure for acochlearine was established on the basis of 1H, 13C, DEPT, homonuclear 1H COSY, NOESY, HSQC and HMBC NMR studies.

2ß- and 16ß-hydroxylase activity of CYP11A1 and direct stimulatory effect of estrogens on pregnenolone formation.

The biosynthesis of steroid hormones in vertebrates is initiated by the cytochrome P450 CYP11A1, which performs the side-chain cleavage of cholesterol thereby producing pregnenolone. In this study, we report a direct stimulatory effect of the estrogens estradiol and estrone onto the pregnenolone formation in a reconstituted in vitro system consisting of purified CYP11A1 and its natural redox partners. We demonstrated the formation of new products from 11-deoxycorticosterone (DOC), androstenedione, testosterone and dehydroepiandrosterone (DHEA) during the in vitro reaction catalyzed by CYP11A1. In addition, we also established an Escherichia coli-based whole-cell biocatalytic system consisting of CYP11A1 and its redox partners to obtain sufficient yields of products for NMR-characterization. Our results indicate that CYP11A1, in addition to the previously described 6ß-hydroxylase activity, possesses a 2ß-hydroxylase activity towards DOC and androstenedione as well as a 16ß-hydroxylase activity towards DHEA. We also showed that CYP11A1 is able to perform the 6ß-hydroxylation of testosterone, a reaction that has been predominantly attributed to CYP3A4. Our results are the first evidence that sex hormones positively regulate the overall production of steroid hormones suggesting the need to reassess the role of CYP11A1 in steroid hormone biosynthesis and its substrate-dependent mechanistic properties.

Biosynthesis of a hopane triterpene and three diterpenes in the liverwort Fossombronia alaskana.

The biosynthesis of the triterpene 22-(30)-hopene-29-acid and the diterpenes 7,17-sacculatadiene-11,12-dial (sacculatal), trans-phytol and a new neoverrucosane-type diterpenoid (5-oxo-neoverrucos-(13)-ene) was studied by incorporation of [1-13C]-labelled glucose into axenic cultures of the artic liverwort Fossombronia alaskana. Quantitative 13C NMR spectroscopic analysis of the resulting labelling patterns showed that the isoprene units of the triterpene are derived from the mevalonic acid pathway, whereas the isoprene units of the diterpenes are built up via the methylerythritol phosphate pathway.

Sesquiterpenoids and diterpenoids from the Chilean liverwort Lepicolea ochroleuca.

The ether extract of the Chilean liverwort Lepicolea ochroleuca yielded three sesquiterpenoids, ent-4 beta-Hydroxy-10 alpha-methoxyaromadendrane, ent-3 beta-Hydroxyspathulenol, and 1,10-Dioxotayloriane, as minor components. The major components were ledol and 13-epi-neoverrucosan-5 beta-ol, four other minor fusicoccanoids were identified.

Isolation of new alkylthiosulfides from the essential oil and extracts from the bark of Scorodophloeus zenkeri Harms.

2,3,5-trithiahexane, 2,3,4,6-tetrathiaheptane, 2,4,5,7-tetrathiaoctane, two pentathianonanes, 2,4,5,7,9-pentathiadecane and two hexathiaundecanes were isolated from the essential oil and extracts from the bark of Scorodophloeus zenkeri Harms. Four other thioalkanes were found in small amounts in the essential oil.

Comfortable labor with intrathecal narcotics.

Aggressive pursuit of high-quality health care had guided the Health Service of the United States Army to establish a labor analgesia program within its hospitals. A dedicated Labor Epidural Service can be quite expensive, especially from the manpower standpoint. Therefore, the Anesthesia Service at Reynolds Army Community Hospital, Fort Sill, Oklahoma, implemented a program of intrathecal narcotic injection as an alternative to costly labor epidural analgesia. After reviewing a patient fact sheet, 150 laboring patients volunteered for labor intrathecal analgesia (LIA). Once active labor began, the patient received intrathecal morphine (0.25 mg) and fentanyl (25 micrograms). The pain level before and after the LIA was evaluated by the visual analog schedule method. At 2 weeks follow-up the intrathecal narcotic-assisted labor was subjectively reported by the patients. Ninety-four percent of the patients agreed that the LIA worked well and that they would do it again. LIA was found to be a well-accepted, cost-saving, very effective approach to labor analgesia.

Gabapentin for the treatment of tinnitus: a case report.

The objective of this article is to discuss the clinically effective use of gabapentin in patients with tinnitus. The author describes the case of a man who came to the office complaining of tinnitus of 10 months' duration. The patient was started on gabapentin and maintained on a regimen of 500 mg/day in divided doses. Subsequently, he reported that he was free of tinnitus approximately 23 days a month and that he experienced a 75% decrease in symptoms during the remaining days. At 2 years' follow-up, he remains noise- and pain-free on 500 mg/day of gabapentin.