Triazole-based chromogenic and non-chromogenic receptors for halides

We designed and synthesized a series of triazole-based receptors for anion recognition. Our studies demonstrated that an amide-linked triazole unit is a promising moiety for anion recognition. We synthesized various chromogenic and non-chromogenic receptors based on this moiety. Receptor 11 binds very strongly (K = 102,750 M⁻¹) to fluoride. Receptor 18 changes color from faint yellow to orange upon binding to fluoride.     

Separation of potentially therapeutic peptide hormones by liquid chromatography. Optimisation of the composition and pH of the mobile phase

The aim of this work is to optimise the proportion of the organic modifier and the pH of the mobile phase, in order to separate a series of peptide hormones with therapeutic interest in the molecular mass range from 500 to 6000. The composition of the mobile phase was optimised by establishing relationships between retention parameters and either the scale of solvent polarity, or the Kamlet–Taft multiparameter solvent scale of the eluent, using linear solvation energy relationships. Likewise, linear correlations between the chromatographic retention and Reichardt’s E^N_T parameter were obtained. These relationships allowed an important reduction of the experimental retention data needed for developing a given separation. In addition, a model describing the effect of the correctly measured pH of the mobile phase on retention in LC was established and tested for the series of selected peptides using an octadecylsilica column. The proposed equations permit the prediction of the optimum pH and also permit the determination of the acidity constants of the peptides in the hydro-organic mixtures using a minimum number of measurements.     

1,3-Phenyl linked urea-based receptors for anions and the facile cyclization to imidazolidinedione

Amino acid-based molecules containing a bis-urea moiety have been synthesized and demonstrated for their anion binding affinities. Compound 1c binds phosphate and sulfate with binding constants of 3.6 × 10³ M⁻¹ and 4.3 × 10³ M⁻¹, respectively. These molecules undergo proton transfer upon treatment with fluoride, resulting in the formation of imidazolidinediones. The crystal structure of one such diimidazolidinedione displays self-assembly through nonconventional hydrogen bonding interactions.     

Enantioselective binding of amino acids and amino alcohols by self-assembled chiral basket-shaped receptors

Amino acid appended diphenylglycoluril-based chiral molecular receptors 2 and 3 have been prepared and their aggregation has been studied in water at various pH's and in chloroform. The binding of several biologically relevant guests with aromatic moieties to these aggregates has been studied with UV-Vis spectroscopy in competition experiments with 4-(4-nitrophenylazo)resorcinol (Magneson) and 2-(4-hydroxyphenylazo)benzoic acid (HABA) as probes. Aggregates of chiral host 2b showed binding of catecholamines and aromatic amino acids in an aqueous environment, as well as discrimination between amino acid enantiomers, and can be considered a mimic for adrenergic receptors.     

Design and synthesis of ninhydrin-based cyclophanes as potential neutral receptors for quaternary ammonium cations

Four ninhydrin-based cyclophanes 4a, 4b, 6a, and 6b were designed and synthesized. Two rectangular type cyclophanes (4a and 4b) and two square type cyclophanes (6a and 6b) were prepared in 8-43% yields.     

Quantitation of anabolic hormones and their metabolites in bovine serum and urine by liquid chromatography-tandem mass spectrometry

A specific and sensitive method based on tandem mass spectrometry with on-line high-performance liquid chromatography using atmospheric pressure chemical ionisation (LC–APCI-MS–MS) for the quantitation of anabolic hormone residues (17β-19-nortestosterone, 17β-testosterone and progesterone) and their major metabolites (17-19-nortestosterone and 17-testosterone) in bovine serum and urine is reported. [²H₂]17β-Testosterone was used as internal standard. The analytes were extracted from urine (following enzymatic hydrolysis) and serum samples by liquid–liquid extraction and purified by C₁₈ solid-phase extraction. Ionisation was performed in a heated nebulizer interface operating in the positive ion mode, where only the protonated molecule, [M+H]⁺, was generated for each analyte. This served as precursor ion for collision-induced dissociation and two diagnostic product ions for each analyte were identified for the unambiguous hormone confirmation by selected reaction monitoring LC–MS–MS. The overall inter-day precision (relative standard deviation) ranged from 6.37 to 2.10% and from 6.25 to 2.01%, for the bovine serum and urine samples, respectively, while the inter-day accuracy (relative error) ranged from −5.90 to −3.18% and from −6.40 to −2.97%, for the bovine serum and urine samples, respectively. The limit of quantitation of the method was 0.1 ng/ml for all the hormones in bovine serum and urine. On account of its high sensitivity and specificity the method has been successfully used to confirm illegal hormone administration for regulatory purposes.     

Influence of terminal substituents on the halide anion binding of foldamer-based receptors

Foldamers 1–4 incorporating different terminal substituents have been designed and synthesized for binding halide anions.~1H NMR titration experiments carried out in DMSO-d_6/CDCl_3(15/85, v/v)demonstrated that the short oligo (aryltriazole)s backbone 1 could not bind halide anions unless that amide H-bond donors were incorporated at the termini of the oligomer. Terminal substituents on oligo(aryltriazoleamide)s foldamers 2–4 display a considerable influence on the binding affinities of the foldamers for halide anions. Large steric hindrance of the terminal substituents was found to be unfavorable for binding halide anions, but aromatic π-π interactions between two terminal substituents are capable of stabilizing the conformation of foldamers thus giving rise to an enhancement in the binding strengths. However, the terminal substituents were found to hardly affect the binding selectivity in the studied cases.     

Separation and characterization of multicomponent peptide mixtures by liquid chromatography-electrospray ionization mass spectrometry. Application to crude products of the synthesis of leuprolide

Leuprolide is a synthetic structural analogue of luteinizing hormone-releasing hormone used for the treatment of a large number of diseases related with the regulation of sexual hormones. Solid-phase peptide synthesis is used to obtain leuprolide peptidic hormone, but this synthetic procedure results in complex mixtures that need separation and characterization. Here, liquid chromatography coupled with mass spectrometry using electrospray ionization, (LC–ES-MS), was used for the separation and characterization of multicomponent peptide mixtures of crudes of synthesis of leuprolide. To optimize the LC separation process, the method of linear solvation energy relationships was applied and the powerful coupling LC–ES-MS permitted rapid and reliable characterization of the reaction product.     

Neurophysins: molecular and cellular aspects.

Neurophysins are linear cystine-rich proteins containing 93–95 amino acid residues which like the neurohypophysial hormones oxytocin and vasopressin are formed in the hypothalamus and travel from there to the hypophysial posterior lobe. A species usually contains two (or three) neurophysins which differ only slightly in chain length and/or sequence. Many observatios suggest that both oxytocin and one of the neurophysins as well as vasopressin and the other neurophysin have a common precursor whose long chain is split into neurophysin and hormone. It can be shown on rats having considerable diabetes insipidus that a single gene controls the biosynthesis of the vasopressin and one of the neurophysins.     

Water-soluble aminocalix[4]arene receptors with hydrophobic and hydrophilic mouths

We report the new water-soluble aminocalix[4]arene hosts 1 and 2 with deep hydrophobic cavity facilitating hydrophobic mouth and hydrophilic mouth, respectively. The ¹H NMR titrations revealed that host 1 shows high selectivity for neutral guests 9 and 10, with log K of 4.2 and 4.6, respectively. The host 2 shows log K of 4.9 for binding with guest 15. Moreover, the binding ability of the host 2 for guest 14 is stronger by a factor of 1000 than that of the host 1.     

Molecular receptors for monosaccharides: di(pyridyl)naphthyridine and di(quinolyl)naphthyridine

The recognition capabilities of two molecular receptors 2,7-di(3′-pyridyl)-1,8-naphthyridine (DPN) and 2,7-di(3′-quinolyl)-1,8-naphthyridine (DQN) toward monosaccharides in chloroform were evaluated. Both DPN and DQN possess a naphthyridine core moiety, in which two pyridinic nitrogen atoms serve as the proton acceptors. Attached to the C2 and C7 positions of naphthyridine are two identical arms, each of which consists of pyridine (DPN) or quinoline (DQN) moiety that also acts as the proton acceptor. The arrangement of hydroxyl groups in monosaccharides offers the proton donors complementary to the proton acceptors of DPN (or DQN) to form a quadruply hydrogen bonds complex. The binding processes were studied by UV-vis, fluorescence and ¹H NMR spectrophotometric titrations as well as electrospray ionization mass spectroscopy. The binding strength between DPN (or DQN) and examined monosaccharides was comparable to that for many other hydrogen-bonding host molecules previously reported.     

The Role of Birth Control in the Survival of the Human Race

Analysis of the growth of the world's population shows that if no trenchant measures are taken, the number of the earth's inhabitants is likely to double to 8 billion people within as few as 35 years. Hormonal contraception is presently the best method available which would be capable of counteracting this trend. 6.5 tons of estrogen and 32 tons of progestogen would in theory be sufficient to protect the 500 million women of child-bearing age from unwanted pregnancies for one year.—In addition, the history, industrial methods of synthesis, mode of action and side effects of steroid contraceptives as well as the possible future developments are briefly mentioned.     

Preferential binding of the magnesium ion by anthraquinone based chromogenic receptors

Two new anthraquinone based receptors have been synthesized. A colour change for both these receptors could be detected when group IIA metal ions were added in DMF solution at room temperature. No such colour change was noticed for group IA metal ions. Association constants for these receptors towards Mg²⁺, Ca²⁺, Sr²⁺ and Ba²⁺ were evaluated by systematic spectrophotomeric titrations and they follow the order K_Mg(II) ? K_Ca(II) > K_Sr(II) ? K_Ba(II). The association constants for L₁ were found to be higher than those for L₂ toward group IIA metal ions. Ab initio quantum chemical calculations have been performed to rationalize these observed results. X-ray structural analysis shows a helical structure for one of the receptor molecules.     

Determination of melatonin in biological samples by capillary electrophoresis

The determination of melatonin (MLT) in physiological samples was investigated using capillary electrophoresis (CE). Mouse blood was collected in tubes containing EDTA, centrifuged at 1500 g for 20 min at 4°C, and stored at −20°C. Plasma samples were extracted with dichloroethane, centrifuged and the aqueous phase was discarded. Then the organic phase was evaporated to dryness. The residue was dissolved in deionized water and filtered with a microfilter (0.22 μm). Separations were carried out using a CE system equipped with a fused silica capillary [80 cm (effective length 52 cm)×75 μm I.D.] and an ultraviolet–visible detector (200 nm), and programmed to provide 25 mM 2-(N-morpholino)ethanesulfonic acid (pH 5.7). Injection was performed hydrostatically by elevating the sample by 10 cm at the cathodic side of the capillary. The calibration curve, reproducibility, recovery and limit of detection were examined, and validation of the method was performed. The result showed that MLT in blood could be easily determined with the new method.     

The hormonal system of plants

Higher plants generate active substances, termed phytohormones, having the character of tissue hormones. Some of these compounds have been isolated and identified, namely ethylene, heteroauxins, and gibberellic acids. Cell-elongation inhibitors have been detected, but not yet isolated or identified. Natural and synthetic substances with hormone-analogous effects and those with a hormone-antagonistic effect have become known; evidently, they act on the hormonal system of plants which regulates growth, differentiation, and development and can serve as model substances for as yet unknown phytohormones. Certain physiological phenomena suggest the existence of additional phytohormones.     

The chemistry and biochemistry of insulin

The protein hormone insulin occurs widely in the animal kingdom. Although its biological function is always the same, its amino-acid composition varies widely. Insulin consists of two polypeptide chains, which are linked by three cystine residues to form a bicyclic system with a 20-membered and an 85-membered ring. The protein crystallizes in various forms with foreign ions. In solution, insulin normally forms aggregates of 2n molecules. The hormone can be regenerated from the separated polypeptide chains, and its total synthesis has been achieved in a similar manner from synthesized peptide chains. In the biosynthesis of insulin, the two chains are evidently built up separately and subsequently linked together. Insulin promotes the synthesis of glycogen, fat, and protein in the organism; insulin deficiency leads to an increase in the blood-sugar level. At the molecular level, the mechanism of action of the hormone is still unknown. Current hypotheses are discussed. No specific active center has so far been detected in the insulin molecule, which contains several antigenic regions.     

Hormone

Ohne Zusammenfassung     

Chemistry and Biosynthesis of the Hypothalamic Releasing and Inhibiting Neurohormones

The hypothalamus secretes hormones which in turn affect the release of hormones from the anterior lobe of the pituitary gland. Evidence has so far been adduced for the existence of seven hypothalamic releasing hormones and three inhibiting hormones. These neurohormones are all oligopeptides and occur in only nanogram amounts in the hypothalamus. The study of synthetic analogs has provided valuable information regarding their mechanism of action.