Synthesis of isomeric 11-hydroxy 11-methyl prostaglandins

The synthesis of several novel 11-substituted prostaglandins has been achieved from PGA₂ methyl ester from the marine coral . The configuration of the substituents at position 11 is based on the nuclear magnetic resonance properties.     

Synthesis of (±)-11-deoxy-15-ethynyl prostaglandins

This article describes the preparation of (±)-11-deoxy-15-ethynyl prostaglandins ( & ). The key step involves a conjugate addition of the substituted 1-lithio-1-oct-1-ene ( ) to the cyclopentenone ( & ) to furnish 11-deoxy-prostaglandin skeleton in a simple fashion. Of particular interest in this synthesis is the preparation of alkyl side chain ( ) which was achieved in an efficient three-step synthesis starting from the readily available β-iodo vinyl ketone ( ).     

Assignment of absolute configuration using chiral reagents and NMR spectroscopy

An overview of chiral reagents that are used to assign the absolute configuration of particular classes of compounds using NMR spectroscopy is presented. The use of chiral derivatizing agents, chiral solvating agents, metal complexes, and liquid crystals is described. Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

Structure-activity relationships in a series of 11-deoxy prostaglandins

A series of 11-deoxy prostaglandin derivatives and some naturally occurring prostaglandins have been investigated in the anaesthetized artificially respired guinea-pig for their effect on blood pressure, bronchial resistance (overflow pressure at constant volume), tracheal segment pressure, and on intestinal and uterine smooth muscle. The compounds were administered intravenously. Prostaglandins E₁, E₂ and F_2α produced responses that were qualitatively similar to those in the literature. Prostaglandin A₂ (100 μg) was a bronchoconstrictor, although it decreased tracheal segment pressure and blood pressure. Prostaglandin B₂ (100 μg) caused double elevations in blood pressure, tracheal segment pressure and bronchial resistance. The intensity of bronchoconstriction produced by PGB₂ was of the same order as with PGF_2α. A number of structure-activity relationships were found. 11-Deoxygenation lowered the biological activity of the natural prostaglandins PGE₁ and PGF_1α. The vasodepressor and bronchodilator responses of 11-deoxy PGE₁ were converted to vasopressor and bronchoconstrictor by epimerisation at C-15. Introduction of a methyl group at C-15 of 11-deoxy PGF_1α both increased and prolonged vasopressor and bronchoconstrictor activity. At C-9 both the keto and β-hydroxy group imparted vasodepressor and bronchodilator activity, while the α-hydroxy led to vasopressor and bronchoconstrictor activity. Extension of the omega sidechain by two methylene groups radically reduced the activity of 11-deoxy PGF_1α and its derivatives.These experiments indicate that steric differences in the prostaglandin structures studied can result in diametrically opposed profiles of biological activity. Further, small variations in the prostaglandin molecule can lead to differences in potency and/or profile of activity in the guinea-pig.     

Assignment of the absolute configuration of zwitterionic and neutral macropodumines by means of TDDFT CD calculations

Macropodumines B and C (1, 2) are fused pentacyclic alkaloids previously isolated from the Chinese medicinal plant Daphniphyllum macropodum. Macropodumine B (1) possesses an amazing structural feature of a cyclopentadienyl carbanion, stabilized as a zwitterion by an internal iminium cation, which was confirmed by X-ray diffraction analysis. On the basis of the X-ray geometry, the absolute configuration of 1 was determined by employing the solid-state CD/TDDFT approach. The absolute configuration of 2 was instead determined by using TDDFT CD calculations on DFT-optimized geometries, in comparison with CD spectra recorded in solution.     

Assignment of absolute configuration to an improved enantioselective naproxen selector

Assignment of absolute configuration to a recently developed chiral selector useful in the separation of the underivatized enantiomers of naproxen and other nonsteroidal anti-inflammatory drugs (NSAIDs) is described. Circular dichroism, ¹H NMR, and X-ray diffraction have been used to confirm the original assignment which was based solely upon elution orders from HPLC chiral stationary phases. All of these techniques agree in the assignment of the (S,S) absolute configuration to the enantiomer of the chiral selector which associates preferentially with (S)-naproxen. © 1994 Wiley-Liss, Inc.     

Auditory-motor learning during speech production in 9-11-year-old children

Background

Hearing ability is essential for normal speech development, however the precise mechanisms linking auditory input and the improvement of speaking ability remain poorly understood. Auditory feedback during speech production is believed to play a critical role by providing the nervous system with information about speech outcomes that is used to learn and subsequently fine-tune speech motor output. Surprisingly, few studies have directly investigated such auditory-motor learning in the speech production of typically developing children.

Methodology/Principal Findings

In the present study, we manipulated auditory feedback during speech production in a group of 9–11-year old children, as well as in adults. Following a period of speech practice under conditions of altered auditory feedback, compensatory changes in speech production and perception were examined. Consistent with prior studies, the adults exhibited compensatory changes in both their speech motor output and their perceptual representations of speech sound categories. The children exhibited compensatory changes in the motor domain, with a change in speech output that was similar in magnitude to that of the adults, however the children showed no reliable compensatory effect on their perceptual representations.

Conclusions

The results indicate that 9–11-year-old children, whose speech motor and perceptual abilities are still not fully developed, are nonetheless capable of auditory-feedback-based sensorimotor adaptation, supporting a role for such learning processes in speech motor development. Auditory feedback may play a more limited role, however, in the fine-tuning of children''s perceptual representations of speech sound categories.     

Assignment of the absolute configuration of [n]-ladderanes by TD-DFT optical rotation calculations

In this study, we report theoretical specific rotation values for a series of cis-/trans-alkylated-[5]-ladderanes and cis-/trans-methylated-[n]-ladderanes. Using time-dependent density functional response theory optical rotation calculations, we can assign (+) and (-) optical rotation signs to trans-(S)-alkyl-[5]-ladderane and trans-(R)-alkyl-[5]-ladderane configurations, respectively. In order to qualitatively validate our absolute configuration predictions, we computed optical rotation values at three different levels of theory--B3LYP, RI-BP86, and Hartree-Fock--using the aug-cc-pVDZ basis set. We observe a novel rung-parity-controlled oscillatory optical rotatory phenomenon in our computations, which, to the best of our knowledge, has never been reported or observed before. Furthermore, this preliminary analysis of optical rotation properties in this class of compounds should facilitate the correct absolute stereochemical assignment of natural and synthetic ladderanes, such as the trans-isomer of pentacyclic C(20)-fatty acid methyl ester (pentacycloanammoxic methyl ester), without the need for derivatization, in particular for cases where NMR or X-ray crystal structures are not readily available.     

Assignment of absolute configuration of 3-hydroxy beta-lactams by the NMR "mix and shake" method

The absolute configurations of several 3-hydroxy beta-lactams were assigned by the NMR "mix and shake" methodology developed by Riguera and co-workers. The results from the NMR study correlated perfectly with the absolute configurations obtained from X-ray crystallographic structure analyses and chiral-phase HPLC data.     

Cardiovascular effects of delta 9- and delta 9(11)-tetrahydrocannabinol and their interaction with epinephrine

The administration of delta-9-tetrahydrocannabinol (delta 9-THC, 0.078-5.0 mg/kg, i.v.) to rats anesthetized with pentobarbital caused as much as a 50% decrease in mean arterial blood pressure, heart rate and respiratory rate in a dose-dependent manner. Delta-9(11)-tetrahydrocannabinol (delta 9(11)-THC) was approximately 8-fold less potent than delta 9-THC in its hypotensive effect and had smaller effects on heart and respiratory rates that were not dose-related at doses below 5 mg/kg. Alternate injections of epinephrine (2 micrograms/kg) with vehicle and increasing cannabinoid doses (1.25-5.0 mg/kg) indicated a potentiation of both the duration of the pressor effect and the magnitude of the reflex bradycardic effect of epinephrine by both delta 9- and delta 9(11)-THC. Epinephrine also produced arrhythmias in rats receiving cannabinoids, but not in rats receiving alternate injections of vehicle. It is concluded that both cannabinoids have adverse effects on the cardiovascular system and adverse interactions with epinephrine in rats anesthetized with pentobarbital.     

Assignment of absolute configuration and optical purity determination of (R)- and (S)-econazole nitrate by enantioselective HPLC: Method development and application

A method is described for the synthesis and optical purity determination of (?)-(R)- and (+)-(S)-econazole via the optically pure intermediates, (R)- and (S)-imidazolylethanol, which are available by chromatographic resolution or by fractional crystallization of diastereomeric O,O′-disubstituted (R*;R*)- or (S*;S*)-tartaric acid monoesters of the parent imidazolylethanol racemate. Furthermore, this method allows the chromatographic assignment of the absolute configuration of the chiral center of the imidazolylethanol enantiomers and consequently of econazole enantiomers. In addition, a direct liquid chromatographic enantioseparation method for the determination of the optical purity of (R)- and (S)-econazole and other chiral imidazoles on a protein type CSP (OVM) is described and applied to confirm chromatographically the absolute configuration evaluations. © 1994 Wiley-Liss, Inc.