Intrinsic optical activity and environmental perturbations: solvation effects in chiral building blocks

The non-resonant interaction of electromagnetic radiation with an isotropic ensemble of chiral molecules, which causes the incident state of linear polarization to undergo a signed rotation, long has served as a metric for gauging the enantiomeric purity of asymmetric syntheses. While the underlying phenomenon of circular birefringence (CB) typically is probed in the condensed phase, recent advances in ultrasensitive circular-differential detection schemes, as exemplified by the techniques of Cavity Ring-Down Polarimetry (CRDP), have permitted the first quantitative analyses of such processes to be performed in rarefied media. Efforts to extend vapor-phase investigations of CB to new families of chiral substrates will be discussed, with particular emphasis directed towards the elucidation of intrinsic (e.g., solvent-free) properties and their mediation by environmental perturbations (e.g., solvation). Specific species targeted by this work will include the stereoselective building blocks phenylpropylene oxide and $\alpha$-methylbenzyl amine, both of which exhibit pronounced solvent-dependent changes in measured optical activity. The nature of chiroptical response in different environments will be highlighted, with quantum-chemical calculations serving to unravel the structural and electronic provenance of observed behavior

NATURAL OPTICAL ACTIVITY OF CHIRAL EPOXIDES: THE INFLUENCE OF STRUCTURE AND ENVIRONMENT ON THE INTRINSIC CHIROPTICAL RESPONSE

Chiral epoxides built upon nominally rigid frameworks that incorporate aryl substituents have been shown to provide versatile backbones for asymmetric syntheses designed to generate novel pharmaceutical and catalytic agents. The ubiquity of these species has motivated the present studies of their intrinsic (solvent-free) circular birefringence (CB), the measurement of which serves as a benchmark for quantum-chemical predictions of non-resonant chiroptical behavior and as a beachhead for understanding the often-pronounced mediation of such properties by environmental perturbations (e.g., solvation). The optical rotatory dispersion (or wavelength-resolved CB) of (R)-styrene oxide (R-SO) and (S,S)-phenylpropylene oxide (S-PPO) have been interrogated under ambient solvated and isolated conditions, where the latter efforts exploited the ultrasensitive techniques of cavity ring-down polarimetry. Both of the targeted systems display marked solvation effects as evinced by changes the magnitude and (in the case of R-SO) the sign of the extracted specific optical rotation, with the anomalously large response evoked from S-PPO distinguishing it from other members of the epoxide family. Linear-response calculations of dispersive optical activity have been performed at both density-functional and coupled-cluster levels of theory to unravel the structural and electronic origins of experimental findings, thereby suggesting the possible involvement of hindered torsional motion along dihedral coordinates adjoining phenyl and epoxide moieties

A combined experimental and theoretical study of optical rotatory dispersion for (R)-glycidyl methyl ether in aqueous solution

The dispersive optical activity for aqueous solutions of non-rigid (R)-glycidyl methyl ether (R-GME) has been explored synergistically from experimental and theoretical perspectives. Density functional theory analyses performed with the polarizable continuum model for implicit solvation identified nine low-lying stable conformers that are interconverted by rotation about two large-amplitude torsional coordinates. The antagonistic chiroptical signatures predicted for these structural isomers were averaged under a Boltzmann-weighting ansatz to estimate the behavior expected for a thermally equilibrated ensemble. This led to optical rotatory dispersion profiles that reproduced the overall shape of observations but failed to achieve uniform agreement with measured specific-rotation values even when anharmonic vibrational corrections were applied. A mixed QM/FQ paradigm, whereby quantum-mechanical (QM) calculations of optical activity were combined with classical molecular dynamics simulations of explicit solvation that included mutual-polarization effects by means of fluctuating charges (FQ), was enlisted to elucidate the microsolvation environment and gauge its impact upon conformer distributions and response properties. Although quantitative accord with experiments remained elusive, this approach revealed strong variations in the magnitude and sign of rotatory powers for R-GME as the configuration of surrounding water molecules evolved, thereby highlighting the inherently dynamical nature of the solvated chiroptical response, calling into question the validity of "static" descriptions based on the presumption of distinct energy minima, and giving insight into the inherent complexity posed by the modeling of such properties for solvated systems

Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers

The effect of rifampin on the in vivo metabolism of the antiretroviral drug efavirenz was evaluated in healthy volunteers. In a cross-over placebo control trial, healthy subjects (n = 20) were administered a single 600 mg oral dose of efavirenz after pretreatment with placebo or rifampin (600 mg/day for 10 days). Plasma and urine concentrations of efavirenz, 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz were measured by LC-MS/MS. Compared to placebo treatment, rifampin increased the oral clearance (by ∼2.5-fold) and decreased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-∞) of efavirenz (by ∼1.6- and ∼2.5-fold respectively) (p < 0.001). Rifampin treatment substantially increased the Cmax and AUC0-12h of 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz, metabolic ratio (AUC0-72h of metabolites to AUC0-72h efavirenz) and the amount of metabolites excreted in urine (Ae0-12hr) (all, p < 0.01). Female subjects had longer elimination half-life (1.6-2.2-fold) and larger weight-adjusted distribution volume (1.6-1.9-fold) of efavirenz than male subjects (p < 0.05) in placebo and rifampin treated groups respectively. In conclusion, rifampin enhances CYP2B6-mediated efavirenz 8-hydroxylation in vivo. The metabolism of a single oral dose of efavirenz may be a suitable in vivo marker of CYP2B6 activity to evaluate induction drug interactions involving this enzyme

Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109885/1/cpt6100343.pd

Rapid Identification of the Hepatic Cytochrome P450 2C19 Activity Using a Novel and Noninvasive [ 13 C]Pantoprazole Breath Test

ABSTRACT We tested the hypothesis that the stable isotope [ 13 C]pantoprazole is O-demethylated by cytochrome P450 CYP2C19 and that the 13 CO 2 produced and exhaled in breath as a result can serve as a safe, rapid, and noninvasive phenotyping marker of CYP2C19 activity in vivo. Healthy volunteers who had been genotyped for the CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles were administered a single oral dose of [ 13 C]pantoprazole sodium-sesquihydrate (100 mg) with 2.1 g of sodium bicarbonate. Exhaled 13 CO 2 and 12 CO 2 were measured by IR spectroscopy before (baseline) and 2.5 to 120 min after dosing. Ratios of 13 CO 2 / 12 CO 2 after [ 13 C]pantoprazole relative to 13 CO 2 / 12 CO 2 at baseline were expressed as change over baseline (DOB). Maximal DOB, DOB 15 to DOB 120 , and area under the DOB versus time curve (AUC 0 -120 and AUC 0 -ϱ ) were significantly different among three genotype groups (CYP2C19*1/ *1, n ϭ 10; CYP2C19*1/*2 or CYP2C19*1/*3, n ϭ 10; and CYP2C19*2/*2, n ϭ 5) with predicted extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs) of CYP2C19, respectively (Kruskal-Wallis test, p Ͻ 0.01); linear regression analysis indicated a gene-dose effect relationship (r 2 ranged between 0.236 and 0.522; all p Ͻ 0.05). These breath test indices were significantly lower in PMs than IMs (p Ͻ 0.05) or EMs (p Ͻ 0.01) of CYP2C19. [ 13 C]Pantoprazole plasma exposure showed significant inverse correlation with breath test indices in the respective subjects (Pearson r ϭ Ϫ0.74; p ϭ 0.038). These feasibility data suggest that the [ 13 C]pantoprazole breath test is a reliable, rapid, and noninvasive probe of CYP2C19 and seems to be a useful tool to optimize drug therapy metabolized by CYP2C19

Long-Term Results of Cell-Free Biodegradable Scaffolds for In Situ Tissue-Engineering Vasculature: In a Canine Inferior Vena Cava Model

We have developed a new biodegradable scaffold that does not require any cell seeding to create an in-situ tissue-engineering vasculature (iTEV). Animal experiments were conducted to test its characteristics and long-term efficacy. An 8-mm tubular biodegradable scaffold, consisting of polyglycolide knitted fibers and an L-lactide and ε-caprolactone copolymer sponge with outer glycolide and ε-caprolactone copolymer monofilament reinforcement, was implanted into the inferior vena cava (IVC) of 13 canines. All the animals remained alive without any major complications until euthanasia. The utility of the iTEV was evaluated from 1 to 24 months postoperatively. The elastic modulus of the iTEV determined by an intravascular ultrasound imaging system was about 90% of the native IVC after 1 month. Angiography of the iTEV after 2 years showed a well-formed vasculature without marked stenosis or thrombosis with a mean pressure gradient of 0.51±0.19 mmHg. The length of the iTEV at 2 years had increased by 0.48±0.15 cm compared with the length of the original scaffold (2–3 cm). Histological examinations revealed a well-formed vessel-like vasculature without calcification. Biochemical analyses showed no significant differences in the hydroxyproline, elastin, and calcium contents compared with the native IVC. We concluded that the findings shown above provide direct evidence that the new scaffold can be useful for cell-free tissue-engineering of vasculature. The long-term results revealed that the iTEV was of good quality and had adapted its shape to the needs of the living body. Therefore, this scaffold would be applicable for pediatric cardiovascular surgery involving biocompatible materials

Evaluating Sex and Age Differences in ADI-R and ADOS Scores in a Large European Multi-site Sample of Individuals with Autism Spectrum Disorder

Research on sex-related differences in Autism Spectrum Disorder (ASD) has been impeded by small samples. We pooled 28 datasets from 18 sites across nine European countries to examine sex differences in the ASD phenotype on the ADI-R (376 females, 1763 males) and ADOS (233 females, 1187 males). On the ADI-R, early childhood restricted and repetitive behaviours were lower in females than males, alongside comparable levels of social interaction and communication difficulties in females and males. Current ADI-R and ADOS scores showed no sex differences for ASD severity. There were lower socio-communicative symptoms in older compared to younger individuals. This large European ASD sample adds to the literature on sex and age variations of ASD symptomatology