In vivo assessment of the permeability of the blood--brain barrier and blood-retinal barrier to fluorescent indoline derivatives in zebrafish

ABSTRACT: BACKGROUND: Successful delivery of compounds to the brain and retina is a challenge in the development of therapeutic drugs and imaging agents. This challenge arises because internalization of compounds into the brain and retina is restricted by the blood--brain barrier (BBB) and blood-retinal barrier (BRB), respectively. Simple and reliable in vivo assays are necessary to identify compounds that can easily cross the BBB and BRB. METHODS: We developed six fluorescent indoline derivatives (IDs) and examined their ability to cross the BBB and BRB in zebrafish by in vivo fluorescence imaging. These fluorescent IDs were administered to live zebrafish by immersing the zebrafish larvae at 7--8 days post fertilization in medium containing the ID, or by intracardiac injection. We also examined the effect of multidrug resistance proteins (MRPs) on the permeability of the BBB and BRB to the ID using MK571, a selective inhibitor of MRPs. RESULTS: The permeability of these barriers to fluorescent IDs administered by simple immersion was comparable to when administered by intracardiac injection. Thus, this finding supports the validity of drug administration by simple immersion for the assessment of BBB and BRB permeability to fluorescent IDs. Using this zebrafish model, we demonstrated that the length of the methylene chain in these fluorescent IDs significantly affected their ability to cross the BBB and BRB via MRPs. CONCLUSIONS: We demonstrated that in vivo assessment of the permeability of the BBB and BRB to fluorescent IDs could be simply and reliably performed using zebrafish. The structure of fluorescent IDs can be flexibly modified and, thus, the permeability of the BBB and BRB to a large number of IDs can be assessed using this zebrafish-based assay. The large amount of data acquired might be useful for in silico analysis to elucidate the precise mechanisms underlying the interactions between chemical structure and the efflux transporters at the BBB and BRB. In turn, understanding these mechanisms may lead to the efficient design of compounds targeting the brain and retina.     

Molecular recognition of ketomalonates by asymmetric aldol reaction of aldehydes with secondary-amine organocatalysts

A diastereo- and enantioselective aldol reaction between aldehydes and a synthetically useful ketomalonate 1c as a hydrated form was developed, and either anti- or syn-aldol adducts having a chiral tetrasubstituted carbon center were obtained in high enantioselectivities by use of a tetrazole analogue of L-proline (S)-2 or an axially chiral amino sulfonamide (S)-3 as catalyst.     

Minimaxity of a preliminary test estimator for the mean of normal distribution

Summary The problem is to estimate the mean of the normal distribution under the situation where there is vague information that the mean might be equal to zero. A minimax property of the preliminary test estimator obtained by the use of AIC (Akaike information Criterion) procedure is proved under a loss function based on the Kullback-Leibler information measure.     

Molecular design,synthesis, and magnetic characterization of poly(phenylacetylene) with pi-toporegulated pendant nitronyl nitroxide radicals as models for organic superpara- and ferromagnets

The present article describes the synthesis and magnetic properties of poly(phenylacetylene) ( 3 ) with pi-toporegulated pendant stable 4,4,5,5-tetramethylimidazolin-3-oxide-1-yloxyl radicals topologically participating in the pi-conjugated system of poly(phenylacetylene). Polyradical 3 was prepared by the condensation reaction of poly(p-ethynylbenzaldehyde) with 2,3-bis(hydroxylamino)-2,3-dimethylbutane followed by oxidation with lead dioxide. The spin concentration of 3 determined by the ESR spectroscopic method was 1.1 × 10²¹ spins/g. This value approximately corresponds to 0.5 unpaired electron spin per the repeating unit. A powder ESR spectrum of 3 gave a 100% Lorentzian single line showing spin-exchange narrowing. The vibrating sample magnetometer (VSM) measurement of 3 afforded a straight line with a positive slope, suggesting that 3 has predominant paramagnetic properties within an experimental error.     

Foreword

The world of catalysis has grown and broadened greatly. The necessity of catalytic technology in solving the contemporary environmental and industrial problems is obvious. Catalysis will be even more important in the next century in relation to global preservation and the supply of energy and resources. What we now need are truly innovative and useful catalysts and what we lack is the methodology of how to make those catalysts. We may have to admit that, in spite of a large number of published papers, there are many mere trial-and-error type repetitions and very few new and significant findings or concepts. This is due to the very complex nature of catalysts, industrial catalysts in particular. It is not easy to find the right way to proceed. One positive step to assist in finding the right way may be to promote a close and quick exchange of information and new concepts worldwide. We now start a new journal from Japan affiliated with the Catalysis Society of Japan: Catalysis Surveys from Japan. The main aim of this new journal is to disseminate as early as possible the important findings or movements from Japan which possibly lead to new concepts for the design of useful catalysts. Rapid, invited, short reviews or accounts from academia and industry will constitute the major part of Catalysis Surveys from Japan. Surveys of recent progress and activities in catalytic science and technology and related areas in Japan will be covered regularly as well. The journal will be issued twice a year. We would appreciate it if colleagues around the world who read the articles in Catalysis Surveys from Japan would send us critical comments. If requested and deemed appropriate, the comments will be included in the journal. We will be very happy if this small, new journal stimulates global communication between scientists and engineers in the world of catalysis, and assists in the development of innovative useful catalysts.     

A problem in the spectrophotometric determination of dissolved total phosphorus in brackish anoxic waters

When dissolved total phosphorus in anoxic brackish waters was determined spectrophotometrically by the heteropoly molybdenum blue method after oxidation with potassium peroxodisulfate, negative dissolved organic phosphorus contents were obtained from the differences between the total phosphorus and inorganic phosphorus contents. A major cause of this inconsistency is coprecipitation of phosphate with the colloidal hydrated iron(III) oxide produced fro miron in these waters, or the formation of iron(III) phosphate during the oxidation process. The problem can be avoided by oxidation with nitric and perchloric acids.     

Electronic and vibrational surface-enhanced Raman scattering: from atomically defined Au(111) and (100) to roughened Au

In surface-enhanced Raman spectra, vibrational peaks are superimposed on a background continuum, which is known as one major experimental anomaly. This is problematic in assessing vibrational information especially in the low Raman-shift region below 200 cm⁻¹, where the background signals dominate. Herein, we present a rigorous comparison of normal Raman and surface-enhanced Raman spectra for atomically defined surfaces of Au(111) or Au(100) with and without molecular adsorbates. It is clearly shown that the origin of the background continuum is well explained by a local field enhancement of electronic Raman scattering in the conduction band of Au. In the low Raman-shift region, electronic Raman scattering gains additional intensity, probably due to a relaxation in the conservation of momentum rule through momentum transfer from surface roughness. Based on the mechanism for generation of the spectral background, we also present a practical method to extract electronic and vibrational information at the metal/dielectric interface from the measured raw spectra by reducing the thermal factor, the scattering efficiency factor and the Purcell factor over wide ranges in both the Stokes and the anti-Stokes branches. This method enables us not only to analyse concealed vibrational features in the low Raman-shift region but also to estimate more reliable local temperatures from surface-enhanced Raman spectra.

Both electronic and vibrational information at the metal/dielectric interface were explicitly extracted from surface-enhanced Raman spectra.     

Efficient methods for the preparation of alkyl-aryl and symmetrical or unsymmetrical dialkyl ethers between alcohols and phenols or two alcohols by oxidation-reduction condensation

Oxidation-reduction condensation via alkoxydiphenylphosphines (diphenylphosphinite esters) (1), generated in situ from chlorodiphenylphosphine (2) and alcohols, 2,6-dimethyl-1,4-benzoquinone (3), and phenols proceeds smoothly to afford alkyl-aryl ethers in good to high yields under neutral conditions. In a similar fashion, a new and efficient method for the preparation of symmetrical or unsymmetrical dialkyl ethers in good to high yields is established via tetrafluoro-1,4-benzoquinone (fluoranil) (4), alcohols, and 1 formed in situ from (n)BuLi-treated alcohols and 2. This method is applicable also to the etherification of chiral secondary or tertiary alcohols with retention or inversion of configurations. The inverted ethers are afforded by treating chiral alkoxydiphenylphosphines and achiral alcohols, while the reaction of achiral alkoxydiphenylphosphines and chiral alcohols forms retained ethers.