Semisynthesis of isetexane diterpenoid analogues and their cytotoxic activity

Isetexane diterpene analogues were semisynthesized from demethylsalvicanol isolated from Perovskia abrotanoides (Labiatae). The structure and cytotoxic activity relationships (SAR) of the natural parent diterpene, demethylsalvicanol, and its semisynthetic analogues were studied by using P388 murine leukemia cells.     

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.     

Structure–Activity Studies on the Fluorescent Indicator in a Displacement Assay for the Screening of Small Molecules Binding to RNA

A series of xanthone and thioxanthone derivatives with aminoalkoxy substituents were synthesized as fluorescent indicators for a displacement assay in the study of small‐molecule–RNA interactions. The RNA‐binding properties of these molecules were investigated in terms of the improved binding selectivity to the loop region in the RNA secondary structure relative to 2,7‐bis(2‐aminoethoxy)xanthone (X2S) by fluorimetric titration and displacement assay. An 11‐mer double‐stranded RNA and a hairpin RNA mimicking the stem loop IIB of Rev response element (RRE) RNA of HIV‐1 mRNA were used. The X2S derivatives with longer aminoalkyl substituents showed a higher affinity to the double‐stranded RNA than the parent molecule. Introduction of a methyl group on the aminoethoxy moiety of X2S effectively modulated the selectivity to the RNA secondary structure. Methyl group substitution at the C1′ position suppressed the binding to the loop regions. Substitution with two methyl groups on the amino nitrogen atom resulted in reducing the affinity to the double‐stranded region by a factor of 40 %. The effect of methyl substitution on the amino nitrogen atom was also observed for a thioxanthone derivative. Titration experiments, however, suggested that thioxanthone derivatives showed a more prominent tendency of multiple binding to RNA than xanthone derivatives. The selectivity index calculated from the affinity to the double‐stranded and loop regions suggested that the N,N‐dimethyl derivative of X2S would be suitable for the screening of small molecules binding to RRE.     

Structure and Mechanical Properties of Chitosan/Poly(Vinyl Alcohol) Blend Films

Summary: The origins of the thermal and mechanical properties of chitosan and poly(vinyl alcohol) (PVA) with inter- and intra-hydrogen bonds were investigated systematically by using X-ray, DSC, positron annihilation and viscoelastic measurements. Based on their individual properties, the characteristics of the blend films were estimated in relation to their morphology and mechanical properties as a function of chitosan content. The characteristics of the blend films were also analyzed in terms of the deviation from a simple additive rule of chitosan and PVA content. These results suggested that the miscibility of chitosan and PVA could be ensured by entanglement of the amorphous chain segments of chitosan and PVA. Further detailed analysis revealed that the chitosan content on the film surface is higher than that of the admixture content of chitosan after elongation, although the chitosan and PVA chains were crystallized independently. The elongation could be achieved for the blend films whose PVA content was higher than 50% and the drawn blend films were transparent. Thus, it may be expected that sufficiently entangled meshes formed between chitosan and PVA amorphous chains within the film, the PVA content being higher than 50%, were maintained under the elongation process.     

Full-field quantitative phase imaging by white-light interferometry with active phase stabilization and its application to biological samples

We report a Koehler-illumination-based full-field, actively stabilized, low-coherence phase-shifting interferometer, which is built on a white-light Michelson interferometer. By using a phase-stepping technique we can obtain full-field phase images of the sample. An actively stabilized phase-lock circuit is employed in the system to reduce phase noise. An application to human epithelial cells (HeLa cells) is achieved in our experiment. The advancement of this technique rests in its ability to take images of unstained biological samples quantitatively and on a nanometer scale.     

Evolution of the Kondo effect in a quantum dot probed by shot noise

We measure the current and shot noise in a quantum dot in the Kondo regime to address the nonequilibrium properties of the Kondo effect. By systematically tuning the temperature and gate voltages to define the level positions in the quantum dot, we observe an enhancement of the shot noise as temperature decreases below the Kondo temperature, which indicates that the two-particle scattering process grows as the Kondo state evolves. Below the Kondo temperature, the Fano factor defined at finite temperature is found to exceed the expected value of unity from the noninteracting model, reaching 1.8±0.2.     

A photochemical synthesis of 3-aryl-1-methylquinolinones

A number of fluorescent 3-aryl-1-methylquinolinones 3 were synthesized by the regiospecific photocoupling reaction of 3-halo-1-methylquinolinones 1 with aromatic and heteroaromatic compounds 2 . An unusual photocoupling product 4 was obtained in the photolysis of 3-iodo-1-methylquinolinone in the presence of benzene. The structure of 4 was unequivocally established by an X-ray crystallographic analysis.