Chemical 'Jekyll and Hyde's: small-molecule inhibitors of developmental signaling pathways

Small molecules that perturb developmental signaling pathways can have devastating effects on embryonic patterning, as evidenced by the chemically induced onset of cyclopic lambs and children with severely shortened limbs during the 1950s. Recent studies, however, have revealed critical roles for these pathways in human disorders and diseases, spurring the re-examination of these compounds as new targeted therapies. In this tutorial review, we describe four case studies of teratogenic compounds, including inhibitors of the Hedgehog (Hh), Wnt, and bone morphogenetic protein (BMP) pathways. We discuss how these teratogens were discovered, their mechanisms of action, their utility as molecular probes, and their potential as therapeutic agents. We also consider current challenges in the field and possible directions for future research.     

Colloidal crystallization of thermo-sensitive gel spheres of poly (N-isopropyl acrylamide). Influence of degree of cross-linking of the gels

Morphology, phase diagram, and reflection spectroscopy of the colloidal crystals of thermo-sensitive gel spheres, poly (N-isopropylacrylamide) having degrees of cross-linking 10 and 2?mol.% (pNIPAm(200?C10) and pNIPAm(200?C2)) were studied. Giant colloidal single crystals formed at very low gel concentrations. Critical concentrations of melting increased as the degree of cross-linking decreased in the range from 10 to 0.5?mol.% and/or suspension temperature increased from 20 to 45?°C. The critical concentration decreased sharply as the suspensions were deionized with coexistence of the mixtures of cation- and anion-exchange resins. Density of a gel sphere (gel concentration in weight percent divided by that in volume percent) increased sharply as the degree of cross-linking and/or temperature increased. These results demonstrated that the colloidal crystallization takes place by the extended electrical double layers formed around the gel spheres in addition of the excluded-volume effect of the gels. Most of the researchers including the authors have believed that the crystallization of the gel spheres takes place by the excluded-volume effect. However, the present work clarified that the colloidal interfaces, which are inevitable for the formation of the electrical double layers, are formed firmly between the water phase and gel spheres, though the gel spheres contain a lot of water molecules in the sphere region.     

Isolation, structure determination, and synthesis of allo-RA-V and neo-RA-V, RA-series bicyclic peptides from Rubia cordifolia L

Two bicyclic hexapeptides, allo-RA-V (4) and neo-RA-V (5), and one cyclic hexapeptide, O-seco-RA-V (6), were isolated from the roots of Rubia cordifolia?L. Their gross structures were elucidated on the basis of spectroscopic analysis and X-ray crystallography of compound 5. The absolute stereochemistry of compounds 4 and 5 were established by their total syntheses, and the absolute stereochemistry of compound 6 by chemical correlation with deoxybouvardin (3). Comparison of the 3D structures of highly active RA-VII (1) with less-active compounds 4 and 5 suggests that the orientation of the Tyr-5 and/or Tyr-6 phenyl rings plays a significant role in their biological activity. The isolation of peptides 4-6, along with compound 3, and the comparison of their structures seem to indicate that peptide 6 may be the common precursor to bicyclic peptides 3-5 in the plant.     

Conformations and 13C NMR chemical shifts of some polyamides in the solid state as studied by high-resolution 13C NMR spectroscopy

High-resolution ¹³Carbon nuclear magnetic resonance (NMR) spectra of Nylons 4, 6, and 66 in the solid state were measured over a wide range of temperature. From the results, it was found that resonance lines of crystalline and noncrystalline components were separable and their chemical shifts were determined. The ¹³C chemical shift behavior is closely related to their conformation. The origin of the conformational effects on the chemical shifts is discussed.     

Chromatographic study of optical resolution : VI. Separation of isomers of facial tris(aminoacidato) mixed ligand chelates with d-tartrate and antimony d-tartrate adsorbed on an anion-exchange resin

A systematic study was made of the chromatographic separation of enantiomers of a series of fac-[Co(β-ala)_n(α-ala)_3−n] through an anion-exchange column adsorbing chiral and achiral anions such as d-tartrate, antimony d-tartrate, chloride and sulphate. It was found that both the retention volume and the separation factor of the enantiomeric pair increase with increasing number of β-ala ligands when eluted through the d-tartrate form of the resin. On the other hand, when eluted through the antimony d-tartrate form of the resin, the trend of the retention volumes and the separation factors is the reverse of that for the d-tartrate form. These results are discussed in comparison with the results obtained for the corresponding series of fac-[Co(β-ala)_n(gly)_3−n].     

Dynamics of positive charge carriers on Si chains of polysilanes

The transient absorption of radical cations of a variety of substituted polysilanes is discussed quantitatively in terms of the molar extinction coefficient and oscillator strength by nanosecond pulse radiolysis. Oxygen-saturated polysilane solutions in benzene exhibit a strong transient absorption band ascribed to the polysilane radical cation. The transient species react with N,N,N',N'-tetramethyl-p-phenylene-diamine (TMPD) to produce TMPD radical cations. On the basis of the molar extinction coefficient of the TMPD radical cation, the molar extinction coefficients for the radical cations of polysilanes are found to increase in the range 3.3 x 10(4) to 2.0 x 10(5) M(-)(1) cm(-)(1) with increasing polymer segment length. The stepwise increase in the total oscillator strength with an increase in the number of phenyl rings directly bonded to the Si skeleton suggests the delocalization of the positive polaron state and/or the SOMO state over the phenyl rings, indicating the importance of phenyl rings in intermolecular hole transfer processes.     

Morphology of drawn syndiotactic polypropylene films

Morphological studies were conducted to investigate the drawability of melt-quenched (MQ) and slowly cooled (MSC) films of syndiotactic polypropylene (sPP) with a high syndiotactic pentad fraction. Transmission electron microscopy (TEM) using the ruthenium tetraoxide staining and ultrathin sectioning method revealed that amorphous chains as the matrix of MQ film played a role in drawability of the film by their alignment to machine direction (MD) and partial crystallizations into nanofibrils. On the other hand, the initial strain induced, rotations of clusters of long lamellar crystals as the major entity of MSC film accompanying breaks of long lamellae and formation of crazes and microvoids at the cluster boundary. Compared with a homogeneous thinning of MQ film by drawing, ca. 100 nm-thick layer slips along MD and parallel to the film surface took place in MSC film. This gave rise to the formation of V-shaped bent lamellar morphology and their further break into a smaller cluster of stacked lamellae which were aligned oblique by ca. 35° from MD. With elongation, some nanofibrils formed from chains generated by the partial breaks of lamellae are aligned perpendicular to the remained oblique lamellae and others parallel to MD in region where lamellar morphology almost disappeared. No chain slips in the nanofibrils can be related to a low elongation at break, i.e. a low ductility of sPP films. The lower elongation at break for MSC film than for MQ one can be interpreted by microvoids initially formed in the neck region and later moved to the fully drawn part, the microvoids initiating the break of the drawn film.     

Family of site-selective molecular optical switches

[reaction: see text] We describe the design, synthesis, and characterization of a family of thiol-reactive optical switches for labeling proteins and other biomolecules. Site-selective introduction of photochromic probes within biomolecules is being used as part of a new approach for optical control of biomolecular interactions and activities within cells. The thiol-reactive photochromic probes described in this report include a spironaphthoxazine and five spirobenzopyrans. The location of the thiol-reactive group on the spirobenzopyran is different for each probe; this feature can be used to control the geometry of the optical switch within a bioconjugate. The photochromes undergo rapid and reversible, optically driven transitions between a colorless spiro (SP) state and a brightly colored merocyanine (MC) state. The MC absorption of a spironaphthoxazine conjugate is red shifted by more than 100 nm compared to the equivalent spirobenzopyran, which may be exploited for the independent control of the MC to SP transition for up to two different spironaphthoxazine and spirobenzopyran conjugates within the same sample.     

Synthesis and biological activity of a stereoisomeric mixture of the mating hormone of Phytophthora

The first synthesis of a stereoisomeric mixture of hormone α1, the mating hormone of Phytophthora, was achieved, and the synthetic mixture was confirmed to be hormonally active.     

New chromane derivatives isolated from the brown alga, Sargassum micracanthum

Two new chromane type meroterpenoids were isolated from the methanolic extract of the brown alga, Sargassum micracanthum. Their structures were elucidated based on spectroscopic analysis and chemical conversion. The absolute stereochemistry of the methyl group at C-8' in 1 and related compounds were determined by modified Mosher's method.