Total synthesis of calystegine A7

A straightforward chiral pool synthesis for the glycosidase inhibitor calystegine A₇ (isolated from Lycium chinense) from methyl α-d-glucopyranoside is described. Keysteps of this synthesis include a ultrasound assisted Zn-mediated tandem ring opening reaction followed by a Grubbs' catalyst mediated ring closure metathesis.     

Simulation of semidilute suspensions of non-Brownian fibers in shear flow

Particle-level simulations are performed to study semidilute suspensions of monodispersed non-Brownian fibers in shear flow, with a Newtonian fluid medium. The incompressible three-dimensional Navier-Stokes equations are used to describe the motion of the medium, while fibers are modeled as chains of fiber segments, interacting with the fluid through viscous drag forces. The two-way coupling between the solids and the fluid phase is taken into account by enforcing momentum conservation. The model includes long-range and short-range hydrodynamic fiber-fiber interactions, as well as mechanical interactions. The simulations rendered the time-dependent fiber orientation distribution, whose time average was found to agree with experimental data in the literature. The viscosity and first normal stress difference was calculated from the orientation distribution using the slender body theory of Batchelor [J. Fluid Mech. 46, 813 (1971)], with corrections for the finite fiber aspect ratios. The viscosity was also obtained from direct computation of the shear stresses of the suspension for comparison. These two types of predictions compared well in the semidilute regime. At higher concentrations, however, a discrepancy was seen, most likely due to mechanical interactions, which are only accounted for in the direct computation method. The simulated viscosity determined directly from shear stresses was in fair agreement with experimental data found in the literature. The first normal stress difference was found to be proportional to the square of the volume concentration of fibers in the semidilute regime. As concentrations approached the concentrated regime, the first normal stress difference became proportional to volume concentration. It was also found that the coefficient of friction has a strong influence on the tendency for flocculation as well as the apparent viscosity of the suspension in the semidilute regime.     

A new approach to variational problems with multiple scales

We introduce a new concept, the Young measure on micropatterns, to study singularly perturbed variational problems that lead to multiple small scales depending on a small parameter ε. This allows one to extract, in the limit ε → 0, the relevant information at the macroscopic scale as well as the coarsest microscopic scale (say ε^α) and to eliminate all finer scales. To achieve this we consider rescaled functions Rx (t) := x (s + ε^αt) viewed as maps of the macroscopic variable s ∈ Ω with values in a suitable function space. The limiting problem can then be formulated as a variational problem on the Young measures generated by R^εx. As an illustration, we study a one‐dimensional model that describes the competition between formation of microstructure and highest gradient regularization. We show that the unique minimizer of the limit problem is a Young measure supported on sawtooth functions with a given period. © 2001 John Wiley & Sons, Inc.     

Cover Picture

The cover picture shows the metalloporphyrin heterodimer [(tpp)Mo$\rm{\mathop{-}^{4}}$Re(oep)](+) with the novel [Mo$\rm{\mathop{-}^{4}}$Re](5+) core. The core represents the first example of a quadruple bond between elements of different triads, thus proving that heterometallic quadruple bonds are not limited to the Group 6 metals. From the space-filling model it is clear that there is no interaction between the stabilizing porphyrin ligands. The ORTEP plot in a projection along the Re-Mo axis emphasizes the perfectly eclipsed geometry of the porphyrins, which is unambiguous proof of the existence of the quadruple bond in the solid state. The diamagnetism and large magnetic anisotropy of the cation, as determined by (1)H NMR spectroscopy, indicate that the quadruple bond is retained in solution. A logical and well-defined synthetic route was used to synthesize the dimer, and can be extended to other metalloporphyrins to generate further novel quadruple bonds (the picture was generated by Marina Boulan, St. Petersburg, Russia), full details are reported by J. P. Collman et al. on p. 1271 ff.     

Multifunctional gold nanoparticle-peptide complexes for nuclear targeting

The ability of peptide-modified gold nanoparticles to target the nucleus of HepG2 cells was explored. Five peptide/nanoparticle complexes were investigated, particles modified with (1) the nuclear localization signal (NLS) from the SV 40 virus; (2) the adenovirus NLS; (3) the adenovirus receptor-mediated endocytosis (RME) peptide; (4) one long peptide containing the adenovirus RME and NLS; and (5) the adenovirus RME and NLS peptides attached to the nanoparticle as separate pieces. Gold nanoparticles were used because they are easy to identify using video-enhanced color differential interference contrast microscopy, and they are excellent scaffolds from which to build multifunctional nuclear targeting vectors. For example, particles modified solely with NLS peptides were not able to target the nucleus of HepG2 cells from outside the plasma membrane, because they either could not enter the cell or were trapped in endosomes. The combination of NLS/RME particles (4) and (5) did reach the nucleus; however, nuclear targeting was more efficient when the two signals were attached to nanoparticles as separate short pieces versus one long peptide. These studies highlight the challenges associated with nuclear targeting and the potential advantages of designing multifunctional nanostructured materials as tools for intracellular diagnostics and therapeutic delivery.     

Laser-induced temperature jump electrochemistry on gold nanoparticle-coated electrodes

Laser-induced temperature jumps (LITJs) at gold nanoparticle-coated indium tin oxide (ITO) electrodes in contact with electrolyte solutions have been measured using temperature-sensitive redox probes and an infrared charge-coupled device. Upon irradiation with 532 nm light, interfacial temperature changes of ca. 20 degrees C were recorded for particle coverages of ca. 1 x 1010 cm-2. In the presence of a redox molecule, LITJ yields open-circuit photovoltages and photocurrents that are proportional to the number of particles on the surface. When ssDNA was used to chemisorb nanoparticles to the ITO surface, solution concentrations as low as 100 fM of target ssDNA-modified nanoparticles could be detected at the electrode surface.     

Application of chemiluminescence for the detection of peroxy compounds in high-performance liquid chromatography

The possibility of applying post-column reaction and chemiluminescence to determine organic peroxy compounds by RP-HPLC was investigated. Conditions of qualitative and quantitative analyses have been established. The applicability of the method has been demonstrated for a series of compounds representative of the most important groups of peroxy-type compounds, that is, hydroperoxides, dialkyl peroxides, diacyl peroxides, peroxyesters, and peroxyacids.     

High-content analysis in preclinical drug discovery

High-Content Analysis (HCA) has developed into an established tool and is used in a wide range of academic laboratories and pharmaceutical research groups. HCA is now routinely proving to be effective in providing functionally relevant results. It is essential to select the appropriate HCA application with regard to the targeted compound's cellular function. The cellular impact and compound specificity as revealed by HCA analysis facilitates reaching definitive conclusions at an early stage in the drug discovery process. This technology therefore has the potential to substantially improve the efficiency of pharmaceutical research. Recent advances in fluorescent probes have significantly boosted the success of HCA. Auto-fluorescent proteins which minimally hinder the functioning of the living cell have been playing a decisive role in cell biology research. For companies the severely restricted license conditions regarding auto-fluorescent proteins hamper their general use in pharmaceutical research. This has opened the field for other solutions such as self-labeling protein technology, which could potentially replace the well established methods that utilize auto-fluorescent proteins. In addition, direct labeling techniques have improved considerably and may supersede many of the approaches based on fusion proteins. Following sample preparation, treated cells are imaged and the resulting multiple fluorescent signals are subjected to contextual and statistical analysis. The extraordinary advantage of HCA is that it enables the large-scale and simultaneous quantification and correlation of multiple phenotypic responses and physiological reactions using sophisticated software solutions that permit assay-specific image analysis. Hence, HCA once more has demonstrated its outstanding potential to significantly support establishing effective pharmaceutical research processes in order to both advance research projects and cut costs.