Synthesis of C-5 benzoyl and azido functionalized 2,2′-dithiobis-and 2,2′-diselenobis(1H-indoles)

Novel methods for the synthesis of C-5 benzoyl and azido analogues of 2,2′-dithiobis(1H-indole), 1, and 2,2′-diselenobis(1H-indole), 2, are described to further explore the structure activity relationships in this region of the molecule. Analogues 3-i displayed inhibitory activity (IC₅₀ = 0.45-2.03 μ) toward the catalytic domain of the epidermal growth factor receptor tyrosine kinase that was equivalent to or better than that of unsubstituted compounds 1 and 2. The regiochemistry of Friedel-Crafts benzoylation onto 1 was determined by X-ray crystallography. To test the potential for compounds of this class to interact with the epidermal growth factor receptor tyrosine kinase via a sulfhydryl exchange mechanism, reaction of a 2,2′-dithiobis(1H-indole) with glutathione was carried out and the product characterized.     

A multifaceted approach to the interpretation of NMR order parameters: a case study of a dynamic alpha-helix

The model-free approach (Lipari, G.; Szabo, A. J. Am. Chem. Soc. 1982, 104, 4546-4559; 4559-4570) is the standard method for the analysis of NMR relaxation data from proteins. The method assigns to each interaction vector a generalized order parameter S(2), which is a measure of the spatial restriction that the vector experiences in a molecular reference frame. A variety of techniques for the interpretation of S(2) values and their underlying assumptions are tested here for a dynamic alpha-helix represented by an ensemble of peptide structures that satisfies a set of predefined constraints. A self-consistent picture is developed that characterizes the influence of major determinants, including backbone dihedral angle fluctuations and their correlations, separability of internal and overall motion, the preservation of hydrogen bonds, restricted end-to-end distance fluctuations, locally anisotropic dynamics, and local contacts between interaction vector atoms and their environment. Many of the features parallel experimental NMR and computational observations of helices in proteins. The understanding gained from this model system is expected to contribute toward the ever more detailed interpretation of experimental order parameter profiles.     

Wave front interaction model of stabilized propagating wave segments

A wave front interaction model is developed to describe the relationship between excitability and the size and shape of stabilized wave segments in a broad class of weakly excitable media. These wave segments of finite size are unstable but can be stabilized by feedback to the medium excitability; they define a separatrix between spiral wave behavior and contracting wave segments. Unbounded wave segments (critical fingers) lie on the asymptote of this separatrix, defining the boundary between excitable and subexcitable media. The model predictions are compared with results from numerical simulations.     

Differential thermoelectric power of dilute Fe in Cu-rich CuNi alloys

Data for related pairs of alloys over the range 1.5 ?T ? 300 K have been fit with a sum of two expression. One expression, due to Fe-nucleated Ni-clusters, produces a Ni-deficiency effect. The other expression, exhibiting a broad low temperature minimum, is an s-d exchange model expression, containing both spin and potential scattering contributions.     

Interface approximation of Darcy flow in a narrow channel

A mixed formulation is introduced for the singular problem of Darcy flow in a porous medium in a region containing a narrow fracture or channel with width and high permeability . The solution converges as ε → 0 to that of Darcy flow coupled to tangential flow on the lower‐dimensional interface or boundary. Copyright © 2012 John Wiley & Sons, Ltd.     

Resonance pacemakers in excitable media

Chemical waves are initiated in an excitable medium by resonance with local periodic forcing of the excitability. Experiments are carried out with a photosensitive Belousov-Zhabotinsky medium, in which the excitability is varied according to the intensity of the imposed illumination. Complex resonance patterns are exhibited as a function of the amplitude and frequency of the forcing. Local resonance-induced wave initiation transforms the medium globally from a quiescent excitable steady state to a periodic state of successive traveling waves.     

The synthesis of symmetrical (2‐indolyl)ethynes and reduced congeners via palladium‐catalyzed couplings of 2‐bromoindole precursors

Starting from a series of 2‐bromo‐1‐methylindole precursors ( 1b‐e ) activated in the 3‐position with aldehyde, ester, or amide functionality, two approaches have been developed toward the synthesis of 2,2′‐bis(indolyl)ethynes and reduced congeners via palladium(0)‐ or palladium(II)‐catalyzed couplings. The first approach utilized Sonogashira coupling of (trimethylsilyl)acetylene to introduce the two‐carbon linker followed by desilylation and further coupling with starting 2‐bromoindole. A second shorter and more efficient route engaged the starting 2‐bromoindole in a double Stille coupling with bis(tributylstannyl) acetylene or (E)‐1,2‐bis(tributylstannyl)ethylene to provide desired homodimers in one step. Subsequent transformations of dimeric intermediates led to target acids 7a‐c and derived amides 8a‐c and 9 . When tested against a panel of tyrosine kinases, each target compound was found to be inactive.     

Collective behavior of particle-like chemical waves

Stabilized waves in weakly excitable media propagate with constant velocity and can be directionally controlled with applied excitability gradients. Multiple waves with directional control governed by pairwise interaction potentials form cohesive groups. Processional modes arise in collections of waves with random initial conditions, in which spontaneous alignment plays an essential role. Rotational modes occur with special initial conditions, and highly complex orbits are exhibited in larger groups. The ordered behavior is associated with waves following paths of minimum potential.