Multidimensional De Novo Design Reveals 5‐HT2B Receptor‐Selective Ligands

We report a multi‐objective de novo design study driven by synthetic tractability and aimed at the prioritization of computer‐generated 5‐HT_2B receptor ligands with accurately predicted target‐binding affinities. Relying on quantitative bioactivity models we designed and synthesized structurally novel, selective, nanomolar, and ligand‐efficient 5‐HT_2B modulators with sustained cell‐based effects. Our results suggest that seamless amalgamation of computational activity prediction and molecular design with microfluidics‐assisted synthesis enables the swift generation of small molecules with the desired polypharmacology.     

Stress functions and internal stresses in linear three-dimensional anisotropic elasticity

A stress function method is presented in order to give a general solution of the incompatibility problem of three-dimensional linear anisotropic elasticity theory. A relation between the internal stress tensor in terms of derivatives of a sixth-order stress function tensor will be derived. Using this formulation the so far open problem of the representation of the second-order stress function tensor by the fourth-order stress function tensor in anisotropic elasticity theory is solved in general.     

Scaling theory for nonequilibrium systems

We develop a general scaling theory of one-dimensional systems withN components having applications to disorder-order-transitions or order-order transitions of non-equilibrium systems, such as lasers, hydrodynamical systems and non-equilibrium chemical reactions. We include both cases of soft and hard modes. Since fluctuations play a decisive role at the transition point, we take fully account of them. We start from general equations of motion which contain nonlinear forces (or rates), diffusion terms and fluctuating forces. These equations depend on external parameters. When linearized around their steady state solutions, the equations allow for stable, marginal or unstable solutions. The solutions near critical points are represented as superpositions of marginal solutions, whose amplitudes are determined by comparing the coefficients of the scaling parameter up to third order. The scaling of the fluctuating forces and, in the case of chemical reactions, their correlation functions are derived in detail.     

New interpretation and size of strange attractor of the Lorenz model of turbulence

Using the equivalence of the Lorenz equations with laser equations we show how the irregular jumping from one segment of the variable space to the other one can be understood. We also estimate the size of the Lorenz attractor.     

2,2′:3′,2′′‐Terthiophene‐Based all‐Thiophene Dendrons and Dendrimers: Synthesis,Structural Characterization,and Properties

The synthesis of generational dendritic oligothiophenes (DOTs) has been successfully achieved by a divergent/convergent approach that involves halogenation, boronation, and palladium‐catalyzed Suzuki coupling reactions. The key point in the presented synthetic approach is the use of trimethylsilyl (TMS) protecting groups, which allow for the core‐lithiation and subsequent boronation of the dendrons and for the peripheral ipso‐substitution with iodine monochloride or N‐bromosuccimide. In addition, the TMS protecting groups can be completely removed by using tetrabutylammonium fluoride, thus yielding only‐thiophene‐based dendrons and dendrimers. Due to their highly branched structure, all these synthesized DOTs are soluble in organic solvents. Chemical structures were confirmed by NMR spectroscopic, mass spectrometric, and elemental analysis. Concentration‐dependent ¹H NMR spectroscopic investigations revealed that the higher generation compounds tend to aggregate in solution. Such an aggregation behavior was further confirmed by measuring with MALDI‐TOF MS. Both MALDI‐TOF MS and gel‐permeation chromatography (GPC) analyses confirmed the monodispersity of the DOTs. Furthermore, GPC results revealed that these DOT molecules adopt a condensed globular molecular shape. Their optical and electronic properties were also investigated. The results indicated that these DOTs comprise various conjugated α‐oligothiophenes with different chain lengths, which results in the higher generation compounds showing broad and featureless UV/Vis absorption spectra and ill‐defined redox waves.     

Melanotropin Receptors I. Synthesis and Biological Activity of Nα-(5-Bromovaleryl)-Nα-deacetyl-α-melanotropin

Chemical synthesis and biological activities of a new α-melanotropin derivative are described. N^α-(5-Bromovaleryl)-N^α-deacetyl-α-melanotropin contains the 5-bromopentanoyl group as a chemical ‘handle’ in place of the acetyl group of the natural hormone. The synthesis involved a new protected intermediate which allowed the selective deprotection of either the N^α or N^α amino group. The title compound reacted with sodium thiosulfate to give N^α-deacetyl-N^α-(5-(sulfothio)valeryl)-α-melanotropin, a key intermediate for the preparation of tobaccomosaic virus/α-melanotropin disulfide conjugates. As a basis for the study of the conjugates, biological activities of the title compound on Cloudman S-91 mouse melanoma cell cultures (tyrosinase stimulation, binding, and cyclic AMP accumulation) were determined. They proved to be quite similar to the corresponding α-melanotropin activities. Differences in bindings may be explained by stronger hydrophobic interaction of the new derivative with the lipid phase of the target cell membranes.     

The convergence of the slaving principle in a simplified model

We prove the convergence of the slaving principle in a model consisting of two nonlinear equations with two variables,s andu, which represent in the linear regime the stable mode and unstable mode, respectively.We show explicitly how the stable modes becomes increasingly dependent on the unstable modeu and approaches a definite power series ofu regardless of the initial condition fors. This power series is called slaving function and is shown to be absolutely and uniformly convergent on a closed disc, which contains the point describing the asymptotic behavior of the system. For some finite time, we show that the approximation involved in the substitution of the slaving function for the original stable modes decreases exponentially with time.     

Cover Picture

The cover picture shows the synthesis of novel conjugated macrocycles assembled from oligothiophenes bearing terminal acetylene groups. Under pseudo-high-dilution conditions the oxidative cyclooligomerization first gives the oligothiophenediynes, the precursors to the new class of alpha-cyclo[n]thiophenes. The detailed structure of macrocycles with up to 76 ring members and cavities of up to 3 nm could be investigated by means of X-ray structure analysis, scanning tunneling microscopy, and quantum chemical calculations (see the molecular model top right). The novel rings combine the excellent electronic properties of the corresponding linearly conjugated oligomers with the possibility of complexing large organic guest molecules or other objects (the tower of the Cathedral at Ulm represents a nanometer-sized, rodlike entity), which should have new fundamental properties and applications. The background shows the image obtained by scanning electron microscopy of a self-assembled and perfectly ordered monolayer of macrocycles on a graphite surface. More on these fascinating nanometer-sized rings can be found in the communication by P. B?uerle et al. on p. 3481 ff.     

Melanotropin Receptors II. Synthesis and Biological Activity of α-Melanotropin/Tobacco Mosaic Virus Disulfide Conjugates

Asymmetric disulfide conjugates of mercaptosuccinyl tobacco mosaic virus (TMV ～ SH) with N^α-desacetyl-N^α-5-(mercaptovaleryl)-α-melanotropin were prepared via the S-sulfoderivative of the peptide. The conjugates, TMV ～ S? S ～ α-MSH(n), contained up to n = 330 disulfide-linked peptide molecules/virion. Similarly, fluorescent conjugates, Rh(m) ～ TMV ～ S? S ～ α-MSH(n) were prepared, containing m ≈? 200 rhodamine molecules linked to the virions by thiourea bridges. Such conjugates were designed to study α-MSH receptor localization and dynamics (mainly internalization), because the carrier virions which served to enhance specific receptor binding and as fluorescent or radioactive markers may be detached from the neuropeptides at will by reduction. Reduction occurred in solution and on the cell surface, but not in the cytoplasm, thus allowing detection of internalized agonist-receptor complexes. The conjugates were superpotent agonists for tyrosinase stimulation in Cloudman S-91 melanoma cell cultures, but were inactive for cyclic AMP accumulation. Their rather rapid internalization and the influence of reducing agents and other agonists on their biologic activity suggest a close connection between receptor location and biologic response as well as the presence of essential receptor HS-groups.     

Gas phase thermal isomerization of 4-acetyl−5-methyl-isoxazole

The gas phase thermal isomerization of 4-acetyl?5-methyl-isoxazole affords 3-cyano?2,4-pentanedione as the only product in good agreement with previous proposed isomerization mechanism for isoxazoles. On the other hand, kinetic parameters and MO theoretical calculations do not agree with those previously reported. An alternative reaction mechanism which explains this fact is discussed.