Macrocycle synthesis strategy based on step-wise “adding and reacting” three components enables screening of large combinatorial libraries

Macrocycles provide an attractive modality for drug development, but generating ligands for new targets is hampered by the limited availability of large macrocycle libraries. We have established a solution-phase macrocycle synthesis strategy in which three building blocks are coupled sequentially in efficient alkylation reactions that eliminate the need for product purification. We demonstrate the power of the approach by combinatorially reacting 15 bromoacetamide-activated tripeptides, 42 amines, and 6 bis-electrophile cyclization linkers to generate a 3780-compound library with minimal effort. Screening against thrombin yielded a potent and selective inhibitor (K_i = 4.2 ± 0.8 nM) that efficiently blocked blood coagulation in human plasma. Structure–activity relationship and X-ray crystallography analysis revealed that two of the three building blocks acted synergistically and underscored the importance of combinatorial screening in macrocycle development. The three-component library synthesis approach is general and offers a promising avenue to generate macrocycle ligands to other targets.

Combination of three efficient chemical reactions allows for solution-phase synthesis of 3780 macrocycles and identification of potent thrombin inhibitor.     

Derivation of class II force fields. VIII. Derivation of a general quantum mechanical force field for organic compounds

A class II valence force field covering a broad range of organic molecules has been derived employing ab initio quantum mechanical "observables." The procedure includes selecting representative molecules and molecular structures, and systematically sampling their energy surfaces as described by energies and energy first and second derivatives with respect to molecular deformations. In this article the procedure for fitting the force field parameters to these energies and energy derivatives is briefly reviewed. The application of the methodology to the derivation of a class II quantum mechanical force field (QMFF) for 32 organic functional groups is then described. A training set of 400 molecules spanning the 32 functional groups was used to parameterize the force field. The molecular families comprising the functional groups and, within each family, the torsional angles used to sample different conformers, are described. The number of stationary points (equilibria and transition states) for these molecules is given for each functional group. This set contains 1324 stationary structures, with 718 minimum energy structures and 606 transition states. The quality of the fit to the quantum data is gauged based on the deviations between the ab initio and force field energies and energy derivatives. The accuracy with which the QMFF reproduces the ab initio molecular bond lengths, bond angles, torsional angles, vibrational frequencies, and conformational energies is then given for each functional group. Consistently good accuracy is found for these computed properties for the various types of molecules. This demonstrates that the methodology is broadly applicable for the derivation of force field parameters across widely differing types of molecular structures. Copyright 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1782-1800, 2001     

Electrothermal stirring for heterogeneous immunoassays

A technique is proposed to enhance microfluidic immuno-sensors, for example, immunoassays, in which a ligand immobilized on a microchannel wall specifically binds analyte flowing through the channel. These sensors can be limited in both response time and sensitivity by the diffusion of analyte to the sensing surface. In certain applications, the sensitivity and response of these heterogeneous immunoassays may be improved by using AC electrokinetically-driven microscale fluid motion to enhance antigen motion towards immobilized ligands. Specifically, the electrothermal effect is used to micro-stir analyte near the binding surface. Numerical simulations of antigen in a microchannel flow subjected to the electrothermal effect show that 6 V(rms) applied to electrodes near a binding region can increase binding in the first few minutes by a factor of seven. The effectiveness of electrothermal stirring is a strong function of the Damk?hler number. The greatest binding enhancement is possible for high Damk?hler numbers, where the reaction is limited by diffusion. Based on these results, the utility of this technique for diffusion-limited microfluidic sensor applications is demonstrated.     

Mass spectrometry in structural and stereochemical problems–CXCV: The structure of the [C6H6O]+˙ ion in the spectrum of phenyl alkyl ethers

The [C₆H₆O]⁺˙ ion from C₆H₅OC₄H₉ is structurally similar to the molecular ion from phenol as demonstrated by ¹³C labeling.     

ESCA: Elektronen-Spektroskopie für chemische Analyse

Eine Substanzprobe, auf die Röntgen-Strahlung einwirkt, emittiert Photo- und Auger-Elektronen. Die Energiespektren der emittierten Elektronen geben Informationen über die Elektronen-struktur in der Probe — und zwar von den innersten atomaren Niveaus und ihrer Abhängigkeit von der chemischen Umgebung bis hin zu den Molekülorbitalen der Valenzelektronen sowie der Bandstruktur bei Festkörpern. Solche Elektronenspektren können jetzt mit hochauflösenden Instrumenten registriert werden; ihre Analyse ergibt neue Aspekte für die Untersuchung der chemischen Bindung. Die zu diesem Zweck entwickelte und inzwischen zu einem hohen Grad von Vollkommenheit ausgebaute Methode der Elektronenspektroskopie wird im folgenden als ESCA (Electron Spectroscopy for Chemical Analysis) bezeichnet.     

An inequality between thep- and (p, 1)-summing norm of finite rank operators fromC(K)-spaces

We show, for any operatorT from aC(K)-space into a Banach space with rank (T)≤n, the inequality , whereC≤4.671 is a numerical constant. The factor (1+logn)^1−1/p is asymptotically correct. This inequality extends a result of Jameson top ≠ 2. Several applications are given — one is a positive solution of a conjecture of Rosenthal and Szarek: For 1≤p<q<2,      

Novel perturbation expansion for the Langevin equation

We discuss the randomly driven systemdx/dt= -W(x) +f(t), wheref(t) is a Gaussian random function or stirring force withf(t)f(t)=2(t–t), andW(x) is of the formgx ¹⁺². The parameter is a measure of the nonlinearity of the equation. We show how to obtain the correlation functionsx(t)f(t)···x(t( n)) _f as a power series in. We obtain three terms in the expansion and show how to use Padé approximants to analytically continue the answer in the variable. By using scaling relations, we show how to get a uniform approximation to the equal-time correlation functions valid for allg and.     

Aortic elastin fluorescence afterin vivo labeling with Congo red

Congo red (CR) is an azo dye which not only preferentially binds to elastin, an extracellular matrix protein found in the media of arterial vessel walls, but also fluoresces when it binds to this protein. Protein solubilization data following laser irradiation of elastin:CR suspensions determined that the amount of elastin solubilized by laser irradiation increased with the increase in CR. The saturation point of CR to elastin was attained when 400 g CR was added to 20 mg elastin suspension. When 20 ml of a 5% CR solution in 5% dextrose was administered intravenously, the CR was absorbed in levels sufficient to produce fluorescence of the main arteries in rabbits. Layers of tissue both in the media of the vessels and at the endothelial/intimal interface were clearly differentiated. Therefore, the elastin:CR complex appears to be an ideal system in which the elastin fluorescence could aid in distinguishing between normal and diseased tissue in certain pathological conditions, such as atherosclerosis and some types of breast tumors.     

Fourier analysis of the approximation power of principal shift-invariant spaces

The approximation order provided by a directed set {S _h } _h>0 of spaces, each spanned by thehZ ^d -translates of one function, is analyzed. The nearoptimal approximants of [R2] from eachs _h to the exponential functions are used to establish upper bounds on the approximation order. These approximants are also used on the Fourier transform domain to yield approximations for other smooth functions, and thereby provide lower bounds on the approximation order. As a special case, the classical Strang-Fix conditions are extended to bounded summable generating functions.The second part of the paper consists of a detailed account of various applications of these general results to spline and radial function theory. Emphasis is given to the case when the scale {s _h } is obtained froms ₁ by means other than dilation. This includes the derivation of spectral approximation orders associated with smooth positive definite generating functions.