Limiting the Number of Potential Binding Modes by Introducing Symmetry into Ligands: Structure‐Based Design of Inhibitors for Trypsin‐Like Serine Proteases

In the absence of X‐ray data, the exploration of compound binding modes continues to be a challenging task. For structure‐based design, specific features of active sites in different targets play a major role in rationalizing ligand binding characteristics. For example, dibasic compounds have been reported as potent inhibitors of various trypsin‐like serine proteases, the active sites of which contain several binding pockets that can be targeted by cationic moieties. This results in several possible orientations within the active site, complicating the binding mode prediction of such compounds by docking tools. Therefore, we introduced symmetry in bi‐ and tribasic compounds to reduce conformational space in docking calculations and to simplify binding mode selection by limiting the number of possible pocket occupations. Asymmetric bisbenzamidines were used as starting points for a multistage and structure‐guided optimization. A series of 24 final compounds with either two or three benzamidine substructures was ultimately synthesized and evaluated as inhibitors of five serine proteases, leading to potent symmetric inhibitors for the pharmaceutical drug targets matriptase, matriptase‐2, thrombin and factor Xa. This study underlines the relevance of ligand symmetry for chemical biology.     

Synthesis of [5,6]-Bicyclic Heterocycles with a Ring-Junction Nitrogen Atom: Rhodium(III)-Catalyzed C−H Functionalization of Alkenyl Azoles

The first syntheses of privileged [5,6]-bicyclic heterocycles, with ring-junction nitrogen atoms, by transition metal catalyzed C−H functionalization of C-alkenyl azoles is disclosed. Several reactions are applied to alkenyl imidazoles, pyrazoles, and triazoles to provide products with nitrogen incorporated at different sites. Alkyne and diazoketone coupling partners give azolopyridines with various substitution patterns. In addition, 1,4,2-dioxazolone coupling partners yield azolopyrimidines. Furthermore, the mechanisms for the reactions are discussed and the utility of the developed approach is demonstrated by iterative application of C−H functionalization for the rapid synthesis of a patented drug candidate.     

<Emphasis Type="Italic">Ab initio</Emphasis> nuclear structure calculations with transformed realistic interactions

We discuss three elements of modern ab initio nuclear structure theory with an emphasis on the role of correlations in the nuclear many-body problem. Starting from the QCD-motivated construction of a realistic nuclear interaction we review two methods to derive phase-shift equivalent tamed interactions, the Unitary Correlation Operator Method and the Similarity Renormalization Group. Eventually we use these interactions for ab initio calculations within the importance truncated no-core shell model.     

Asymmetric reduction of azirines; a new route to chiral aziridines

The first enantioselective reduction of aromatic 2H-azirines yields aziridines in up to 70% ee, using the aminoalcohol-[RuCl2(p-cymene)]2 catalyzed asymmetric transfer hydrogenation reaction.     

Artifacts,assumptions, and ambiguity: Pitfalls in comparing experimental results to numerical simulations when studying electrical stimulation of the heart

Insidious experimental artifacts and invalid theoretical assumptions complicate the comparison of numerical predictions and observed data. Such difficulties are particularly troublesome when studying electrical stimulation of the heart. During unipolar stimulation of cardiac tissue, the artifacts include nonlinearity of membrane dyes, optical signals blocked by the stimulating electrode, averaging of optical signals with depth, lateral averaging of optical signals, limitations of the current source, and the use of excitation-contraction uncouplers. The assumptions involve electroporation, membrane models, electrode size, the perfusing bath, incorrect model parameters, the applicability of a continuum model, and tissue damage. Comparisons of theory and experiment during far-field stimulation are limited by many of these same factors, plus artifacts from plunge and epicardial recording electrodes and assumptions about the fiber angle at an insulating boundary. These pitfalls must be overcome in order to understand quantitatively how the heart responds to an electrical stimulus. (c) 2002 American Institute of Physics.