Cycloadditions of isobenzofuran to a constrained template bearing neighboring dienophiles

A high yielding synthesis of the pentacyclic diene-dione 1 has enabled investigation of its reactivity as a double dienophile in Diels-Alder [4+2] cycloadditions with isobenzofuran, leading to novel and highly symmetrical three-sided cavitands 3 and 4.

Countering cooperative effects in protease inhibitors using constrained b-strand-mimicking templates in focused combinatorial libraries

A major problem in de novo design of enzyme inhibitors is the unpredictability of the induced fit, with the shape of both ligand and enzyme changing cooperatively and unpredictably in response to subtle structural changes within a ligand. We have investigated the possibility of dampening the induced fit by using a constrained template as a replacement for adjoining segments of a ligand. The template preorganizes the ligand structure, thereby organizing the local enzyme environment. To test this approach, we used templates consisting of constrained cyclic tripeptides, formed through side chain to main chain linkages, as structural mimics of the protease-bound extended beta-strand conformation of three adjoining amino acid residues at the N- or C-terminal sides of the scissile bond of substrates. The macrocyclic templates were derivatized to a range of 30 structurally diverse molecules via focused combinatorial variation of nonpeptidic appendages incorporating a hydroxyethylamine transition-state isostere. Most compounds in the library were potent inhibitors of the test protease (HIV-1 protease). Comparison of crystal structures for five protease-inhibitor complexes containing an N-terminal macrocycle and three protease-inhibitor complexes containing a C-terminal macrocycle establishes that the macrocycles fix their surrounding enzyme environment, thereby permitting independent variation of acyclic inhibitor components with only local disturbances to the protease. In this way, the location in the protease of various acyclic fragments on either side of the macrocyclic template can be accurately predicted. This type of templating strategy minimizes the problem of induced fit, reducing unpredictable cooperative effects in one inhibitor region caused by changes to adjacent enzyme-inhibitor interactions. This idea might be exploited in template-based approaches to inhibitors of other proteases, where a beta-strand mimetic is also required for recognition, and also other protein-binding ligands where different templates may be more appropriate.

Multiple paths extraction in images using a constrained expanded trellis

Single shortest path extraction algorithms have been used in a number of areas such as network flow and image analysis. In image analysis, shortest path techniques can be used for object boundary detection, crack detection, or stereo disparity estimation. Sometimes one needs to find multiple paths as opposed to a single path in a network or an image where the paths must satisfy certain constraints. In this paper, we propose a new algorithm to extract multiple paths simultaneously within an image using a constrained expanded trellis (CET) for feature extraction and object segmentation. We also give a number of application examples for our multiple paths extraction algorithm.

A safety catch linker for Fmoc-based assembly of constrained cyclic peptides

A new safety-catch linker for Fmoc solid-phase peptide synthesis of cyclic peptides is reported. The linear precursors were assembled on a tert-butyl protected catechol derivative using optimized conditions for Fmoc-removal. After activation of the linker using TFA, neutralization of the N-terminal amine induced cyclization with concomitant cleavage from the resin yielding the cyclic peptides in DMF solution. Several constrained cyclic peptides were synthesized in excellent yields and purities. Copyright (c) 2005 European Peptide Society and John Wiley & Sons, Ltd.

Structural mimicry of two cytochrome b(562) interhelical loops using macrocycles constrained by oxazoles and thiazoles

A major chemical challenge is the structural mimicry of discontinuous protein surfaces brought into close proximity through polypeptide folding. We report the design, synthesis, and solution structure of a highly functionalized saddle-shaped macrocyclic scaffold, constrained by oxazoles and thiazoles,upporting two short peptide loops projecting orthogonally from the same face of the scaffold. This structural mimetic of two interhelical loops of cytochrome b(562) illustrates a promising approach to structurally mimicking discontinuous loops of proteins.

Space efficient quantile summary for constrained sliding windows on a data stream

In many online applications, we need to maintain quantile statistics for a sliding window on a data stream. The sliding windows in natural form are defined as the most recent N data items. In this paper, we study the problem of estimating quantiles over other types of sliding windows. We present a uniform framework to process quantile queries for time constrained and filter based sliding windows. Our algorithm makes one pass on the data stream and maintains an E-approximate summary. It uses O((1)/(epsilon2) log(2) epsilonN) space where N is the number of data items in the window. We extend this framework to further process generalized constrained sliding window queries and proved that our technique is applicable for flexible window settings. Our performance study indicates that the space required in practice is much less than the given theoretical bound and the algorithm supports high speed data streams.

Mixed-state entanglement in the light of pure-state entanglement constrained by superselection rules

We show that the classification of bi-partite pure entangled states when local quantum operations are restricted, e.g., constrained by local superselection rules, yields a structure that is analogous in many respects to that of mixed-state entanglement, including such exotic phenomena as bound entanglement and activation. This analogy aids in resolving several conceptual puzzles in the study of entanglement under restricted operations. Specifically, we demonstrate that several types of quantum optical states that possess confusing entanglement properties are analogous to bound entangled states. Also, the classification of pure-state entanglement under restricted operations can be much simpler than for mixed state entanglement. For instance, in the case of local Abelian superselection rules all questions concerning distillability can be resolved.