Novel Peptide‐Heterocycle Hybrids: Synthesis and Preliminary Studies on Calpain Inhibition

New peptidic compounds, having peptide chains linked to bi‐ and tricyclic heterocycles (peptide‐heterocycle hybrids), have been synthesized. The heterocyclic components are derivatives of partially reduced isoquinoline and pyrido[1,2‐b]isoquinoline bearing α,β‐unsaturated carbonyl functionalities. The heterocyclic compounds have been used as acylating agents in coupling reactions with short N‐unprotected peptides. Based on our interest on potential calpain inhibitors, we have used short (2–4 amino acids) peptides with hydrophobic amino acids of the two enantiomeric series. We report preliminary studies on the inhibition of calpain, with some compounds having IC₅₀ values in the nanomolar range.     

A Parallel Semisynthetic Approach for Structure–Activity Relationship Studies of Peptide YY

The gut hormone peptide YY (PYY) is postprandially secreted from enteroendocrine L cells and is involved in the regulation of energy homeostasis. The N‐terminal truncated version PYY(3–36) decreases food intake and has potential as an anti‐obesity agent. The anorectic effect of PYY(3–36) is mediated through Y₂ receptors in the hypothalamus, vagus, and brainstem regions, and it is well known that the C‐terminal tetrapeptide sequence of PYY(3–36) is crucial for Y₂ receptor activation. The aim of this work was to develop a semisynthetic methodology for the generation of a library of C‐terminally modified PYY(3–36) analogues. By using an intein‐based expression system, PYY(3–29) was generated as a C‐terminal peptide α‐thioester. Heptapeptides bearing an N‐terminal cysteine and modifications at one of the four C‐terminal positions were synthesized in a 96‐well plate by parallel solid‐phase synthesis. In the plate format, an array of [Ala30]PYY(3–36) analogues were generated by ligation, desulfurization, and subsequent solid‐phase extraction. The generated analogues, in which either Arg33, Gln34, Arg35, or Tyr36 had been substituted with proteinogenic or non‐proteinogenic amino acids, were tested in a functional Y₂ receptor assay. Generally, substitutions of Tyr36 were better tolerated than modifications of Arg33, Gln34, and Arg35. Two analogues showed significantly improved Y₂ receptor selectivity; therefore, these results could be used to design new drug candidates for the treatment of obesity.     

In Vivo Structure–Activity Relationship Studies Support Allosteric Targeting of a Dual Specificity Phosphatase

Dual specificity phosphatase 6 (DUSP6) functions as a feedback attenuator of fibroblast growth factor signaling during development. In vitro high throughput chemical screening attempts to discover DUSP6 inhibitors have yielded limited success. However, in vivo whole‐organism screens of zebrafish identified compound 1 (BCI) as an allosteric inhibitor of DUSP6. Here we designed and synthesized a panel of analogues to define the structure–activity relationship (SAR) of DUSP6 inhibition. In vivo high‐content analysis in transgenic zebrafish, coupled with cell‐based chemical complementation assays, identified structural features of the pharmacophore of 1 that were essential for biological activity. In vitro assays of DUSP hyperactivation corroborated the results from in vivo and cellular SAR. The results reinforce the notion that DUSPs are druggable through allosteric mechanisms and illustrate the utility of zebrafish as a model organism for in vivo SAR analyses.     

A Native Chemical Ligation Handle that Enables the Synthesis of Advanced Activity‐Based Probes: Diubiquitin as a Case Study

We present the development of a native chemical ligation handle that also functions as a masked electrophile that can be liberated during synthesis when required. This handle can thus be used for the synthesis of complex activity‐based probes. We describe the use of this handle in the generation of linkage‐specific activity‐based deubiquitylating enzyme probes that contain substrate context and closely mimic the native ubiquitin isopeptide linkage. We have generated activity‐based probes based on all seven isopeptide‐linked diubiquitin topoisomers and demonstrated their structural integrity and ability to label DUBs in a linkage‐specific manner.     

Effect of the Helical Tether of a Resin‐Supported Peptide Catalyst for Friedel–Crafts‐Type Alkylation in Water

A detailed investigation of the helical part of the resin‐supported peptide catalyst possessing a turn motif and helical unit was conducted to clarify the structure‐activity relationship. The peptide catalyst with an α‐ or 3₁₀‐helical tether was effective for an enantioselective Friedel–Crafts‐type alkylation in water. From the spectral analysis of the peptide with an optimum sequence, it was demonstrated that the helical moiety of the peptide catalyst played a role for stabilizing a terminal turn structure.     

Cover Picture: Structure–Activity Relationship Analysis of the Peptide Deformylase Inhibitor 5‐Bromo‐1H‐indole‐3‐acetohydroxamic Acid (ChemMedChem 2/2009)

The cover picture shows a “reverse” indole derivative in complex with Bacillus stearothermophilus peptide deformylase (PDF). This compound was selected from a structure–activity relationship study as a potent inhibitor of bacterial PDFs and shows antibacterial activity toward Bacillus subtilis as well as other pathogens such as Streptococcus pneumoniae and Staphylococcus aureus. For more details, see the Full Paper by I. Artaud et al. on p. 261 ff.

     

Structure–Activity Relationship,Biological, and Pharmacological Characterization of the Proline Sulfonamide ACT‐462206: a Potent,Brain‐Penetrant Dual Orexin 1/Orexin 2 Receptor Antagonist

The orexin system consists of two G‐protein‐coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB‐649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT‐462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non‐rapid eye movement (non‐REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT‐462206 shows anxiolytic‐like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.     

Copper‐Catalyzed Synthesis of Imidazo[1,2‐a]pyridines through Tandem Imine Formation‐Oxidative Cyclization under Ambient Air: One‐Step Synthesis of Zolimidine on a Gram‐Scale

A new copper‐catalyzed oxidative cyclization via C H amination between 2‐aminopyridines and methyl aryl/heteroaryl ketones has been developed under ambient air. Imidazo[1,2‐a]pyridines containing a wide range of functional groups have been synthesized from basic and easily available starting materials. This simple, one‐pot reaction protocol is applicable for the direct preparation of zolimidine (a marketed antiulcer drug) on a large scale.     

Time‐Dependent Diaryl Ether Inhibitors of InhA: Structure–Activity Relationship Studies of Enzyme Inhibition,Antibacterial Activity,and in vivo Efficacy

The diaryl ethers are a novel class of antituberculosis drug candidates that inhibit InhA, the enoyl‐ACP reductase involved in the fatty acid biosynthesis (FASII) pathway, and have antibacterial activity against both drug‐sensitive and drug‐resistant strains of Mycobacterium tuberculosis. In the present work, we demonstrate that two time‐dependent B‐ring modified diaryl ether InhA inhibitors have antibacterial activity in a mouse model of TB infection when delivered by intraperitoneal injection. We propose that the efficacy of these compounds is related to their residence time on the enzyme, and to identify structural features that modulate drug–target residence time in this system, we have explored the inhibition of InhA by a series of B‐ring modified analogues. Seven ortho‐substituted compounds were found to be time‐dependent inhibitors of InhA, where the slow step leading to the final enzyme–inhibitor complex (EI*) is thought to correlate with closure and ordering of the InhA substrate binding loop. A detailed mechanistic understanding of the molecular basis for residence time in this system will facilitate the development of InhA inhibitors with improved in vivo activity.     

Copper‐Catalyzed Domino SN2′/Coupling Reaction: A Versatile and Facile Synthesis of Cyclic Compounds from Baylis–Hillman Acetates

A variety of substituted quinoline/pyridine, thiochromene and naphthalene derivatives, which might be of biological and medicinal value, were synthesized by copper‐catalyzed domino S_N2′/coupling, S_N2′/deacylation/coupling and S_N2′/coupling/elimination reactions. The method provides a general and convenient approach to the synthesis of various substituted cyclic compounds from the corresponding Baylis–Hillman (B‐H) acetates and N‐/S‐/C‐nucleophiles.     

Acrylonitrile‐based copolymer membranes for the separation of methanol from a methanol–toluene mixture through pervaporation

The membrane selection criteria for the preferential permeation of a particular component were examined for the pervaporative separation of methanol from a mixture of methanol and toluene. One polyacrylonitrile homopolymer and five different copolymer membranes (i.e., acrylonitrile with maleic anhydride, acrylic acid, methacrylic acid, methyl methacrylate, and styrene) were prepared through emulsion polymerization. All these monomers were selected on the basis of the solubility parameter concept. The second monomer had an influence on the permselectivity and flux, and this effect was investigated. The structures of the copolymers, the features of their sorption layers, and their permeation paths were examined. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 96: 243–252, 2005     

Effects of Difference in Ionic Radii on Chemical Ordering in Mixed‐Cation Silicate Glasses: Insights from Solid‐State 17O and 7Li NMR of Li–Ba Silicate Glasses

Understanding of the extent of cation disorder and its effect on the properties in glasses and melts is among the fundamental puzzles in glass sciences, materials sciences, physical chemistry, and geochemistry. Particularly, the nature of chemical ordering in mixed‐cation silicate glasses is not fully understood. The Li–Ba silicate glass with significant difference in the ionic radii of network‐modifying cations (~0.59 Å) is an ideal system for revealing unknown details of the effect of network modifiers on the extent of mixing and their contribution to the cation mobility. These glasses also find potential application as energy and battery materials. Here, we report the detailed atomic environments and the extent of cation mixing in Li–Ba silicate glasses with varying X_BaO [BaO/(Li₂O + BaO)] using high‐resolution solid‐state nuclear magnetic resonance (NMR) spectroscopy. The first ¹⁷O MAS and 3QMAS NMR spectra for Li–Ba silicate glasses reveal the well‐resolved peaks due to bridging oxygen (Si–O–Si) and those of the nonbridging oxygens including Li–O–Si and mixed {Li, Ba}–O–Si. The fraction of Li–O–Si decreases with an increase in X_BaO and is less than that predicted by a random Li–Ba distribution. The result demonstrates a nonrandom distribution of Li⁺ and Ba⁺ around NBOs characterized by a prevalence of the dissimilar Li–Ba pair. Considering the previously reported experimental results on chemical ordering in other mixed‐cation silicate glasses, the current results reveal a hierarchy in the degree of chemical order that increases with an increase in difference in ionic radius of the cation in the glasses [e.g., K–Mg (~0.66 Å) ≈Ba–Mg (~0.63 Å) ≈Li–Ba (~0.59 Å) > Na–Ba (~0.33 Å) > Na–Ca (~0.02 Å)]. The ⁷Li MAS NMR spectra of the Li–Ba silicate glasses show that the peak maximum increases with increasing X_BaO, suggesting that the average Li coordination number and thus Li–O distance decrease slightly with increasing X_BaO, potentially leading to an increased activation energy barrier for Li diffusion. Current experimental results confirm that the degree of chemical ordering due to a large difference in ionic radii controls the transport properties of the mixed‐cation silicate glasses.