Direct Experimental Characterization of a Sialyl Cation.

Sialic acids are monosaccharide residues involved in several biological processes. Controlling the stereoselectivity of sialylation reactions is challenging and mechanistic studies on the structure of its intermediate, the sialyl cation, are scarce. Here it is shown that a sialyl cation can be generated and isolated from an ionized sialic acid precursor.

Location, Location, Location: Establishing Design Principles for New Antibacterials from Ferric Siderophore Transport Systems.

This review strives to assemble a set of molecular design principles that enables the delivery of antibiotic warheads to Gram-negative bacterial targets (ESKAPE pathogens) using iron-chelating siderophores, known as the Trojan Horse strategy for antibiotic development. Principles are derived along two main lines. First, archetypical siderophores and their conjugates are used as case studies for native iron transport.

Does size matter? - Comparing pyranoses with septanoses as ligands of the bacterial lectin FimH.

The pharmacological modulation of disease-relevant carbohydrate-protein interactions represents an underexplored area of medicinal chemistry. One particular challenge in the design of glycomimetic compounds is the inherent instability of the glycosidic bond toward enzymatic cleavage. This problem has traditionally been approached by employing S-, N-, or C-glycosides with reduced susceptibility toward glycosidases.

Characterization and Fate of a Septanosyl Ferrier Cation in the Gas and Solution Phases.

Ferrier reactions follow a mechanistic pathway whereby Lewis acid activation of a cyclic enol ether facilitates departure of an allylic leaving group to form a glycosyl Ferrier cation. Attack on the Ferrier cation provides a new acetal linkage concurrent with the transposition of the alkene moiety. The idiosyncratic outcomes of Ferrier reactions of seven-membered ring carbohydrate-based oxepines prompted an investigation of its corresponding septanosyl Ferrier cation.

Synthesis and Characterization of Preacinetobactin and 5-Phenyl Preacinetobactin.

We report the first total synthesis of 5-phenyl preacinetobactin and its characterization. The route was developed for the synthesis of preacinetobactin, the siderophore critical to the Gram-negative pathogen . It leverages a C5-substituted benzaldehyde as a key starting material and should enable the synthesis of similar analogs.

Synthesis of a Diacetonide-Protected, Mannose-Based Oxepine: Configurational Control of Anomeric Acetate Activation.

Carbohydrate-based oxepines are seven-membered-ring oxacycles containing an enol ether moiety. These compounds have been used as intermediates in the preparation of septanose carbohydrates by functionalization through their double bond. Reported here is a new synthesis of a carbohydrate based oxepine that uses 2,3;4,6-di--acetonide mannose as a key starting material.

Characterization of the low energy conformations and differential reactivities of D-glucose and D-mannose based oxepines.

Carbohydrate-based oxepines are valuable intermediates for the synthesis of septanose carbohydrates. Here we report the characterization of the preferred conformations of D-glucose and D-mannose based oxepines 1 and 2 using computational chemistry and NMR spectroscopy. Monte Carlo conformational searches on 1 and 2 were performed, followed by DFT optimization and single-point energy calculations on the low energy conformations of each oxepine.

Indolyl Septanoside Synthesis for In Vivo Screening of Bacterial Septanoside Hydrolases.

Building-up and breaking-down of carbohydrates are processes common to all forms of life. Glycoside hydrolases are a broad class of enzymes that play a central role in the cleavage of glycosidic bonds, which is fundamental to carbohydrate degradation. The large majority of substrates are five- and six-membered ring glycosides.

Structures of three disubstituted [13]-macro-di-lac-tones reveal effects of substitution on macrocycle conformation.

The synthesis and crystal structures of three new disubstituted [13]-macro-di-lactones, namely, -4,8-dimethyl-1,10-dioxa-cyclo-tridec-5-ene-2,9-dione, CHO, , -4-(4-bromo-phen-yl)-13-methyl-1,10-dioxa-cyclo-tridec-5-ene-2,9-dione CHBrO, , and -11-methyl-4-phenyl-1,10-dioxa-cyclo-tridec-5-ene-2,9-dione, CHO, , are reported and their conformations are put in the context of other [13]-macrodilactone structures reported previously. Together, they show that the number, location, and relative disposition of groups attached at the termini of planar units of the [13]-macrodilactones subtly influence their aspect ratios.

Exploring the physicochemical and antiproliferative properties of biaryl-linked [13]-macrodilactones.

A macrocyclic motif fosters productive protein-small molecule interactions. There are numerous examples of both natural product and designed, synthetic macrocycles that modulate the immune system, slow microbial infection, or kill eukaryotic cells. Reported here are the synthesis, physicochemical characterization, and antiproliferative activity of a group of [13]-macrodilactones decorated with a pendant biaryl moiety.

Post-Glycosylation Diversification (PGD): An Approach for Assembling Collections of Glycosylated Small Molecules.

Many small molecule natural products with antibiotic and antiproliferative activity are adorned with a carbohydrate residue as part of their molecular structure. The carbohydrate moiety can act to mediate key interactions with the target, attenuate physicochemical properties, or both. Facile incorporation of a carbohydrate group on de novo small molecules would enable these valuable properties to be leveraged in the evaluation of focused compound libraries.

The price of flexibility - a case study on septanoses as pyranose mimetics.

Seven-membered ring mimetics of mannose were studied as ligands for the mannose-specific bacterial lectin FimH, which plays an essential role in the first step of urinary tract infections (UTI). A competitive binding assay and isothermal titration calorimetry (ITC) experiments indicated an approximately ten-fold lower affinity for the seven-membered ring mannose mimetic 2--heptyl-1,6-anhydro-d--d-galactitol () compared to -heptyl α-d-mannopyranoside (), resulting exclusively from a loss of conformational entropy. Investigations by solution NMR, X-ray crystallography, and molecular modeling revealed that establishes a superimposable H-bond network compared to mannoside , but at the price of a high entropic penalty due to the loss of its pronounced conformational flexibility.

Epitope-Resolved Detection of Peanut-Specific IgE Antibodies by Surface Plasmon Resonance Imaging.

Peanut allergy can be life-threatening and is mediated by allergen-specific immunoglobulin E (IgE) antibodies. Investigation of IgE antibody binding to allergenic epitopes can identify specific interactions underlying the allergic response. Here, we report a surface plasmon resonance imaging (SPRi) immunoassay for differentiating IgE antibodies by epitope-resolved detection.

Macrocycles All Aflutter: Substitution at an Allylic Center Reveals the Conformational Dynamics of [13]-Macrodilactones.

The shapes adopted by large-ring macrocyclic compounds play a role in their reactivity and their ability to be bound by biomolecules. We investigated the synthesis, conformational analysis, and properties of a specific family of [13]-macrodilactones as models of natural-product macrocycles. The features of our macrodilactones enabled us to study the relationship between stereogenic centers and planar chirality through the modular synthesis of new members of this family of macrocycles.

Unequivocal determination of complex molecular structures using anisotropic NMR measurements.

Assignment of complex molecular structures from nuclear magnetic resonance (NMR) data can be prone to interpretational mistakes. Residual dipolar couplings and residual chemical shift anisotropy provide a spatial view of the relative orientations between bonds and chemical shielding tensors, respectively, regardless of separation. Consequently, these data constitute a reliable reporter of global structural validity.

Synthesis and structure of a carbohydrate-fused [15]-macrodilactone.

The design, synthesis and structural characterization of a new α-d-glucose fused [15]-macrodilactone is reported. The macrolide was synthesized by a route involving sequential acylations of glucose at the C4' and C6' hydroxyl groups followed by an intramolecular Stille reaction previously established for other [15]-macrodilactones. Analysis of the X-ray crystallographic structure of the macrolide revealed a unique conformation of this macrocycle that differs from earlier models for [13]- and [15]-macrodilactones.

A practical and scalable synthesis of carbohydrate based oxepines.

An efficient, seven-step synthesis of carbohydrate based oxepines is reported using per-O-acetyl septanoses as key intermediates. The scope of the synthesis was evaluated by varying both the pyranose starting materials and protecting groups incorporated into the oxepine products. The practicality of the method make it amenable to scale up as demonstrated by the gram-scale synthesis of the d-glucose derived oxepine.

Rules of Macrocycle Topology: A [13]-Macrodilactone Case Study.

Shape is an inherent trait of a molecule that dictates how it interacts with other molecules, either in binding events or intermolecular reactions. Large-ring macrocyclic compounds in particular leverage their shape when they are selectively bound by biomolecules and also when they exhibit macrocyclic diastereoselectivity. Nonetheless, rules that link structural parameters to the conformation of a macrocycle are still rudimentary.

Turning Spiroketals Inside Out: A Rearrangement Triggered by an Enol Ether Epoxidation.

Spiroketals organize small molecule structures into well-defined, three-dimensional configurations that make them good ligands of proteins. We recently discovered a tandem cycloisomerization-dimerization reaction of alkynyl hemiketals that delivered polycyclic, enol-ether-containing spiroketals. Here we describe rearrangements of those compounds, triggered by epoxidation of their enol ethers that completely remodel their structures, essentially turning them "inside out".

Turning Spiroketals Inside Out: A Rearrangement Triggered by an Enol Ether Epoxidation.

Invited for this month's cover picture is the group of Professor Mark Peczuh at the University of Connecticut. The cover picture compares the rearrangement of a small molecule to the process of turning a stuffed animal inside out. The recycled, inside-out stuffed animals are both artistic and philosophically provocative.

Synthesis, structure and reactivity of [15]-macrodilactones.

A strategy for utilizing parameters such as the ring size, planar units and the connections between them, and the location of asymmetric centers has been applied to the design and synthesis of a new class of 15-membered macrocycles. The interplay between three planar units in combination with a hinge atom and a stereogenic center, introduces a planar chirality that defines the molecular topology of these [15]-macrodilactones.

Stereogenic α-carbons determine the shape and topology of [13]-macrodilactones.

The synthesis and characterization of new [13]-macrodilactones substituted at stereogenic centers α- to the carbonyl are reported. When one center is substituted, it directs the topology of the macrocycle; when two centers are substituted, both the shape and the topology are influenced. The findings indicate that the number and configuration of α-centers fine-tune macrocyclic structure.

Cardiac glycoside activities link Na(+)/K(+) ATPase ion-transport to breast cancer cell migration via correlative SAR.

The cardiac glycosides ouabain and digitoxin, established Na(+)/K(+) ATPase inhibitors, were found to inhibit MDA-MB-231 breast cancer cell migration through an unbiased chemical genetics screen for cell motility. The Na(+)/K(+) ATPase acts both as an ion-transporter and as a receptor for cardiac glycosides. To delineate which function is related to breast cancer cell migration, structure-activity relationship (SAR) profiles of cardiac glycosides were established at the cellular (cell migration inhibition), molecular (Na(+)/K(+) ATPase inhibition), and atomic (computational docking) levels.

Ultrasensitive carbohydrate-peptide SPR imaging microarray for diagnosing IgE mediated peanut allergy.

Severity of peanut allergies is linked to allergen-specific immunoglobulin E (IgE) antibodies in blood, but diagnostics from assays using glycoprotein allergen mixtures may be inaccurate. Measuring IgEs specific to individual peptide and carbohydrate epitopes of allergenic proteins is promising. We report here the first immunoarray for IgEs utilizing both peptide and carbohydrate epitopes.

De novo macrolide-glycolipid macrolactone hybrids: Synthesis, structure and antibiotic activity of carbohydrate-fused macrocycles.

Natural product-like macrocycles were designed as potential antibacterial compounds. The macrocycles featured a D-glucose unit fused into a 12- or 13-member macrolactone. The rings are connected via the C6' and anomeric (C1') positions of the monosaccharide.