Stephan Levonis

Boronolectin with divergent fluorescent response specific for free sialic acid

A fluorescent boronate receptor with a unique response to free sialic acid has been developed; this divergent response system may find use in design of other fluorophores to discriminate between structurally similar analytes.

Tapping into Boron/α-Hydroxycarboxylic Acid Interactions in Sensing and Catalysis

Whereas interaction of boron acids (boric and boronic) with diols and neutral sugar ligands has received much global research attention in recent years, the binding of simple α-hydroxycarboxylic and sugar acids by boron has received less attention. Applications of boron-based fluorescent sensors and chemoselective catalysts targeting this functional motif have appeared only in the past 5 years. The present synopsis will focus on rapid developments that have occurred in both areas during this half decade.

Selective Monoesterification of Malonic Acid Catalyzed by Boric Acid

Boric acid catalyzes the monoesterification of malonic acid, likely through a chelation mechanism that is not available to the monoester product. Under more forcing conditions, diesters form to some extent, but conditions can be optimized to favour the monoester product (56-80%). With the easily handled solid acid catalyst, these reactions can be run with excess alcohol as solvent or with stoichiometric amounts of alcohol in acetonitrile with moderate heating.

Comparing Self-Assembling and Covalent Fluorescent Boronolectins for the Detection of Free Sialic Acid

A self-assembling fluorescence sensor with boronic acid functionalities was tested for binding selectivity to the monosaccharide, sialic acid. Working from a previously reported system, a self-assembling system could form an imine in situ that enables a conjugated fluorophore to display a measurable change in fluorescence in the presence of monosaccharide. However, further examination showed that free sugars give a similar fluorescence response to just the m-aminophenylboronic acid moiety on its own. Still, such a self-assembly method may be applicable to cell surface saccharide sensing as aldehydes and ketones are noticeably absent on most cells’ exteriors. The original covalent receptor appears best suited for the detection of free sialic acid.

A Practical Guide to Molecular Docking and Homology Modelling for Medicinal Chemists

Elucidating details of the relationship between molecular structure and a particular biological end point is essential for successful, rational drug discovery. Molecular docking is a widely accepted tool for lead identification however, navigating the intricacies of the software can be daunting. Our objective was therefore to provide a step-by-step guide for those interested in incorporating contemporary basic molecular docking and homology modelling into their design strategy. Three molecular docking programs, AutoDock4, SwissDock and Surflex-Dock, were compared in the context of a case study where a set of steroidal and non-steroidal ligands were docked into the human androgen receptor (hAR) using both rigid and flexible target atoms. Metrics for comparison included how well each program predicted the X-ray structure orientation via root mean square deviation (rmsd), predicting known actives via ligand ranking and comparison to biological data where available. Benchmarking metrics were discussed in terms of identifying accurate and reliable results. For cases where no three dimensional structure exists, we provided a practical example for creating a homology model using Swiss-Model. Results showed an rmsd between X-ray ligands from wild-type and mutant receptors and docked poses were 4.15Å and 0.83Å (SwissDock), 2.69Å and 8.80Å (AutoDock4) and 0.39Å and 0.71Å (Surflex-Dock) respectively. Surflex-Dock performed consistently well in pose prediction (less than 2Å) while Auto- Dock4 predicted known active non-steroidal antiandrogens most accurately. Introducing flexibility into target atoms produced the largest degree of change in ligand ranking in Surflex-Dock. We produced a viable homology model of the P2X1 purireceptor for subsequent docking analysis.

Boric Acid Catalyzed Methyl Esterification of Sugar Acids

Boric acid catalyzes methyl esterification of certain sugar acids (sialic acid, deaminated neuraminic acid) and related natural products (quinic acid) quite cleanly in some cases. However, closely related sugar acids (glucuronic acid, 3-deoxy-d-manno-oct-2-ulosonic acid) failed to esterify under the same conditions. Factors governing this dichotomy are discussed.

2-Propynyl 2-hydroxybenzoate

The title compound, C10H8O3, has been synthesized as part of our investigations into the generation of new antibacterial agents and serves as a building block for the synthesis of compound libraries. The compound crystallizes with two independent molecules in the asymmetric unit. The transoid propynyl ester groups are coplanar with the 2-hydroxybenzoate group with maximum deviations of −0.3507 (3) and 0.1591 (3) Å for the terminal carbons, with intramolecular O—H⋯O hydrogen bonding providing rigidity to the structure and ensuring that the reactivity of the alkyne is not compromised by steric factors. The propynyl group forms intermolecular C—H⋯O interactions with the phenolic O atom. Supramolecular chains along the b axis are found for both molecules with links by weak O—H⋯O intermolecular interactions in the first independent molecule and C—H⋯O interactions in the second.

Poly(ADP-ribose)polymerase, member 14 (PARP14) Inhibitors and Possible Strategies for Designing Selective PARP14 Inhibitors.

Poly(ADP-ribose)polymerase, member 14 (PARP14, alternatively named ARTD8, BAL2, and COAST6) is an intracellular mono(ADP-ribosyl) transferase. PARP14 transfers a negatively charged ADP-ribose unit from a donor NAD+ molecule onto a target protein, post-translationally. PARP14s domain architecture consists of three macrodomains (Macro1, Macro2 and Macro3), a WWE domain and an ARTD (or catalytic domain). The Macro2 and Macro3 domains bind ADPribose (ADPr) with high affinity, whereas the WWE domain stabilizes the protein structure by binding to ADPr derivatives. The catalytic domain is involved in binding the NAD+ and catalyzing the mono- ADP-ribosylation reaction. PARP14 has been identified as a possible anti-cancer and antiinflammatory target. Acting as a transcriptional co-activator for STAT6, PARP14 acts to promote the over activation of the Th2 immune response, thus promoting the metabolic change to an anaerobic state (Warburg effect) and activation of cell survival pathways through JNK2 and the PGI/AMF complex. These changes are consistent with the metabolic sophistication observed in cancer, and the immune imbalance in inflammatory diseases. Current literature on selective and unselective PARP14 inhibitors are reviewed and discussed. Although there is no evidence that selective PARP inhibitors would be advantageous we have proposed some strategies for future design of selective PARP14 inhibitors.

Crystallization-induced amide bond formation creates a boron-centered spirocyclic system

Abstract The 5-nitrosalicylate ester of 2-acetamidophenylboronic acid (C15H10BN2O6) is formed under crystallization conditions from the 5-nitrosalicylate ester of 2-aminophenylboronic acid. The boron at the center of this structure exists as a tetrahedral complex produced by a dative bond with the amide carbonyl. The perpendicular shape produces an unusual packing structure including a bifurcated hydrogen bond between the amide hydrogen and carbonyl groups on two neighboring molecules. We propose that this reaction occurs due to increased Lewis acidity of the nitrosalicylate ester of 2-aminophenylboronic acid.

Can we "starve cancer cells to death" with selective parp14 inhibitors?

COSAs 43 and ANZBCTGs 38 Annual Scientific Meetings. Partners for Progress in Breast Cancer Research and Care. 15–17 November